WO2010133748A1 - Protease inhibitors - Google Patents

Protease inhibitors Download PDF

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Publication number
WO2010133748A1
WO2010133748A1 PCT/FI2010/000031 FI2010000031W WO2010133748A1 WO 2010133748 A1 WO2010133748 A1 WO 2010133748A1 FI 2010000031 W FI2010000031 W FI 2010000031W WO 2010133748 A1 WO2010133748 A1 WO 2010133748A1
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WO
WIPO (PCT)
Prior art keywords
phenoxy
mmol
bis
cyano
required product
Prior art date
Application number
PCT/FI2010/000031
Other languages
French (fr)
Inventor
Rajeev Goswami
Anil Kumar Vuppala
Ramesh Veludandi
Ramesh Sistla
Chakshusmathi Ghadiyaram
Muralidhara Ramachandra
Original Assignee
Orion Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42357464&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010133748(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EP10724546A priority Critical patent/EP2432556A1/en
Priority to KR1020117030101A priority patent/KR20120058468A/en
Priority to US13/321,078 priority patent/US8722930B2/en
Priority to UAA201114969A priority patent/UA105527C2/en
Priority to MX2011011332A priority patent/MX2011011332A/en
Priority to BRPI1011267A priority patent/BRPI1011267A2/en
Priority to NZ595705A priority patent/NZ595705A/en
Application filed by Orion Corporation filed Critical Orion Corporation
Priority to EA201171427A priority patent/EA201171427A1/en
Priority to SG2011073897A priority patent/SG175711A1/en
Priority to JP2012511313A priority patent/JP2012527435A/en
Priority to CN201080021742.2A priority patent/CN102427853B/en
Priority to CA2758222A priority patent/CA2758222A1/en
Priority to AU2010251050A priority patent/AU2010251050A1/en
Publication of WO2010133748A1 publication Critical patent/WO2010133748A1/en
Priority to IL215506A priority patent/IL215506A0/en
Priority to ZA2011/07636A priority patent/ZA201107636B/en
Priority to US14/227,212 priority patent/US20140200225A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • C07C311/47—Y being a hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/62—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/51—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
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    • C07D213/02—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07D213/02—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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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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    • C07D213/04—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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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to therapeutically active compounds and pharmaceutically acceptable salts and esters thereof useful in the treatment of conditions involving matriptase activity, particularly cancer.
  • Cancer drug discovery has traditionally focused on targeting DNA synthesis and cell division, resulting in drugs such as antimetabolites and DNA alkylating agents. Although these drugs show efficacy, their lack of selectivity for tumor cells over normal cells can lead to severe side effects.
  • the recent recognition that certain genes are associated with cancer has resulted in several rational and targeted drugs for cancer therapy.
  • many of the available targeted cancer treatments inhibit only a specific aspect of cancer progression such as proliferation, angiogenesis or metastasis. This limits their utility and necessitates their use in combination with traditional chemotherapeutic agents.
  • targeted cancer drugs include erlotinib (Tarceva ® ) and bevacizumab (Avastin ® ).
  • Erlotinib inhibits cell proliferation, while bevacizumab is an anti-angiogenesis drug.
  • These drugs target kinases or proteins involved in kinase signaling pathways.
  • matriptase a transmembrane serine protease
  • the localization of matriptase on the cell surface makes it more accessible to a potential inhibitor.
  • Matriptase is over-expressed (up to several hundredfold) in all phases of cancer in multiple cancer types and has also been shown to play a role in invasion and metastasis. Therefore, a matriptase inhibitor could comprise a potential first-in-class drug with a broad spectrum of anti-tumor activity including anti- proliferative and anti-invasive activities.
  • Matriptase is a multi-domain 80-kDa type II transmembrane serine protease and belongs to the Sl trypsin-like family. Matriptase is involved in matrix remodeling/degradation, regulation of cell growth and survival, cell motility, cell morphogenesis, and activation of other membrane bound proteins. It is also called the membrane-type serine protease- 1 (MT-SPl), the tumor-associated differentially expressed gene- 15 (TAGD- 15), or epithin in mouse.
  • MT-SPl membrane-type serine protease- 1
  • TAGD- 15 tumor-associated differentially expressed gene- 15
  • Matriptase is overexpressed in a vast array of human tumors of epithelial origin including prostate, ovarian, uterine, colon, epithelial-type mesothelioma, cervical and head and neck squamous cell carcinoma. Epidemiological studies have revealed that increased expression of matriptase relative to HAI-I correlates with the grade of the tumor and results in poor prognosis in breast and ovarian cancer.
  • matriptase The role of matriptase has been well established in pathways involved in cancer even though the exact function of human matriptase has not been elucidated. Matriptase enhances tumor cell proliferation through phosphatidylinositol 3 -Kinase signaling and invasion through the HGF/cMet and uPAR activation. Glycosylation of matriptase by UDP-GIcNAc alpha-mannoside betal-6-N-acetylglucosaminyltransferase (GnT-V) plays a key role in metastasis by increasing the stability of degradation-resistant active form of the enzyme.
  • matriptase activates other proteases such as receptor- bound urokinase-type plasminogen activator (uPA).
  • uPA receptor- bound urokinase-type plasminogen activator
  • uPAR receptor- bound urokinase-type plasminogen activator
  • Overexpression of uPA or its receptor (uPAR) is a feature of malignancy and plays a critical role in angiogenesis, tumor invasion and metastasis. Down-regulation of matriptase inhibits tumor invasion through suppression of uPAR activation.
  • Urokinase-type plasminogen activator plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis.
  • Many cancer cells secrete pro-uPA and its receptor uPAR. Binding of pro-uPA to uPAR leads to its activation, with subsequent generation of plasmin by the uPA-catalyzed hydrolysis of extracellular plasminogen.
  • Hepsin is another type II transmembrane serine protease (TTSP) expressed on the surface of epithelial cells. It has been implicated in ovarian cancer and prostate cancer, where several gene expression studies have identified it as one of the most highly induced genes. Hepsin over-expression was associated with basement membrane disruption and was shown to be connected the HGF/c-Met pathway and uPA pathway connecting hepsin to the pathways leading to basement membrane disruption and tumor progression.
  • TTSP transmembrane serine protease
  • inhibitors of matriptase and other related serine proteases could be of significant therapeutic value because of the following reasons:
  • Matriptase inhibitors have been described earlier e.g. in Enyedy, I. et al., J. Med. Chem., 2001, 44, 1349-1355; and in international patent publications WO 01/97794, WO 2004/058688, WO 2004/101507, WO 2008/085608, WO 2008/107176, WO 2008/097673, WO 2008097676 and WO 2008/107176.
  • Other benzamidine compounds have been described earlier e.g. in Phillips, G. et al., J. Med. Chem., 1999, 42, 1749- 1756; Phillips, G. et al., J. Med. Chem., 1998, 41, 3557-3562; and EP 0 813 525.
  • compounds of formula (I) are serine protease inhibitors.
  • the compounds of formula (I) are potent and selective matriptase inhibitors.
  • the compounds of the invention are able to inhibit invasion and metastasis of various tumor cells and inhibit tumor growth. Compounds of the invention provide also good safety, and are therefore particularly useful in the treatment of cancer.
  • Pi and P 2 are, independently a bond or Ci -3 alkyl; A is CH or N; B is CH or N;
  • Ri is hydrogen, amino, -NH-SO 2 - ZR 9 R] 3 , -NR 4 -CO-ZR 9 Ri 3 , -CO-NR 7 R 8 , -CO-O-ZR 9 R] 3 , -CO-NR 4 -R ⁇ ZR 9 R] 3 or a group of formula
  • ring portion in formula (II) is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 further heteroatoms selected from N, O, S or combinations thereof;
  • R 3 is -C(NRi 7 )NH 2 , or in case A is CH, R 3 can also be amino Ci -7 alkyl;
  • Rio, Ri 4 and R) 5 are independently hydrogen, halogen, hydroxy, Ci -7 alkyl, halogen C -7 alkyl or -C(NR n )NH 2 ;
  • Q is hydrogen or halogen, with a proviso that Ri and Q are not simultaneously hydrogen;
  • R 4 is hydrogen or Ci -7 alkyl
  • Z is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof;
  • R. 9 and R 13 are, independently, hydrogen, halogen, hydroxy, carboxy, C 1-7 alkyl, carboxy Ci -7 alkyl, hydroxy Ci -7 alkyl, Ci -7 alkoxycarbonyl, R A NH 2 or -COR 8 NH 2 ;
  • R A , R B and R x are, independently, a bond or Ci -7 alkyl
  • R 7 and R 8 are, independently, hydrogen, amino Ci -7 alkyl, carboxy Ci -7 alkyl, or in case A is CH, R 7 and R 8 , independently, can also be Cj -7 alkyl, with a proviso that R 7 and Rg are not simultaneously hydrogen;
  • R 2 is Ci -7 alkyl, amino Ci -7 alkyl, carboxy Cj -7 alkyl, Ci -7 alkoxycarbonyl Ci -7 alkyl, Ci -7 alkylamino, carboxy Ci -7 alkylamino, R 0 C(NRi 7 )NH 2 , or a group of formula (III)
  • R D is a bond or C -7 alkyl
  • G is CH or N
  • Rn is hydrogen, halogen, amino, carboxy, amino Ci -7 alkyl, Ci -7 alkoxycarbonyl, halogen C -7 alkoxy, -C(NRi 7 )NH 2, -NHCOR 0 NH 2 , R J NHCOOR U or -CONRi 9 R 20 ;
  • R° is Ci -7 alkyl;
  • R J is a bond or C ]-7 alkyl;
  • R u is hydrogen or Ci -7 alkyl;
  • Ri 2 and R ]6 are, independently, hydrogen, halogen or Ci -7 alkyl; or Ri 2 and Ri 6 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated or aromatic ring which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof, which ring can be substituted;
  • R n is hydrogen, -OH, Ci -7 alkoxy, -0(CO)ORi 8 or -(CO)ORi 8 ;
  • Ri 8 is C -7 alkyl;
  • Ri 9 and R 20 are, independently, hydrogen, Ci -7 alkyl or Ci -7 alkoxy; or a pharmaceutically acceptable salt or ester thereof.
  • compounds of formula (I) wherein A is CH and B is CH.
  • R 3 is -C(NRi 7 )NH 2 and Ri 0 , Rj 4 and Ri 5 are hydrogen.
  • R 2 is a group of formula (III) wherein G is CH, y is 0-1, Rn is -C(NRi 7 )NH 2 or amino Ci -7 alkyl, Ri 2 and Ri 6 are hydrogen, hi still another class of preferred compounds are compounds of formula (I), wherein Pi and P 2 is a bond.
  • compounds of formula (I) wherein Pi is a bond and P 2 is -CH 2 -.
  • ring portion of formula (II) is a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain one further heteroatom N.
  • particularly preferred compounds are those, wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro- quinolinyl or 3,4-dihydro-lH-quinolinyl.
  • Ri is -NR 4 -CO-ZR 9 Ri 3 , -CO-O-ZR 9 Ri 3 , or -CO-NR 4 -R x -ZR 9 Ri 3 .
  • Z is suitably a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain 1 or 2 N atoms. Examples of particularly preferred compounds are those, wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl or quinolinyl.
  • R 4 is hydrogen
  • R x is a bond, R 9 is R A NH 2 and Ri 3 is hydrogen.
  • A is N and B is CH.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier.
  • the present invention provides further a method for the treatment of a matriptase dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • the present invention provides a compound of formula (I) for use in the treatment of a matriptase dependent condition.
  • the present invention provides further a method for the treatment of cancer!, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • the present invention provides a compound of formula (I) for use in the treatment of cancer.
  • the compounds of the invention can be prepared according to the following Schemes. It should be noted that any appropriate leaving groups, e.g. N-protecting groups, such as t-butoxycarbonyl (t-BOC) group, can be used in well known manner during the syntheses in order to improve the selectivity of the reaction steps.
  • N-protecting groups such as t-butoxycarbonyl (t-BOC) group
  • the nitrile group of the compound (V) is reacted with hydroxylamine hydrochloride with a suitable base such as TEA or DIPEA in solvent such as DMF, THF and the like at temperatures ranging from about 20 0 C to 100 0 C to afford the hydroxyamidine compound (VI).
  • a suitable base such as TEA or DIPEA in solvent such as DMF, THF and the like
  • This compound is either first acetylated using acetic anhydride in solvents such as acetic acid at RT and then reduced using a reducing agent such as Zn, Pd/C and the like in solvents such as methanol, ethanol or acetic acid at temperatures ranging from about 20 0 C to 50 0 C to afford the corresponding amidine compound (VIII).
  • hydroxyamidine (VI) is directly reduced with a reducing agent such as Pd/C in solvents such as methanol or acetic acid at a temperature ranging from about 40 0 C to 70 0 C to afford the corresponding amidine compound (VIII).
  • a reducing agent such as Pd/C in solvents such as methanol or acetic acid
  • the nitrile group of the compound of formula (V) is allowed to react with alcoholic HCl for approximately 15 to 48 h at a temperature ranging from about 0 0 C to about RT to afford the corresponding imidate ester (VF). This compound is then subjected to reaction with alcoholic ammonia to get the corresponding amidine compound (VIII).
  • compounds of formula (I), wherein Rj is -CO-NR 4 -R ⁇ ZR 9 R 13 , R 2 is a group of formula (III), and R 9 or R] 3 is -COR 8 NH 2 group linked to a nitrogen atom of the ring portion Z may also be prepared by reacting compound of formula (IX) with a compound of formula HNR 4 -R X -Z-L, wherein L is an acid labile protection group, such as a t-BOC group, attached to the nitrogen atom of the ring portion Z. After deprotection, the amino moiety of the Z ring is coupled with HOOCR 8 NH 2 by acid coupling reaction to obtain first a compound of formula (XVI)
  • compounds of formula (I), wherein R 1 is -CO-NR 4 -R 5 VZR 9 Ri 3 , R 2 is a group of formula (III), and R 9 or Ri 3 is carboxy Ci -7 alkyl or R A NH 2 group linked to a nitrogen atom of the ring portion Z, can be prepared by coupling the amino moiety of the Z ring with a suitable alkylhalide, e.g. XR A NH 2 , wherein X is halogen, to obtain a compound of formula (XVIII)
  • R 2 is C 1-7 alkyl, amino C 1-7 alkyl, carboxy C 1-7 alkyl, Ci -7 alkoxycarbonyl Ci -7 alkyl, Ci -7 alkylamino, carboxy Cj -7 alkylamino, or R 0 C(NRi 7 )NH 2
  • Y is -NH 2 , or -COOH, and following the general procedures of any of Schemes 1 to 9 to obtain the final product.
  • T is hydrogen, halogen, amino, carboxy, amino Ci -7 alkyl, Ci -7 alkoxycarbonyl, halogen Ci -7 alkoxy, -NHCOR 0 NH 2 , R J NHC00R u Or-CONRi 9 R 20 , and Y is - NH 2 , or -COOH, and following the general procedures of any of Schemes 1 to 9 to obtain the final product.
  • Compounds of formula (I), wherein R 3 is amino Ci -7 alkyl or both R 3 and Ri i are amino Ci -7 alkyl can be prepared by treating the nitrile compound of formula (V), (X), (XI), (XII), (XV), (XVI), (XVII), (XVIII) or (XX) with Raney nickel and NH 3 -methanol on hydrogen gas pressure.
  • Compounds of formula (IV) which may be used as intermediates can be prepared according to Scheme 10 in a reaction between halide and alcohol.
  • a base such as potassium carbonate, sodium hydride, cesium carbonate and the like
  • suitable solvent such as DMF, THF and the like
  • halide (or alcohol) compound of formula (XXIII) is reacted with an alcohol (or halide) compound of formula (XXIV), wherein Ti is halogen or a hydroxyl group, in the presence of a base and suitable solvent at temperatures ranging from about 40 0 C to 85 0 C to obtain the nitro compound of formula (XXV).
  • Reduction of the nitro group can be carried out using a reducing agent such as zinc or palladium/carbon under hydrogen pressure along with solvents such as acetic acid/ methanol/ ethanol at temperatures ranging from about 0 0 C to 80 0 C.
  • Pharmaceutically acceptable salts e.g. acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals.
  • Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
  • Pharmaceutically acceptable esters when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form.
  • Non- limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g.
  • halo or halogen, as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.
  • C 1 - 7 alkyl refers to a straight, branched or cyclized, saturated or unsaturated, chain radical having 1 to 7 carbon atoms.
  • Representative examples of Cr 7 alkyl include, but are not limited to, methyl, ethyl, ethenyl, n-propyl, isopropyl, propenyl, n-butyl, isobutyl, sec-butyl, tert- butyl, H-pentyl, isopentyl, neopentyl, «-hexyl, cyclopentyl, cyclohexyl and the like.
  • C 1 - 3 alkyl is an embodiment of "C 1 - 7 alkyl” having 1 to 3 carbon atoms.
  • C 2 - 7 alkenyl refers to a straight, branched or cyclized chain radical having 2 to 7 carbon atoms, and containing one or several double bonds.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH 2 group.
  • carboxy refers to -COOH group.
  • C 1 - 7 alkoxy refers to C 1 - 7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of C 1 - 7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-buioxy, tert-butoxy, and the like.
  • hydroxyl Ci - 7 alkyl refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C 1 - 7 alkyl group, as defined herein.
  • Representative examples of hydroxyl C 1 - 7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 1-hydroxypropyl, 1 -methyl- 1-hydroxyethyl, 1 -methyl- 1 -hydroxypropyl, and the like.
  • halo Ci- 7 alkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a Ci- 7 alkyl group, as defined herein.
  • Representative examples of halo Cp 7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the like.
  • cyano Cr 7 alkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through a Ci- 7 alkyl group, as defined herein.
  • Representative examples of cyano C 1 - 7 alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, and the like.
  • carboxy C 1 - 7 alkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through a C 1 - 7 alkyl group, as defined herein.
  • halogen C 1 - 7 alkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C 1 - 7 alkoxy group, as defined herein.
  • C 1 - 7 alkoxycarbonyl refers to a C 1 - 7 alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • aminocarbonyl refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • amino C 1 - 7 alkyl refers to at least one amino group, as defined herein, appended to the parent molecular moiety through a C] - 7 alkyl group, as defined herein.
  • amino C 1 - 7 alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3- aminopropyl, 2-aminopropyl, 4-aminobutyl, 1 -methyl- 1-aminoethyl, and the like.
  • C 1- 7 alkylamino refers to at least one C 1 - 7 alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.
  • Representative examples of C 1 - 7 alkylamino include, but are not limited to methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, iV-ethyl-N-methylamino, and the like.
  • carboxy C 1 - 7 alkylamino refers to at least one carboxy group, as defined herein, appended to the parent molecular moiety through an C 1 - 7 alkylamino group, as defined herein
  • C 1 - 7 alkoxy C 1 - 7 alkyl refers to at least one C 1 - 7 alkoxy group, as defined herein, appended to the parent molecular moiety through an C 1 - 7 alkyl group, as defined herein.
  • C 1 - 7 alkoxycarbonyl C 1 - 7 alkyl refers to at least one C 1 - 7 alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an Ci- 7 alkyl group, as defined herein.
  • substituted refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C 1 - 7 alkyl, halo C 1 - 7 alkyl, hydroxy, amino, C 1- 7 alkoxy, C 2 - 7 acyl C 1 - 7 alkylamino, amino C 1 - 7 alkyl, nitro, cyano, or thiol substituents.
  • halogen substituents such as fluorine, chlorine, bromine, iodine, or C 1 - 7 alkyl, halo C 1 - 7 alkyl, hydroxy, amino, C 1- 7 alkoxy, C 2 - 7 acyl C 1 - 7 alkylamino, amino C 1 - 7 alkyl, nitro, cyano, or thiol substituents.
  • the "substituted” groups may contain 1 to 3, preferably 1 or 2, most preferably 1 of the above mentioned substituents.
  • the definition of formula (I) above is inclusive of all the possible stereoisomers of the compounds, including geometric isomers, e.g. Zand E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers, and all prodrug esters, e.g. phosphate esters and carbonate esters, and isotopes.
  • the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures.
  • the individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods.
  • optical isomers e.g. enantiomers
  • the conventional resolution methods e.g. fractional crystallisation
  • Compounds of the invention may be administered to a patient in therapeutically effective amounts which range usually from about 0.1 to about 1000 mg per day depending on the age, weight, ethnic group, condition of the patient, condition to be treated, administration route and the protease inhibitor used.
  • the compounds of the invention can be formulated into dosage forms using the principles known in the art.
  • the compound can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art.
  • compositions containing the active compound can be given enterally or parenterally, the oral route being the preferred way.
  • the contents of the active compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to about 20 %, per weight of the total composition.
  • Purified recombinant matriptase was used in a fluorescence-based screening assay using GIn- Ala- Arg peptide as a substrate.
  • enzymatic assays in fluorimetric or colorimetric format for uPA, Factor Xa, thrombin, plasmin and trypsin were established using substrates pyroGlu-Gly-Arg- pNA.HCl, Boc-Gln-Ala-Arg-AMC, CH 3 OCO-D-CHA-Gly-Arg-PNA.AcoH, Pyro GIu- Phe-Lys— pNA.HCl and Boc-Gln-Ala-Arg-AMC, respectively.
  • Enzymatic activity and selectivity of selected compounds of the invention on different proteases is presented in Table 1.
  • the compounds of the invention were found to be potent and selective matriptase inhibitors.
  • Cytotoxicity of the compounds was tested in cell lines or primary cells using Calcein AM assay.
  • This assay measures cell viability by quantitation of cleaved fluorescent product of a cell permeable substrate that is retained in the cytoplasm of cells with uncompromised cytoplasmic membrane integrity.
  • the cells were seeded into 96-well plate and allowed to adhere for a day followed by addition of compound at several different concentrations. After four days of incubation with the compound, media was removed from the cells followed by addition of PBS and addition of Calcein AM reagent at 1 ⁇ M final concentration. The cells were then allowed to incubate at 37 0 C for half an hour followed by reading on the fluorimeter.
  • Percent viability was calculated based on fluorescence value obtained at 485/520 nm with cut off at 495 nm. In the cytotoxicty assays, none of the compounds tested showed any effect up to 10 ⁇ M when tested on the prostate cancer cell lines DU 145 and LnCap.
  • Migration assays were performed to determine the effect of matriptase inhibitors on cell motility.
  • Cells were seeded with 10 ⁇ M test compound into transwell chambers and allowed to migrate for 24 hours using a combination of 10 % FBS and 5 ⁇ g/ml fibronectin as chemoattractant.
  • Cell invasion assays were done for quantitating the degree to which invasive cells penetrate a barrier essentially as in migration assay but with the use of matrigel consisting of basement membrane components in the transwell inserts and incubating for 48 hours.
  • the barrier used was matrigel. This was followed by fixing and staining of the transwell insert with 0.5 % crystal violet in 25 % methanol in order to visualize cells migrated.
  • Soft agar colony formation assays were performed to measure the long-term survival and anchorage-independent growth capacity of tumor cells.
  • DU 145 cells were seeded in 0.7 % nutrient agar with the test compound on an underlay of 1.4 % nutrient agar in a six well plate.
  • liquid cell culture medium containing the compound was added to the well to prevent the agar from drying out and was changed regularly till the completion of the experiment.
  • the cells were allowed to form colonies for a period of about three weeks following which the colonies were stained with 0.005 % solution of crystal violet in 25 % methanol. The colonies were counted under a dissecting microscope.
  • xenograft models were established by injecting 5 x 10 6 DU145 cells with matrigel or 5 x 10 6 PC3 cells without matrigel subcutaneously. Once the tumors reached palpable size ( ⁇ 80 mm3), compound of Example 27 was administered in a vehicle comprising of 2 % ethanol, 10 % hydroxyl cyclodextrin in 0.9 % saline. The compound of Example 27 was dosed subcutaneously to animals with DU145 tumors at 1.5, 5 and 15mg/kg for 15 days. In the PC3 xenograft study, compound of Example 27 was administered at 0.5, 1.5, 5.0 and 15.0 mg/kg daily.
  • Example 27 In the PC3 xenograft study, the compound of Example 27 caused significant and dose-dependent inhibition of tumor growth as shown in Table 5.
  • An MTD study was performed for the compound of Example 27.
  • the objective of the study was to establish the maximum dose that does not induce drug related lethality and/or body weight loss of more than 20 % of baseline weight during the study period of 14 days.
  • the compound was administered at 1, 3, 10 and 30 mg/kg once daily in male athymic mice via subcutaneous route in 5 mice each. Dosing at the tested doses did not show any mortality. Body weight reduction was less than 2 % and no gross changes in clinical signs were seen indicating doses up to 30 mg/kg are well tolerated.
  • the preparation of the compounds of the invention is illustrated by the following Examples.
  • N,7V-Diisopropylethylamine (DIPEA) 0.36 ml (2.08 mmol) followed by 144 mg (2.08 mmol) of hydroxylamine hydrochloride was added to a stirred solution of 2,6-bis- (4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine 0.27 g (0.52 mmol) in 10 ml of ethanol and the flask was heated at 100 0 C for 8 h. The reaction mixture was concentrated under reduced pressure to afford 0.35 g (57.5 %) of the product which was used for the next step without further purification.
  • M + 584.1+1 (actual mass: 584.1).
  • the -Boc group was removed from (4- ⁇ [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)- phenoxy)-pyridine-4-carbonyl]-amino ⁇ cyclohexyl)carbamic acid tert-butyl esters 0.25 g (0.41 mmol) using the procedure of Example 9(d) to afford 0.115 g of the required product.
  • the crude product was purified by reverse-phase preparative HPLC to afford 0.115 g of the required product. Percentage purity (HPLC): 97.73 %, (LCMS): 94.78 %.
  • 2,6-Dihydroxyisonicatonic acid (2.0 g, 12.9 mmol) was dissolved in 20 ml of propane-2-ol at 0 °C. 2 ml of concentrated sulfuric acid was added to the stirred solution of dihydroxy acid at 0 0 C over a period of 10 min and then the contents of the flask were refluxed overnight at 100 °C. The solvent was removed under reduced pressure and the crude residual mixture was dissolved in 250 ml of ethylacetate and washed with water. The organic phase was dried over anhydrous sodium sulphate, concentrated under reduced pressure and subjected to column chromatography, using chloroform : ethylacetate (8 : 2) as eluant to afford 0.5 g of required product.
  • Potassium carbonate 60 mg, 0.43 mmol was added to a stirred and cooled (0 °C) solution of 2-chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester 0.13 g (0.43 mmol) in 10 ml DMF and stirred for 10 min at the same temperature. This was followed by the addition of 76.5 mg (0.43 mmol) of 4-trifluoromethoxy phenol, dissolved in 2 ml of DMF, over a period of 10 min. After the addition was completed, the contents were allowed to stir at RT. This was followed by heating for 3 h at 80 °C.
  • Example 20 4-[5-[4-(2-amino-ethyl)piperidine-l -carbonyl]-3-fluoro-6-(3-trifluoromethoxy phenoxy)-pyridine-2-yloxy]benzamidine
  • 6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy) nicotinic acid (1.3 g, 2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.684 g, 3.0 mmol) were coupled using the procedure of Example 5(c) to afford 1.1 g of the required product.
  • Zinc dust 0.4 g (5.3 mmol) was added portionwise to a reaction flask containing a stirred mixture (10 min) of l,5-bis-(4-cyano-phenoxy)-2-nitrobenzene 1.5 g (4.2 mmol) and 0.085 g (0.08 mmol) of ammonium chloride dissolved in 25 ml of methanol.
  • the reaction mixture was allowed to stir for 1 h at RT.
  • Reaction mixture was filtered through celite and the filtrate was concentrated to afford a brown viscous residue which was partitioned between ethyl acetate and water.
  • Potassium carbonate 0.61 Ig (4.4 mmol) was added to a stirred solution of 3,5- dihydroxy-benzoic acid ethyl ester 0.5 g (1.7 mmol) dissolved in 15 ml of DMF and stirred for 10 min. This was followed by dropwise addition of 4-fluorobenzonitrile 0.82 g (6.8 mmol), dissolved in 5 ml of DMF, and the contents of the flask were stirred at 80 °C for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate.
  • Example 39 N-(3 - Amino-propyl)-3 ,5 -bis-(4-carbamimidoyl-phenoxy)-N-cyclopropyl- benzamide Intermediates (a) and (b) are the same as in Example 26.
  • Example 59 4-[3-(4-aminomethyl benzyloxy)-5-(4-carbamimidoyl phenoxy)benzoyl]- piperazine-1-carboxylic acid ethyl ester
  • Intermediate (a) is the same as in Example 42.
  • Intermediates (b) and (c) are the same as in Example 45.

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Abstract

A compound of formula (I) wherein R1 to R15, P1, P2, A, B and Q are as defined in the claims and pharmaceutically acceptable salts and esters thereof, are disclosed. The compounds of formula (I) possess utility as matriptase inhibitors and are useful in the treatment of matriptase dependent conditions, particularly cancer.

Description

PROTEASE INHIBITORS
Technical field
The present invention relates to therapeutically active compounds and pharmaceutically acceptable salts and esters thereof useful in the treatment of conditions involving matriptase activity, particularly cancer.
Background of the invention
Cancer drug discovery has traditionally focused on targeting DNA synthesis and cell division, resulting in drugs such as antimetabolites and DNA alkylating agents. Although these drugs show efficacy, their lack of selectivity for tumor cells over normal cells can lead to severe side effects. The recent recognition that certain genes are associated with cancer has resulted in several rational and targeted drugs for cancer therapy. However, many of the available targeted cancer treatments inhibit only a specific aspect of cancer progression such as proliferation, angiogenesis or metastasis. This limits their utility and necessitates their use in combination with traditional chemotherapeutic agents. Examples of such targeted cancer drugs include erlotinib (Tarceva®) and bevacizumab (Avastin®). Erlotinib inhibits cell proliferation, while bevacizumab is an anti-angiogenesis drug. These drugs target kinases or proteins involved in kinase signaling pathways. Recent findings indicate that matriptase, a transmembrane serine protease, plays a role in triggering the formation of tumor cells. Unlike kinases, the localization of matriptase on the cell surface makes it more accessible to a potential inhibitor. Matriptase is over-expressed (up to several hundredfold) in all phases of cancer in multiple cancer types and has also been shown to play a role in invasion and metastasis. Therefore, a matriptase inhibitor could comprise a potential first-in-class drug with a broad spectrum of anti-tumor activity including anti- proliferative and anti-invasive activities.
Matriptase is a multi-domain 80-kDa type II transmembrane serine protease and belongs to the Sl trypsin-like family. Matriptase is involved in matrix remodeling/degradation, regulation of cell growth and survival, cell motility, cell morphogenesis, and activation of other membrane bound proteins. It is also called the membrane-type serine protease- 1 (MT-SPl), the tumor-associated differentially expressed gene- 15 (TAGD- 15), or epithin in mouse. Matriptase is overexpressed in a vast array of human tumors of epithelial origin including prostate, ovarian, uterine, colon, epithelial-type mesothelioma, cervical and head and neck squamous cell carcinoma. Epidemiological studies have revealed that increased expression of matriptase relative to HAI-I correlates with the grade of the tumor and results in poor prognosis in breast and ovarian cancer.
The role of matriptase has been well established in pathways involved in cancer even though the exact function of human matriptase has not been elucidated. Matriptase enhances tumor cell proliferation through phosphatidylinositol 3 -Kinase signaling and invasion through the HGF/cMet and uPAR activation. Glycosylation of matriptase by UDP-GIcNAc alpha-mannoside betal-6-N-acetylglucosaminyltransferase (GnT-V) plays a key role in metastasis by increasing the stability of degradation-resistant active form of the enzyme. Furthermore, matriptase activates other proteases such as receptor- bound urokinase-type plasminogen activator (uPA). Overexpression of uPA or its receptor (uPAR) is a feature of malignancy and plays a critical role in angiogenesis, tumor invasion and metastasis. Down-regulation of matriptase inhibits tumor invasion through suppression of uPAR activation.
Several other "trypsin like serine proteases" such as uPA, trypsin, plasmin, hepsin and kallikrein play a critical role in cancer affecting various pathways leading to angiogenesis, invasion and metastasis. Urokinase-type plasminogen activator (uPA) plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis. Many cancer cells secrete pro-uPA and its receptor uPAR. Binding of pro-uPA to uPAR leads to its activation, with subsequent generation of plasmin by the uPA-catalyzed hydrolysis of extracellular plasminogen. The increased production of plasmin leads to degradation of extracellular matrix both by plasmin itself and by other proteases that are activated by plasmin. The surface location of bound uPA provides directionality to the degradation of matrix, thereby assisting the directional migration of cancer cells. uPA in complex with uPAR also affects other biological processes including signaling pathways that influence cell proliferation. Hepsin is another type II transmembrane serine protease (TTSP) expressed on the surface of epithelial cells. It has been implicated in ovarian cancer and prostate cancer, where several gene expression studies have identified it as one of the most highly induced genes. Hepsin over-expression was associated with basement membrane disruption and was shown to be connected the HGF/c-Met pathway and uPA pathway connecting hepsin to the pathways leading to basement membrane disruption and tumor progression.
Therefore, inhibitors of matriptase and other related serine proteases could be of significant therapeutic value because of the following reasons:
- potential to be used as a 'mono-therapy' due to wide expression and activity of matriptase and other proteases in both early and late stages of cancer - superior safety profile due to localization of matriptase, uPA and hepsin at the cell membrane which avoids the need of cellular entry of the drug
- superior efficacy profile due to tumor-specific expression
- potential for reducing morbidity due to a larger therapeutic window that results from fewer therapy-related side effects typically associated with cytotoxic agents
Matriptase inhibitors have been described earlier e.g. in Enyedy, I. et al., J. Med. Chem., 2001, 44, 1349-1355; and in international patent publications WO 01/97794, WO 2004/058688, WO 2004/101507, WO 2008/085608, WO 2008/107176, WO 2008/097673, WO 2008097676 and WO 2008/107176. Other benzamidine compounds have been described earlier e.g. in Phillips, G. et al., J. Med. Chem., 1999, 42, 1749- 1756; Phillips, G. et al., J. Med. Chem., 1998, 41, 3557-3562; and EP 0 813 525.
Summary of the invention
It has been found that compounds of formula (I) are serine protease inhibitors. In particular, it has been found that the compounds of formula (I) are potent and selective matriptase inhibitors. The compounds of the invention are able to inhibit invasion and metastasis of various tumor cells and inhibit tumor growth. Compounds of the invention provide also good safety, and are therefore particularly useful in the treatment of cancer.
The compounds of the present invention have a structure represented by formula (I)
Figure imgf000005_0001
wherein
Pi and P2 are, independently a bond or Ci-3 alkyl; A is CH or N; B is CH or N;
Ri is hydrogen, amino, -NH-SO2- ZR9R]3, -NR4-CO-ZR9Ri3, -CO-NR7R8, -CO-O-ZR9R]3, -CO-NR4-R^ZR9R]3 or a group of formula
Figure imgf000005_0002
wherein the ring portion in formula (II) is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 further heteroatoms selected from N, O, S or combinations thereof;
R3 is -C(NRi7)NH2, or in case A is CH, R3 can also be amino Ci-7 alkyl;
Rio, Ri4 and R)5 are independently hydrogen, halogen, hydroxy, Ci-7 alkyl, halogen C-7 alkyl or -C(NRn)NH2;
Q is hydrogen or halogen, with a proviso that Ri and Q are not simultaneously hydrogen;
R4 is hydrogen or Ci-7 alkyl; Z is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof;
R.9 and R13 are, independently, hydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy Ci-7 alkyl, hydroxy Ci-7 alkyl, Ci-7 alkoxycarbonyl, RANH2 or -COR8NH2;
RA, RB and Rx are, independently, a bond or Ci-7 alkyl;
R7 and R8 are, independently, hydrogen, amino Ci-7 alkyl, carboxy Ci-7 alkyl, or in case A is CH, R7 and R8, independently, can also be Cj-7 alkyl, with a proviso that R7 and Rg are not simultaneously hydrogen; R2 is Ci-7 alkyl, amino Ci-7 alkyl, carboxy Cj-7 alkyl, Ci-7 alkoxycarbonyl Ci-7 alkyl, Ci-7 alkylamino, carboxy Ci-7 alkylamino, R0C(NRi7)NH2, or a group of formula (III)
Figure imgf000006_0001
(III)
y = 0-2; RD is a bond or C-7 alkyl; G is CH or N;
Rn is hydrogen, halogen, amino, carboxy, amino Ci-7 alkyl, Ci-7 alkoxycarbonyl, halogen C-7 alkoxy, -C(NRi7)NH2, -NHCOR0NH2, RJNHCOORU or -CONRi9R20; R° is Ci-7 alkyl; RJ is a bond or C]-7 alkyl; Ru is hydrogen or Ci-7 alkyl;
Ri2 and R]6 are, independently, hydrogen, halogen or Ci-7 alkyl; or Ri2 and Ri6 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated or aromatic ring which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof, which ring can be substituted;
Rn is hydrogen, -OH, Ci-7 alkoxy, -0(CO)ORi8 or -(CO)ORi8; Ri8 is C-7 alkyl;
Ri9 and R20 are, independently, hydrogen, Ci-7 alkyl or Ci-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof. In one class of preferred compounds are compounds of formula (I), wherein A is CH and B is CH. A subclass of these preferred compounds are compounds wherein R3 is -C(NRi7)NH2 and Ri0, Rj4 and Ri5 are hydrogen. In one class of preferred compounds are compounds wherein R2 is a group of formula (III) wherein G is CH, y is 0-1, Rn is -C(NRi7)NH2 or amino Ci-7 alkyl, Ri2 and Ri6 are hydrogen, hi still another class of preferred compounds are compounds of formula (I), wherein Pi and P2 is a bond. In still another class of preferred compounds are compounds of formula (I), wherein Pi is a bond and P2 is -CH2-.
In one class of preferred compounds are compounds of formula (I), wherein Ri is a group of formula (II). In another class of preferred compounds are compounds of formula (I), wherein the ring portion of formula (II) is a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain one further heteroatom N. Examples of particularly preferred compounds are those, wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro- quinolinyl or 3,4-dihydro-lH-quinolinyl. In another class of preferred compounds are compounds of formula (I), wherein Ri is -NR4-CO-ZR9Ri3, -CO-O-ZR9Ri3, or -CO-NR4-Rx-ZR9Ri3. Z is suitably a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain 1 or 2 N atoms. Examples of particularly preferred compounds are those, wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl or quinolinyl. hi a subclass of preferred compounds are compounds, wherein Z is cyclohexyl or piperidinyl, R4 is hydrogen, Rx is a bond, R9 is RANH2 and Ri3 is hydrogen.
In another class of preferred compounds are compounds of formula (I), wherein
A is N and B is CH.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier.
The present invention provides further a method for the treatment of a matriptase dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
The present invention provides a compound of formula (I) for use in the treatment of a matriptase dependent condition. The present invention provides further a method for the treatment of cancer!, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
The present invention provides a compound of formula (I) for use in the treatment of cancer.
Detailed description of the invention
The compounds of the invention can be prepared according to the following Schemes. It should be noted that any appropriate leaving groups, e.g. N-protecting groups, such as t-butoxycarbonyl (t-BOC) group, can be used in well known manner during the syntheses in order to improve the selectivity of the reaction steps.
Compounds of formula (I), wherein R1 is -NH-SO2- ZR9R13, R3 is -C(NR17)NH2, R2 is a group of formula (III) and Rn is -C(NRj7)NH2 can be prepared according to the Scheme 1 or Scheme 2 by sulfonylating the amino group of the compound of formula (FV) with suitable sulfonylchloride Cl-SO2-ZR9R13 using a base such as sodium hydride, TEA, DIPEA or combinations thereof along with solvents such DMF, THF and the like at temperatures ranging from about 0 0C to 80 0C. The reaction affords the sulfonamide of formula (V).
SCHEME 1.
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
Figure imgf000009_0004
SCHEME 2.
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
Compound of formula (V) is converted to the corresponding imidate (VF) or hydroxyamidine (VI) derivative as explained below.
Using the method of Scheme 1, the nitrile group of the compound (V) is reacted with hydroxylamine hydrochloride with a suitable base such as TEA or DIPEA in solvent such as DMF, THF and the like at temperatures ranging from about 20 0C to 100 0C to afford the hydroxyamidine compound (VI). This compound is either first acetylated using acetic anhydride in solvents such as acetic acid at RT and then reduced using a reducing agent such as Zn, Pd/C and the like in solvents such as methanol, ethanol or acetic acid at temperatures ranging from about 20 0C to 50 0C to afford the corresponding amidine compound (VIII). Alternatively the hydroxyamidine (VI) is directly reduced with a reducing agent such as Pd/C in solvents such as methanol or acetic acid at a temperature ranging from about 40 0C to 70 0C to afford the corresponding amidine compound (VIII).
Subsequent to the above step, deprotection of the product from any protecting groups such as t-BOC, where applicable, is carried out with appropriate reagents such as HCl - TFA or the like to afford the required final compounds.
Using the method of Scheme 2, the nitrile group of the compound of formula (V) is allowed to react with alcoholic HCl for approximately 15 to 48 h at a temperature ranging from about 0 0C to about RT to afford the corresponding imidate ester (VF). This compound is then subjected to reaction with alcoholic ammonia to get the corresponding amidine compound (VIII).
Compounds of formula (I), wherein R1 is -CO-NR7R8, and R2 is a group of formula (III) and Rn is -C(NRi7)NH2, can be prepared according to the Scheme 3 by coupling the carboxylic group of compound (IX) with amine HNR7R8. The reaction is carried out in the presence of suitable coupling reagents, such as PyBOP, EDCHCl or HOBt and the like, and a base such as DIPEA, TEA and the like in a solvent of such as THF, DMF and the like under inert atmosphere at a temperature ranging from about 0 0C to 40 0C. The reaction affords the desired amide compound of formula (X). Starting from compound (X) and following the last steps of Scheme 1 or 2 affords the final product. SCHEME 3.
Figure imgf000012_0001
Compounds of formula (I), wherein R] is -CO-NR4-R^ZR9Ri3, R2 is a group of formula (III) and Rn is -C(NR]7)NH2, can be prepared according to the Scheme 4 such as to obtain first a compound of formula (XI) and following then the last steps of Scheme 1 or 2 to obtain the final product.
SCHEME 4.
Figure imgf000012_0002
Compounds of formula (I), wherein R1 is -CO-O-ZR9R13, and R2 is a group of formula (III) and Rn is -C(NRi7)NH2, can be prepared according to the Scheme 5 such as to obtain first a compound of formula (XXXII) and following then the last steps of Scheme 1 or 2 to obtain the final product.
SCHEME 5.
Figure imgf000013_0001
Figure imgf000013_0002
Compounds of formula (I), wherein R1 is -NH-CO-ZR9Ri3, and R2 is a group of formula (III) and Rn is -C(NRj7)NH2, can be prepared according to the Scheme 6 such as to obtain first a compound of formula (XXXI) and following then the last steps of Scheme 1 or 2 to obtain the final product.
SCHEME 6.
Figure imgf000014_0001
Compounds of formula (I), wherein Ri is a group of formula (II), and R2 is a group of formula (III) and Rn is -C(NRi7)NH2, can be prepared according to the Scheme 7 such as to obtain first a compound of formula (XII) and following then the last steps of Scheme 1 or 2 to obtain the final product.
SCHEME 7.
Figure imgf000015_0001
Compounds of formula (I), wherein Ri is a group of formula (II), R2 is a group of formula (III), and R9 or Ri3 is -COR3NH2 group linked to a nitrogen atom of the ring portion of formula (II), can be prepared according to the Scheme 8 such as to obtain first a compound of formula (XV) by a acid coupling reaction and following then the last steps of Scheme 1 or 2 to obtain the final product. L is an acid labile protection group such as a t-BOC group. SCHEME 8.
Figure imgf000016_0001
HOOCR6NH,
Figure imgf000016_0002
Similarly, compounds of formula (I), wherein Rj is -CO-NR4-R^ZR9R13, R2 is a group of formula (III), and R9 or R] 3 is -COR8NH2 group linked to a nitrogen atom of the ring portion Z, may also be prepared by reacting compound of formula (IX) with a compound of formula HNR4-RX-Z-L, wherein L is an acid labile protection group, such as a t-BOC group, attached to the nitrogen atom of the ring portion Z. After deprotection, the amino moiety of the Z ring is coupled with HOOCR8NH2 by acid coupling reaction to obtain first a compound of formula (XVI)
Figure imgf000017_0001
and following then the last steps of Scheme 1 or 2 to obtain the final product.
Compounds of formula (I), wherein Rj is a group of formula (II), R2 is a group of formula (III), and R9 or Ri3 is carboxy Ci-7 alkyl or RANH2 group linked to a nitrogen atom of the ring portion of formula (II), may be prepared according to the Scheme 9 such as to obtain first a compound of formula (XVII) by an alkylhalide reaction and following then the last steps of Scheme 1 or 2 to obtain the final product.
SCHEME 9.
XRANH,
Figure imgf000018_0001
Similarly, compounds of formula (I), wherein R1 is -CO-NR4-R5VZR9Ri3, R2 is a group of formula (III), and R9 or Ri3 is carboxy Ci-7 alkyl or RANH2 group linked to a nitrogen atom of the ring portion Z, can be prepared by coupling the amino moiety of the Z ring with a suitable alkylhalide, e.g. XRANH2, wherein X is halogen, to obtain a compound of formula (XVIII)
Figure imgf000018_0002
and following then the last steps of Scheme 1 or 2 to obtain the final product.
Compounds of formula (I), wherein R2 is Ci-7 alkyl, amino Ci-7 alkyl, carboxy Ci-7 alkyl, Ci-7 alkoxycarbonyl Ci-7 alkyl, Ci-7 alkylamino, carboxy Ci-7 alkylamino, or R0C(NRi7)NH2, may be prepared starting from a compound of formula (XIX),
Figure imgf000019_0001
pax)
wherein R2 is C1-7 alkyl, amino C1-7 alkyl, carboxy C1-7 alkyl, Ci-7 alkoxycarbonyl Ci-7 alkyl, Ci-7 alkylamino, carboxy Cj-7 alkylamino, or R0C(NRi7)NH2, and Y is -NH2, or -COOH, and following the general procedures of any of Schemes 1 to 9 to obtain the final product.
Compounds of formula (I), wherein R2 is a group of formula (III) and Rn is hydrogen, halogen, amino, carboxy, amino Ci-7 alkyl, Ci-7 alkoxycarbonyl, halogen Ci-7 alkoxy, -NHCOR0NH2, RJNHC00Ru or -CONRi9R20 may be prepared starting from a compound of formula (XX),
Figure imgf000019_0002
wherein T is hydrogen, halogen, amino, carboxy, amino Ci-7 alkyl, Ci-7 alkoxycarbonyl, halogen Ci-7 alkoxy, -NHCOR0NH2, RJNHC00Ru Or-CONRi9R20, and Y is - NH2, or -COOH, and following the general procedures of any of Schemes 1 to 9 to obtain the final product.
Compounds of formula (I), wherein R3 is amino Ci-7 alkyl or both R3 and Ri i are amino Ci-7 alkyl, can be prepared by treating the nitrile compound of formula (V), (X), (XI), (XII), (XV), (XVI), (XVII), (XVIII) or (XX) with Raney nickel and NH3-methanol on hydrogen gas pressure. Compounds of formula (IV) which may be used as intermediates can be prepared according to Scheme 10 in a reaction between halide and alcohol. A halide (or alcohol) of formula (XXI), wherein Mi and M2 is halogen or a hydroxyl group, is treated with an alcohol (or halide) of formula (XXII), wherein Li is halogen or a hydroxyl group, in the presence of a base such as potassium carbonate, sodium hydride, cesium carbonate and the like in suitable solvent, such as DMF, THF and the like, at temperatures ranging from about 0 0C to 45 0C to obtain a halide (or alcohol) compound of formula (XXIII).
The halide (or alcohol) compound of formula (XXIII) is reacted with an alcohol (or halide) compound of formula (XXIV), wherein Ti is halogen or a hydroxyl group, in the presence of a base and suitable solvent at temperatures ranging from about 40 0C to 85 0C to obtain the nitro compound of formula (XXV). Reduction of the nitro group can be carried out using a reducing agent such as zinc or palladium/carbon under hydrogen pressure along with solvents such as acetic acid/ methanol/ ethanol at temperatures ranging from about 0 0C to 80 0C.
SCHEME 10.
Figure imgf000021_0001
(XXI) (XXII)
Figure imgf000021_0002
(XXJII)
Figure imgf000021_0003
Compounds (IX) which may be used as intermediates can be prepared in a similar manner using a reaction between halide and alcohol according to Scheme 11 , wherein Mi, M2, Li and Tj mean halogen or a hydroxyl group. Hydrolysis of ester group of the compound of formula (XXVIII) can be carried out using a base such as lithium hydroxide, sodium hydroxide and the like in solvent such as THF-water mixture at temperatures ranging from about 0 0C to 25 0C. SCHEME Il,
Figure imgf000022_0001
(XXVI) (XXII)
Figure imgf000022_0002
(XXVII)
Figure imgf000022_0003
Compounds of formula (XIX) which may be used as intermediates can be prepared using a reaction between halide and alcohol according to Scheme 12, wherein M2 and Li mean halogen or a hydroxyl group, Y1 means -NO2, -NH2, -COOEt or -COOH group, R2 is Ci-7 alkyl, amino Ci-7 alkyl, carboxy Ci-7 alkyl, Ci-7 alkoxycarbonyl C]-7 alkyl, Ci-7 alkylamino, carboxy Cj-7 alkylamino, R0C(NRi7)NH2, and Y means - NH2 or -COOH group. SCHEME 12.
Figure imgf000023_0001
Figure imgf000023_0002
(XXX)
Figure imgf000023_0003
(XIX)
Compounds of formula (I) wherein Ri0, R14 and/or Ri5 is halogen, halogen Ci-7 alkyl or -C(NR17)NH2 can be prepared according to the above Schemes starting from compound (XXII) that contain 1 to 3 further nitrile, halogen and/or halogen C1-7 alkyl substituents in the ring portion.
Pharmaceutically acceptable salts, e.g. acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals. Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non- limiting examples of these esters include esters of aliphatic or aromatic alcohols, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter/-butyl esters. Phosphate esters and carbonate esters, are also within the scope of the invention. The terms employed herein have the following meanings:
The term "halo" or "halogen", as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.
The term "C 1-7 alkyl", as employed herein as such or as part of another group, refers to a straight, branched or cyclized, saturated or unsaturated, chain radical having 1 to 7 carbon atoms. Representative examples Of Cr7 alkyl include, but are not limited to, methyl, ethyl, ethenyl, n-propyl, isopropyl, propenyl, n-butyl, isobutyl, sec-butyl, tert- butyl, H-pentyl, isopentyl, neopentyl, «-hexyl, cyclopentyl, cyclohexyl and the like. "C 1-3 alkyl" is an embodiment of "C 1-7 alkyl" having 1 to 3 carbon atoms.
The term "C2-7 alkenyl", as employed herein as such or as part of another group, refers to a straight, branched or cyclized chain radical having 2 to 7 carbon atoms, and containing one or several double bonds.
The term "hydroxy", as employed herein as such or as part of another group, refers to an -OH group.The term "cyano", as employed herein as such or as part of another group, refers to a -CN group. The term "amino", as employed herein as such or as part of another group, refers to a -NH2 group. The term "carboxy", as employed herein as such or as part of another group, refers to -COOH group. The term "carbonyl", as employed herein as such or as part of another group, refers to a carbon atom double- bonded to an oxygen atom (C=O).
The term "C 1-7 alkoxy", as employed herein as such or as part of another group, refers to C 1-7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of C 1-7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-buioxy, tert-butoxy, and the like.
The term "hydroxyl Ci -7 alkyl", as employed herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein. Representative examples of hydroxyl C 1-7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3- hydroxypropyl, 1-hydroxypropyl, 1 -methyl- 1-hydroxyethyl, 1 -methyl- 1 -hydroxypropyl, and the like.
The term "halo Ci-7 alkyl", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a Ci-7 alkyl group, as defined herein. Representative examples of halo Cp7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and the like.
The term "cyano Cr7 alkyl", as employed herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through a Ci-7 alkyl group, as defined herein. Representative examples of cyano C 1-7 alkyl include, but are not limited to, cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 2-cyanopropyl, and the like.
The term "carboxy C 1-7 alkyl", as employed herein as such or as part of another group, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through a C1 -7 alkyl group, as defined herein.
The term "halogen C1 -7 alkoxy", as employed herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C1 -7 alkoxy group, as defined herein.
The term "C1 -7 alkoxycarbonyl", as employed herein as such or as part of another group, refers to a C 1-7 alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term "aminocarbonyl", as employed herein as such or as part of another group, refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. The term "amino C 1-7 alkyl", as employed herein, refers to at least one amino group, as defined herein, appended to the parent molecular moiety through a C] -7 alkyl group, as defined herein. Representative examples of amino C 1-7 alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 1-aminoethyl, 2,2-diaminoethyl, 3- aminopropyl, 2-aminopropyl, 4-aminobutyl, 1 -methyl- 1-aminoethyl, and the like.
The term "C 1-7 alkylamino", as employed herein as such or as part of another group, refers to at least one C 1-7 alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein. Representative examples of C 1-7 alkylamino include, but are not limited to methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, iV-ethyl-N-methylamino, and the like.
The term "carboxy C1 -7 alkylamino", as employed herein as such or as part of another group, refers to at least one carboxy group, as defined herein, appended to the parent molecular moiety through an C 1-7 alkylamino group, as defined herein
The term "C 1-7 alkoxy C1 -7 alkyl", as employed herein, refers to at least one C1 -7 alkoxy group, as defined herein, appended to the parent molecular moiety through an C1 -7 alkyl group, as defined herein.
The term "C 1-7 alkoxycarbonyl C1 -7 alkyl", as employed herein, refers to at least one C1 -7 alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an Ci-7 alkyl group, as defined herein.
The term "substituted" as used herein in connection with various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine, or C 1-7 alkyl, halo C1 -7 alkyl, hydroxy, amino, C 1-7 alkoxy, C2-7 acyl C 1-7 alkylamino, amino C 1-7 alkyl, nitro, cyano, or thiol substituents.
The "substituted" groups may contain 1 to 3, preferably 1 or 2, most preferably 1 of the above mentioned substituents. The definition of formula (I) above is inclusive of all the possible stereoisomers of the compounds, including geometric isomers, e.g. Zand E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers, and all prodrug esters, e.g. phosphate esters and carbonate esters, and isotopes. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used.
Compounds of the invention may be administered to a patient in therapeutically effective amounts which range usually from about 0.1 to about 1000 mg per day depending on the age, weight, ethnic group, condition of the patient, condition to be treated, administration route and the protease inhibitor used. The compounds of the invention can be formulated into dosage forms using the principles known in the art. The compound can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. Suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may be also used. The compositions containing the active compound can be given enterally or parenterally, the oral route being the preferred way. The contents of the active compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to about 20 %, per weight of the total composition.
The present invention will be explained in more detail by the following experiments and examples. The experiments and examples are meant only for illustrating purposes and do not limit the scope of the invention defined in claims. EXPERIMENTS
1. Inhibition of matriptase and other proteases
Methods
Purified recombinant matriptase was used in a fluorescence-based screening assay using GIn- Ala- Arg peptide as a substrate. In this assay the cleavage of AMC from Boc-Gln-Ala-Arg-7- amido-4 methylcoumarin hydrochloride (Boc-Gln-Ala-Arg-AMC) (Sigma, USA) was monitored by measuring the increase in fluorescence intensity of AMC released upon proteolytic cleavage at 480 nm (λex= 360 nm). Similarly, enzymatic assays in fluorimetric or colorimetric format for uPA, Factor Xa, thrombin, plasmin and trypsin (Sigma, USA) were established using substrates pyroGlu-Gly-Arg- pNA.HCl, Boc-Gln-Ala-Arg-AMC, CH3OCO-D-CHA-Gly-Arg-PNA.AcoH, Pyro GIu- Phe-Lys— pNA.HCl and Boc-Gln-Ala-Arg-AMC, respectively.
Results
Enzymatic activity and selectivity of selected compounds of the invention on different proteases is presented in Table 1. The compounds of the invention were found to be potent and selective matriptase inhibitors.
TABLE 1. Inhibition of matriptase and other proteases
Figure imgf000029_0001
2. Cytotoxicity and inhibition of migration and invasion
Methods Cytotoxicity of the compounds was tested in cell lines or primary cells using Calcein AM assay. This assay measures cell viability by quantitation of cleaved fluorescent product of a cell permeable substrate that is retained in the cytoplasm of cells with uncompromised cytoplasmic membrane integrity. The cells were seeded into 96-well plate and allowed to adhere for a day followed by addition of compound at several different concentrations. After four days of incubation with the compound, media was removed from the cells followed by addition of PBS and addition of Calcein AM reagent at 1 μM final concentration. The cells were then allowed to incubate at 37 0C for half an hour followed by reading on the fluorimeter. Percent viability was calculated based on fluorescence value obtained at 485/520 nm with cut off at 495 nm. In the cytotoxicty assays, none of the compounds tested showed any effect up to 10 μM when tested on the prostate cancer cell lines DU 145 and LnCap.
Migration assays were performed to determine the effect of matriptase inhibitors on cell motility. Cells were seeded with 10 μM test compound into transwell chambers and allowed to migrate for 24 hours using a combination of 10 % FBS and 5 μg/ml fibronectin as chemoattractant.
Cell invasion assays were done for quantitating the degree to which invasive cells penetrate a barrier essentially as in migration assay but with the use of matrigel consisting of basement membrane components in the transwell inserts and incubating for 48 hours. The barrier used was matrigel. This was followed by fixing and staining of the transwell insert with 0.5 % crystal violet in 25 % methanol in order to visualize cells migrated. Soft agar colony formation assays were performed to measure the long-term survival and anchorage-independent growth capacity of tumor cells. DU 145 cells were seeded in 0.7 % nutrient agar with the test compound on an underlay of 1.4 % nutrient agar in a six well plate. On the day following cell seeding, liquid cell culture medium containing the compound was added to the well to prevent the agar from drying out and was changed regularly till the completion of the experiment. The cells were allowed to form colonies for a period of about three weeks following which the colonies were stained with 0.005 % solution of crystal violet in 25 % methanol. The colonies were counted under a dissecting microscope.
Results
Effects of selected compounds on cytotoxicity, migration and invasion of DU 145 cells are presented in Table 2.
TABLE 2. Effect of selected compounds on DU 145 cells
Figure imgf000031_0001
EC5o values for inhibition of soft agar colony formation of DU 145 cells by selected compounds are presented in Table 3.
TABLE 3. EC50 values for inhibition of soft agar colony formation of DU 145 cells
Figure imgf000032_0001
3. Efficacy in in- vivo tumor models
Methods
In order to determine the in vivo efficacy, xenograft models were established by injecting 5 x 106 DU145 cells with matrigel or 5 x 106 PC3 cells without matrigel subcutaneously. Once the tumors reached palpable size (~80 mm3), compound of Example 27 was administered in a vehicle comprising of 2 % ethanol, 10 % hydroxyl cyclodextrin in 0.9 % saline. The compound of Example 27 was dosed subcutaneously to animals with DU145 tumors at 1.5, 5 and 15mg/kg for 15 days. In the PC3 xenograft study, compound of Example 27 was administered at 0.5, 1.5, 5.0 and 15.0 mg/kg daily.
Results
In DU 145 xenograft study the compound of Example 27 caused a significant reduction in tumor volume as shown in Table 4. TABLE 4. Tumor growth inhibition in DU 145 model upon treatment with the compound of Example 27 (for 15 days)
Figure imgf000033_0001
In the PC3 xenograft study, the compound of Example 27 caused significant and dose-dependent inhibition of tumor growth as shown in Table 5.
TABLE 5. Tumor growth inhibition in PC3 model upon treatment with the compound of Example 27 (for 21 days)
Figure imgf000033_0002
4. Maximum tolerated dose (MTD)
An MTD study was performed for the compound of Example 27. The objective of the study was to establish the maximum dose that does not induce drug related lethality and/or body weight loss of more than 20 % of baseline weight during the study period of 14 days. The compound was administered at 1, 3, 10 and 30 mg/kg once daily in male athymic mice via subcutaneous route in 5 mice each. Dosing at the tested doses did not show any mortality. Body weight reduction was less than 2 % and no gross changes in clinical signs were seen indicating doses up to 30 mg/kg are well tolerated. The preparation of the compounds of the invention is illustrated by the following Examples.
EXAMPLES.
LCMS data has been recorded in +ve mode unless otherwise mentioned.
Example 1. 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
a) 2,6-Bis (4-cyano phenoxy)-3-nitro pyridine
Potassium carbonate (2.09 g, 15.1 mmol) was added to a stirred solution of 2,6- Dichloro-3-nitro pyridine (1.0 g, 5.3 mmol), dissolved in 10 ml of DMF, at a temperature of 5 °C. The flask was stirred for 10 min at the same temperature. 4-Cyano phenol (1.26 g, 10.6 mmol), dissolved in 5 ml of DMF was added dropwise to the reaction mixture over a period of 10 min and the flask was heated to 80 °C for 10-12 h. The reaction mixture was poured into ice-cold water and the product was extracted with 250 ml of ethyl acetate. Ethyl acetate layer was washed with water and brine solution. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1.35 g of the required 2,6-Bis (4-cyano phenoxy)-3- nitro pyridine which was used in the next step without further purification. 1H NMR (DMSOd6): δ 7.06 (IH, d), 7.32 (4H, dd), 7.82 (4H, t), 8.74 (IH, d).
b) 3-Amino-2,6-bis (4-cyano phenoxy) pyridine
10 % Pd/ carbon (0.24 g) was added under hydrogen atmosphere (balloon pressure) to a stirred solution of 2,6-Bis (4-Cyano phenoxy)-3-nitro pyridine (1.20 g, 3.35 mmol) in 20 ml of methanol : ethyl acetate (1 :1) at ambient temperature and the reaction mixture was stirred for Ih. The reaction mixture was filtered through celite, washed with 20 ml of ethyl acetate and concentrated under reduced pressure. Water was added to the residual mixture and it was extracted with ethyl acetate. Ethyl acetate layer was washed with water followed by brine. The organic layer was dried over sodium sulphate to afford 0.95 g of the title product which was used for the next step without further purification. 1H NMR (DMSOd6): δ 5.32 (2H, brs), 6.82 (IH, d), 7.15 (IH, d), 7.22 (2H, d), 7.34 (2H, d), 7.80 (4H, m).
c) 2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
4-Fluoro benzene sulfonyl chloride (0.15 g, 0.77 mmol), dissolved in 2 ml of tetrahydrofuran (THF), was added to a stirred solution of 3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.25 g, 0.77 mmol), triethylamine (0.155 g, 1.54 mmol) and N ,N- diisopropylethylamine (0.1 g, 0.77 mmol), in 10 ml of THF, in an inert atmosphere and stirred at RT for 12 h. The reaction mixture was concentrated and dissolved in 100 ml of ethyl acetate, washed with 1 N HCl followed by saturated brine solution and dried over anhydrous sodium sulphate. The organic phase was concentrated and the crude product was purified by column chromatography to afford 0.3 g of the required compound. 1H NMR (DMSO-d6): δ 6.94 (IH, d), 7.12 (2H, m), 7.25 (IH, d), 7.35 (4H, d), 7.56 (4H, m), 7.80 (4H, m), 8.04 (4H, m).
d) 2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)- pyridine
2,6-Bis-(4-cyano-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine 0.3 g (0.61 mmol) was added to 70 ml of ethanol (saturated with HCl gas at -25 °C) and the reaction mixture was kept in a tight vessel at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford 0.46 g of the crude product which was taken for the next step without purification. Percentage purity: 51.1 %, (M+l) = 578.1+1.
e) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine
0.46 g (0.79 mmol) of 2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-3-(4-fluoro- benzene-sulphonamido)-pyridine was added to 70ml of ammoniated ethanol (ethanol saturated with NH3 gas at -50 °C). The reaction mixture was kept in tight vessel (sealed tube) at room temperature for 48 hrs. The reaction mixture was cooled in dry ice and concentrated under reduced pressure to afford a crude product which was purified by reverse-phase preparative HPLC to afford 0.15 g of the required product. Percentage purity (HPLC): 98.16 %, (LCMS): 95.66 %. 1H NMR (DMSO-d6): δ 6.9 (IH, d), 7.0 (2H, d), 7.3 (4H, m), 7.8 (6H, m), 9.25 (7H, m), 10.3 (IH, s).
Example 2.
2,6-Bis (4-carbamimidoyl phenoxy)-3-(2-naphthyl sulphonamido)-pyridine
Intermediates (a) and (b) are the same as in Example 1.
c) 2,6-Bis-(4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine
2-Naphthyl sulfonyl chloride (0.17 g, 0.76 mmol) was added to a stirred solution of
3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.25 g, 0.76 mmol) along with other reagents as mentioned in Example l(c) to afford 0.27 g of the required product. 1H NMR (DMSOd6): δ 5.38 (IH, brs), 6.82 (IH, d), 7.12 (IH, d), 7.22 (2H, d), 7.35 (2H, dd), 7.44 (IH, d), 7.80 (7H, m), 7.95 (2H, m), 8.15 (2H, d), 8.56 (IH, s).
d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonamido)- pyridine
N,7V-Diisopropylethylamine (DIPEA) 0.36 ml (2.08 mmol) followed by 144 mg (2.08 mmol) of hydroxylamine hydrochloride was added to a stirred solution of 2,6-bis- (4-cyano-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine 0.27 g (0.52 mmol) in 10 ml of ethanol and the flask was heated at 100 0C for 8 h. The reaction mixture was concentrated under reduced pressure to afford 0.35 g (57.5 %) of the product which was used for the next step without further purification. M+= 584.1+1 (actual mass: 584.1).
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphon- amido)-pyridine Acetic anhydride (0.12 ml, 1.25 mmol) was added dropwise to a solution of 2,6-bis- (4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonaniido)-pyridine (0.35 g, 0.59 mmol) in 5 ml of acetic acid at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 0.3 g (51.0 %) of the crude product which was used for the next step without further purification. M+= LCMS (+ve mode) 668.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine
10 % Pd/C (0.1 g) was added under an atmosphere of nitrogen gas to 2,6-bis-(4-(N- acetylhydroxycarbamimidoyl)-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine 0.3 g (0.44 mmol) dissolved in 50 ml methanol. 30 mg of 10 % Pd/C was added under nitrogen atmosphere and the reaction mixture was stirred under hydrogen pressure (balloon) at room temperature for 3 h. The reaction mixture was passed through celite, washed with methanol and concentrated under reduced pressure. The concentrate was purified using reverse-phase preparative HPLC column to afford 0.06 g. of the required product. Percentage purity (HPLC): 85.01 %, (LCMS): 82.7 3%. 1H NMR (DMSO-d6): δ 6.75 (2H, d), 6.9 (IH, d), 7.3 (2H, d), 7.5 (2H, d), 7.65 (2H, m), 7.8 (3H, d), 8.0 (4H, m), 8.35 (IH, s), 9.03 (4H, d), 9.2 (4H, s), 10.2 (IH, s).
Example 3.
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
Intermediates (a) and (b) are the same as in Example 1.
c) 2,6-Bis-(4-cyano phenoxy)-3 -(8-quinoline-sulphonamido)-pyridine
8-Quinoline sulfonyl chloride (0.172 g, 0.76 mmol) was added to a stirred solution of 3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.25 g, 0.76 mmol). Using other reagents and reaction conditions as mentioned in Example l(c) afforded 0.4 g of the required product. 1H NMR (DMSOd6): δ 6.92 (IH, d), 7.11 (IH, d), 7.18 (2H, d), 7.25 (IH, d), 7.51 (2H, d), 7.56 (IH, dd), 7.66 (IH, t), 7.74 (2H, d), 7.80 (2H, m), 7.98 (IH, d), 8.20 (2H, m), 8.38 (IH, d).
d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamido)- pyridine
2,6-Bis-(4-cyano phenoxy)-3-(8-quinoline-sulphonamido)-pyridine 0.4 g (0.77 mmol), DIPEA 0.53 ml (3.08 mmol) and 214 mg (3.08 mmol) of hydroxylamine hydrochloride were used to synthesize 2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)- 3-(8-quinoline-sulphonamido)-pyridine using the procedure of Example 2(d) to afford 0.4 g of the required product. Percentage purity: 94.4 %, (M+l) = 585.1+1.
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline- sulphonamido)-pyridine
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline-sulphonamido)- pyridine 0.4g (0.68 mmol) was acetylated with 0.14 g (1.36 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.4 g of the required product. Percentage purity: 38.6 %, (M+l) = 669.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(8-quinoline-sulphonamido)-pyridine
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(8-quinoline- sulphonamido)-pyridine 0.4 g (0.59 mmol) was reduced using the procedure of Example 2(f) to afford 0.2 g of required product. Percentage purity (HPLC): 95.88 %, (LCMS): 97.3 %. 1H NMR (DMSOd6): δ 6.5 (2H, d), 6.85 (IH, d), 7.25 (2H, d), 7.55 (3H, m), 7.7 (IH, m), 7.8 (2H, d), 8.0 (IH, d), 8.25 (2H, t), 8.4 (IH, d), 8.98 (IH, d), 9.1 (4H, d), 9.2 (4H, d), 9.65 (IH, brs).
Example 4.
2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)- pyridine Intermediates (a) and (b) are the same as in Example 1.
c) N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulfonamide
3,5-difluorobenzene sulfonyl chloride (0.5 g, 2.35 mmol) was added to a stirred solution of 3-amino-2,6-bis (4-cyano phenoxy) pyridine (0.77 g, 2.35 mmol) using the reagents and reaction conditions described in Example l(c) to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 6.82 (IH, d), 6.95 (IH, d), 7.11 (2H, d), 7.24 (3H, m), 7.34 (2H, d), 7.80 (7H, m).
d) 2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene- sulphonamido)-pyridine
N-[2,6-Bis-(4-cyano-phenoxy)-pyridin-3-yl]-3,5-difluoro-benzenesulfonamide 0.9 g (1.78 mmol), DIPEA 1.24 ml (7.12 mmol) and 0.494 g (7.12 mmol) of hydroxylamine hydrochloride were used as described in Example 2(d) to afford 0.8 g of the required product. Percentage purity: 62.1 %, (M+l) = 570.0+1.
e) 2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene- sulphonamido)-pyridine
2,6-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene-sulphon- amido)-pyridine, 0.8 g (1.40 mmol), was acetylated with 0.29 g (3.1 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.8 g of the required product. Percentage purity: 47.3 %. (M+l) = 654.1+1.
f) 2,6-Bis-(4-carbamimidoyl-phenoxy)-3-(3,5-difluoro-benzene-sulphonamido)- pyridine
2,6-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(3,5-difluoro-benzene- sulphonamido)-pyridine, 0.8 g (1.22 mmol), was reduced using the procedure of Example 2(f) to afford 0.2 g of required product. Percentage purity (HPLC): 88.35 %, (LCMS): 93.37 %. 1H NMR (DMSO-d6): δ 6.6 (3H, m), 6.9 (IH, d), 7.05 (2H, d), 7.35 (2H, d), 7.5 (3H, m), 7.8 (2H, m), 7.9 (IH, d), 9.1 (3H, s), 9.25 (3H, s), 10.5 (IH, s).
Example 5. 2-( 1 - { 2,6-Bis-[4-carbamimidoyl-phenoxy] -pyridine-3 -carbonyl } -piperidin-4-yl)- ethylamine
a) 2,6-Bis (4-Cyano phenoxy)-nicotinic acid ethyl ester
Potassium carbonate 1.58 g (11.5 mmol) was added to a stirred solution of 2,6- dichloro-nicotinic acid ethyl ester 1.0 g (4.6 mmol) in 5 ml of DMF and stirred for 10 min. 4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of DMF, was added dropwise to the stirred DMF solution and the flask was stirred at 80 °C for 4 h. The reaction mixture was poured into ice-cold water and the result was partitioned using ethyl acetate. The organic phase was washed with 1 M OfNa2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The oily residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 1.6 g of the required product. Percentage purity: 84.8 %, (M+l) =385.1. 1H NMR (DMSOd6): δ 1.36 (3H, t), 4.22 (2H, q), 6.78 (IH, d), 7.06 (4H, d), 7.58 (4H, d), 8.21 (IH, d).
b) 2,6-Bis (4-cyano phenoxy)-nicotinic acid
0.2 g (8.4 mmol) of lithium hydroxide was added to a stirred solution of 2,6-bis (4- cyano phenoxy)-nicotinic acid ethyl ester, 1.6 g (4.15 mmol), in a mixture of 5 ml of water and 2.5 ml of THF (2:1) at 5 °C and the contents were stirred for 3 h at RT. The reaction mixture was washed with diethylether. 6 N HCl was added to aqueous layer with stirring until the solution attained a pH of 2. The white precipitate obtained was collected, washed with water and dried under reduced pressure to afford l.lg of the required product. Percentage purity (LCMS): 83.2 %, (M+l) = 357.0+1. 1H NMR (DMSO-d6): δ 6.98 (IH, d), 7.26 (4H, d), 7.80 (4H, d), 13.22 (IH, brs). c) (2- { 1 - [2,6-Bis-(4-cyano-phenoxy)-pyridine-3 -carbonyl]-piperidin-4-yl } -ethyl)- carbamic acid tert-butyl ester
A solution of 2,6-Bis (4-cyano phenoxy)-nicotinic acid, 0.335 g (0.94 mmol), in 5 ml of DMF was added dropwise to the stirred suspension of 0.489 g (0.94 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) in 5 ml of DMF and followed by ΛζiV-diisopropylethylamine 0.242 g (1.88 mmol) while the temperature was maintained below 5 0C during the addition. The mixture was stirred for 10 min and a solution of (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.214 g, 0.94 mmol) in 2 ml of DMF was added. The mixture was stirred overnight at RT. The solvent was concentrated under reduced pressure and the residue was dissolved in a mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2 - 3 with 6 N HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with 10 % solution of potassium hydrogen sulphate followed by saturated sodium bicarbonate solutiona and saturated brine solution, and dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.4 g of the required product. Percentage purity: 36.3 %, (M+l) = 567.2. 1H NMR (DMSO- d6): δ 1.35 (3H, m), 1.38 (9H, s), 1.65 (2H, m), 2.71 (2H, m), 2.95 (4H, m), 3.75 (2H, m), 6.80 (IH, t), 6.95 (IH, d), 7.32 (4H, d), 7.68 (IH, m), 7.85 (4H, d).
d) 2-(l-{2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin- 4-yl)-ethylamine
Using (2-{ l-[2,6-bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-piperidin-4-yl}- ethyl)-carbamic acid tert-butyl ester (0.4 g, 0.7 mmol) and following the procedure of Example l(d) afforded 0.4 g of the required product. Percentage purity (LCMS): 30.7 %. (M+l) = 559.2.
e) 2-(l-{2,6-Bis-[4-carbamimidoyl-phenoxy]-pyridine-3-carbonyl}-piperidin-4-yl)- ethylamine Using (2-(l - {2,6-bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}- piperidin-4-yl)-ethylamine (0.4 g, 0.71 mmol) and following the procedure of Example l(e) 0.05 g of the required product was obtained. Percentage purity (HPLC): 93.52 %, (LCMS): 96.46 %. 1H NMR (DMSOd6): δ 1.5 (2H, m), 1.65 (2H, m,), 1.85 (2H, m), 2.8 (3H, m), 3.1 (IH, m), 3.7 (2H, m), 4.5 (IH, d), 6.9 (IH, d), 7.2 (IH, s), 7.4 (4H, t), 7.9 (5H, brs), 8.05 (IH, brs), 9.3 (6H, s).
Example 6.
N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide
Intermediates (a) and (b) are the same as in Example 5.
c) (4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}-cyclohexyl)- carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid 0.335 g (0.94 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.94 mmol) were used to afford 0.35 g of the required product. Percentage purity (LCMS): 86.8 %, (M+ 1) = 553.6 (with BOC). 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.38 (9H, s), 1.82 (4H, m), 3.18 (IH, m), 3.64 (IH, m), 6.74 (IH, d), 6.95 (IH, d,), 7.28 (4H, dd), 7.82 (4H, dd), 8.08 (IH, d), 8.21 (IH, d).
d) 4-( {2,6-Bis- [4-ethoxycarbonimidoyl-phenoxy] -pyridine-3 -carbonyl } -amino)- cyclohexylamine
(4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}-cyclohexyl)carbamic acid tert-butyl ester (0.35 g, 0.63 mmol) was used and the procedure of Example l(d) was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 40.2 %, (M+ 1) = 545.2.
e) N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-nicotinamide 4-({2,6-Bis-[4-ethoxycarbonimidoyl-phenoxy]-pyridine-3-carbonyl}-amino)- cyclohexylamine (0.3 g, 0.55 mmol) was used the procedure of Example l(e) was followed to afford 0.05 g of the required product. Percentage purity (HPLC): 97.07 %, (LCMS): 81.64 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.95 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 6.9 (IH, d), 7.0 (2H, d,), 7.3 (4H, m), 7.8 (6H, m), 9.25 (7H, m), 10.3 (IH, s).
Example 7.
3 - { [2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3 -carbonyl] -amino } -propylamine Intermediates (a) and (b) are the same as in Example 5.
c) (3 - { [2,6-Bis-(4-cyano-phenoxy)-pyridine-3 -carbonyl] -amino } -propyl)-carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-Cyano phenoxy)-nicotinic acid
0.335 g (0.94 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (0.163 g, 0.94 mmol) were used to afford 0.3 g of the required product. Percentage purity (LCMS): 78.7 %, (M+1) = 513.5+1.
d) 3 - { [2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3 -carbonyl] -amino } - propylamine
(3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester (0.3 g, 0.58 mmol) was used following the procedure of Example l(d) to afford 0.3 g of the required product. Percentage purity (LCMS): 38.6 %, (M+l) =505.2.
e) 3 - { [2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl] -amino } - propylamine
3 - { [2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)-pyridine-3 -carbonyl]-amino } - propylamine (0.3 g, 0.59 mmol) was used following the procedure of Example l(e) to afford 0.12 g of the required product. Percentage purity (HPLC): 92.98 %, (LCMS): 97.61 %. 1H NMR (DMSO-d6): δ 1.8 (2H, m), 2.85 (2H, m), 3.45 (2H, m), 6.9 (IH, d), 7.0 (IH, s), 7.2 (IH, d), 7.3 (4H, m), 7.85 (6H, d), 8.3 (IH, d), 8.55 (IH, brs), 9.3 (7H, brs).
Example 8.
3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}propionic acid
Intermediates (a) and (b) are the same as in Example 5.
c) 3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionicacid ethyl ester
Following the procedure of Example 5(c) 2,6-bis (4-Cyano phenoxy)-nicotinic acid
0.5 g (1.42 mmol) and 3 -amino-propionic acid ethyl ester (0.166 g, 1.42 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 30.7 %, (M +1) = 456.1.
d) 3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic acid
3- { [2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl] -amino} -propionic acid ethyl ester (0.5 g, 1.09 mmol) was deesterified using the procedure of Example 5(b) to afford 0.35 g of the required product. Percentage purity (LCMS): 71.6 %, (M+l)= 428.4.
e) 3-{[2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl]amino}- propionic acid
3-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-propionic acid (0.35 g, 0.81 mmol) was used and the procedure of Example l(d) was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 38.6 %, (M+l) = 520.1 +2. f) 3-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]amino}propionic acid
3 - { [2,6-Bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3 -carbonyl] amino } - propionic acid (0.3 g, 0.57 mmol) was used and the procedure of Example l(e) was followed to afford 0.15 g of the required product. Percentage purity (HPLC): 95.73 %, (LCMS): 97.10 %. 1H NMR (DMSOd6): δ 2.3 (IH, m), 3.5 (IH, m), 6.9 (IH, d), 7.04 (IH, s), 7.22 (IH, s), 7.4 (3H, m), 7.88 (2H, d), 8.36 (IH, d), 8.52 (IH, m), 9.3 (4H, d).
Example 9.
3-{4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin-l-yl}- 3 -oxo-propylamine
Intermediates (a) and (b) are the same as in Example 5.
c) 4- [2,6-Bis-(4-cyano-phenoxy)pyridine-3 -carbonyl] -piperazine- 1 -carboxylic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid 1.25 g (3.5 mmol) and piperazine- 1 -carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol) were used to afford 1.2 g of the required product. Percentage purity (LCMS): 95.6 %, (M+ 1) =525.2 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 3.30 (2H, m), 3.42 (4H, m), 3.61 (2H, m), 6.98 (IH, d), 7.35 (4H, m), 7.82 (4H, dd), 8.02 (2H, d).
d) 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-l -carboxylic acid tert-butyl ester 1.2 g (2.28 mmol) was dissolved in 5 ml of DCM at 5 °C under inert atmosphere. 0.7 ml of TFA was added over a 10 min period, while the temperature was maintained at 5 °C. Stirring was continued for Ih at RT and reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residual crude product was purified by column chromatography using chloroform: ethylacetate (8 : 2) as eluant to afford 0.9 g of the required product. Percentage purity (LCMS): 88.2 %, (M+ 1) : 425.1. 1H NMR (DMSOd6): δ 3.15 (2H, m), 3.22 (2H, m), 3.64 (2H, m), 3.85 (2H, m), 7.00 (IH, d), 7.34 (4H, t), 7.82 (4H, t), 8.08 (IH, d), 9.02 (IH, brs).
e) (3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-l-yl}-3-oxo propyl)carbamic acid tert-butyl ester
A solution of 3-tert-butoxycarbonylamino-propionic acid, 0.177 g (0.94 mmol), in 3 ml of DMF was added dropwise to a stirred suspension of 0.72 g (3.76 mmol) of 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and hydroxybenzotriazole (HOBT) 0.508 g (3.76 mmol) in 5 ml of DMF at RT. That was followed by the addition of ΛζN-diisopropylethylamine (DIPEA) 0.242 g (1.88 mmol) while the temperature was maintained below 5 0C . The mixture was stirred for 10 min and a solution of 4-[2,6-Bis-(4-cyano phenoxy)pyridine-3-carbonyl]piperazine (0.4 g, 0.94 mmol) in DMF (10 ml) was added followed by stirring overnight at RT. The reaction mixture was concentrated under reduced pressure and partitioned between water (150 ml) and ethyl acetate (150 ml) after the pH was adjusted to 2 - 3 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.45 g of the required product. Percentage purity (LCMS): 10.3 %. (M+ 1) = 596.2 (with BOC).
f) 3-(4-{2,6-bis-(4-ethoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-piperazin- 1 -yl)-3 -oxo propylamine
(3-{4-[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]piperazin-l-yl}-3-oxo propyl)carbamic acid tert-butyl ester (0.45 g, 0.75 mmol) was used and the procedure of Example l(d) was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 32.8 %, (M+ 1) = 496.1. g) 3-{4-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-3-carbonyl]-piperazin-l-yl}- 3 -oxo-propylamine
3-(4-{2,6-bis-(4-emoxy-carbonimidoylphenoxy)pyridine-3-carbonyl}-piperazin-l- yl)-3-oxo propylamine (0.3 g, 0.60 mmol) was used and the procedure of Example l(e) was followed to afford 0.12 g of the required product. Percentage purity (HPLC): 73.56 %, (LCMS): 97.21 %. 1H NMR (DMSO-d6): δ 1.8 (2H, m), 2.8 (2H, m), 3.4 (3H, m), 6.9 (IH, d), 7.04 (IH, s), 7.20 (IH, s), 7.4 (5H, m), 7.88 (7H, m), 8.32 (IH, d), 8.54 (IH, brs), 9.34 (6H, s).
Example 10.
3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}- piperidinyl)-3-oxo propylamine
Intermediates (a) and (b) are the same as in Example 5.
c) 4-{[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-l- carboxylic acid tert-butyl ester
Following the procedure of Example 5(c) 2,6-bis (4-cyano phenoxy)-nicotinic acid
1.5 g (4.20 mmol) and 4-amino-piperidine-l-carboxylic acid tert-butyl ester (0.84 g, 4.20 mmol) were used to afford 1.7 g of the required product. Percentage purity (LCMS): 74.6 %, (M+l) = 539.2 (with BOC).
d) 2,6-Bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide
Following the procedure of Example 9(d) 4-{[2,6-Bis-(4-cyano-phenoxy)pyridine- 3-carbonyl]amino}piperidine-l-carboxylic acid tert-butyl ester (1.7 g, 3.15 mmol) were used to afford 1.3 g of the required product. Percentage purity (LCMS): 97.9 %, (M+l) = 439.1+1. e) [3-(4-{[2,6-bis-(4-cyano phenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl)-3- oxo propyl] carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.177 g, 0.91 mmol) and 2,6-bis-(4- cyano phenoxy)-N-piperidine-4-yl nicotinamide (0.4 g, 0.91 mmol) and other reagents as described in Example 9(e) were used to afford 0.45 g of the required product. Percentage purity (LCMS): 82.8 %, (M+l) = 610.1+1.
f) { 3 - [4-( { 2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3 -carbonyl } - amino)-piperidin- 1 -yl] -3 -oxo propyl } -carbamic acid tert-butyl ester
[3-(4-{[2,6-bis-(4-cyanophenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl)-3- oxo propyl] carbamic acid tert-butyl ester (0.45 g, 0.73 mmol), hydroxylamine hydrochloride (0.202 g, 2.92 mmol) and DIPEA (0.377 g, 2.92 mmol) were used and the procedure of Example 2(d) was followed to afford 0.4 g of the required product. Percentage purity (LCMS): 68.6 %, (M+l) = 676.3.
g) { 3 - [4-( { 2 ,6-bis-(4-(N-acety lhydroxycarbamimidoyl)-phenoxy)-pyridine-3 - carbonyl }amino)-piperidin-l-yl] -3 -oxo propyl} -carbamic acid tert-butyl ester
{ 3 - [4-( {2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-pyridine-3 -carbonyl } - amino)-piperidin-l-yl]-3-oxo propyl} -carbamic acid tert-butyl ester 0.4 g (0.59 mmol) was acetylated with 0.123 g (1.2 mmol) of acetic anhydride. The procedure of Example 2(e) was followed to afford 0.45 g of the required product. Percentage purity (LCMS): 40.0 %, (M+l) = 660.2+1 (de-boc).
h) [3 -(4- { [2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3 -carbonyl] -amino } - piperidinyl)-3-oxo propyl] carbamic acid tert-butyl ester
{ 3-[4-( { 2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-pyridine-3 - carbonyl}amino)-piperidin-l-yl]-3-oxo propyl} -carbamic acid tert-butyl ester 0.45 g (0.59 mmol) was reduced by using the procedure of Example 2(f) to afford 0.2 g of the required product. Percentage purity (LCMS): 58.5 %. (M+l) = 644.3+1.
i) 3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)pyridine-3-carbonyl]-amino}- piperidinyl)-3-oxo propylamine
The -Boc group was removed from [3-(4-{[2,6-Bis-(4-carbamimidoyl-phenoxy)- pyridine-3-carbonyl] -amino }-piperidinyl)-3-oxo propyl] carbamic acid tert-butyl ester 0.2 g (0.31 mmol) using the procedure of Example 9(d) to afford 0.055 g of the required product. Percentage purity (HPLC): 95.77 %, (LCMS): 88.95 %. 1H NMR
(DMSOd6): δ 1.4 (3H, m), 1.9 (2H, m), 2.6 (IH, m), 3.0 (2H, m), 3.2 (IH, m), 3.7 (2H, d), 4.2 (2H, d), 6.9 (IH, d), 7.05 (IH, s), 7.2 (IH, s), 7.4 (3H, m), 7.9 (5H, s), 8.3 (2H, dd), 9.35 (6H, d).
Example 11.
N-[l-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)- nicotinamide
Intermediates (a) to (d) are the same as in Example 10.
e) [3-(4-{[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl) propyl] carbamic acid tert-butyl ester
0.117 g (0.85 mmol) OfK2CO3 and iV,jV-diisopropylethylamine 0.072 g (0.56 mmol) followed by 0.201 g (0.85 mmol) of (3-bromo-propyl)-carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, were added to a stirred solution of 0.373 g (0.85 mmol) of 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide, dissolved in 5 ml of DMF over a period of 15 min at 20 °C. Reaction mixture was allowed to attain RT and heated to 45 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic phase was washed with 1 M Na2CO3 and saturated brine solution, and dried over sodium sulphate. The solution was concentrated and the oily residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.45 g of the required product. Percentage purity (LCMS): 72.5 %, (M+l) = 596.2+1.
f) 3-(4-[{2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3-carbonyl}amino]- piperidin-1-yl) propylamine
[3-(4-{[2,6-bis-(4-cyano-phenoxy)pyridine-3-carbonyl]amino}piperidine-l-yl) propyl] carbamic acid tert-butyl ester (0.45 g, 0.75 mmol) was used and the procedure of Example l(d) was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 55.6 %, (M+l) = 496.2+1.
g) N-[l-(3-amino-propyl)piperidin-4-yl]-2,6-bis-(4-carbamimidoyl-phenoxy)- nicotinamide
3 -(4- [ {2,6-bis-(4-ethoxycarbonimidoyl-phenoxy)pyridine-3 -carbonyl } amino]- piperidin-1-yl) propylamine (0.3 g, 0.60 mmol) was used by following the procedure of Example l(e) to afford 0.12 g of the required product. Percentage purity (HPLC): 92.11 %, (LCMS): 90.51 %. 1H NMR (DMSOd6): δ 1.8 (2H, m), 2.0 (5H, m), 2.9 (2H, m), 3.15 (4H, m), 4.0 (2H, m), 6.9 (IH, d), 7.35 (3H, d), 7.85 (3H, m), 8.0 (3H, brs), 8.2 (IH, d), 8.5 (IH, d), 9.3 (7H, d), 10.1 (IH, brs).
Example 12.
(2-{l-[2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]-piperidin-4- yl}-ethylamine
a) 2,6-bis (4-Cyano phenoxy)-isonicotinic acid ethyl ester
Potassium carbonate 3.17 g (23.0 mmol) was added to 2,6-dichloro-isonicotinic acid ethyl ester 1.0 g (4.6 mmol), dissolved in 5 ml of DMF, and stirred for 10 min. This was followed by the dropwise addition of 4-hydroxy-benzonitirle 1.64 g (13.8 mmol), dissolved in 5 ml of DMF, followed by stirring at 100 0C for 3 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic phase was washed with 1 M Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The crude oily residue was purified by column chromatography using hexane-ethyl acetate (10: 2) to afford 0.4 g of the required product. Percentage purity (LCMS): 87.4 %. ( M+l) = 385.1+1. 1H NMR (DMSOd6): δ 1.42 (3H, t), 4.44 (2H, q), 7.16 (4H, d), 7.27 (2H, d), 7.64 (4H, d).
b) 2,6-bis (4-Cyano phenoxy)-isonicotinic acid
0.4 g (1.03 mmol) of 2,6-bis (4-Cyano phenoxy)-isonicotinic acid ethyl ester was hydrolysed by using the procedure of Example 5(b) to afford 0.3 g of the required product. 1H NMR (DMSO-d6): δ 7.22 (2H, s), 7.38 (4H, d), 7.82 (4H, d).
c) (2- { 1 -[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-yl } ethyl)- carbamic acid tert-butyl esters
2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.3 g, 0.84 mmol) and (2-piperidin-4- yl-ethyl)-carbamic acid tert-butyl ester (0.191g, 0.84 mmol) were coupled using the procedure of Example 5(c) to afford 0.4 g.of the required product. Percentage purity (LCMS): 79.0 %, (M+l) = 567.2 (with -BOC). 1H NMR (DMSO-d6): δ 1.15 (2H, m), 1.38 (9H, s), 1.62 (2H, m), 1.75 (IH, m), 2.74 (IH, m), 2.88 (3H, m), 3.55 (IH, m), 4.42 (IH, m), 6.80 (IH, m), 6.89 (2H, s), 7.35 (4H, d), 7.84 (4H, d).
d) (2- { 1 - [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] - piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
(2-{l-[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]piperidine-4-yl}ethyl)- carbamic acid tert-butyl esters (0.4 g, 0.70 mmol), hydroxylamine hydrochloride (0.194 g, 2.8 mmol) and DIPEA (0.36 g, 2.8 mmol) were used and the procedure of Example 2(d) was followed to afford 0.3 g of the required product. Percentage purity (LCMS): 59.2 %, (M+l) = 633.3+1. e) (2-{l-[2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters
(2- { 1 - [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] - piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.3 g (0.473 mmol) was acetylated with 0.095 g (0.95 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.3 g of the required product. Percentage purity (LCMS): 56.2 %, (M+ 1) = 717.3+1.
f) (2- { 1 - [2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl] -piperidine-4- yl}ethyl)carbamic acid tert-butyl esters
(2- { 1 - [2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl]-piperidine-4-yl} ethyl) carbamic acid tert-butyl esters 0.3 g (0.41 mmol) was reduced using the procedure of Example 2(f) to afford 0.17 g of required product. Percentage purity (LCMS): 59.3 %, (M+ 1) = 601.3.
g) 2- { 1 - [2,6-Bis-(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl] -piperidine-4- yl}ethylamine
The -Boc group was removed from (2-{l-[2,6-Bis-(4-carbamimidoyl-phenoxy)- pyridine-4-carbonyl]-piperidine-4-yl}ethyl)carbamic acid tert-butyl esters 0.17 g (0.31 mmol) using the procedure of Example 9(d) to afford 50 mg of the required product.
Percentage purity (HPLC): 95.99 %, (LCMS): 98.52 %. 1H NMR (DMSOd6): δ 1.1 (2H, m), 1.5 (2H, m), 1.6 (2H, m), 1.75 (IH, m), 2.7 (IH, m), 2.85 (2H, m), 3.05 (IH, m), 3.55 (IH, m), 4.4 (IH, m), 6.9 (IH, s), 7.4 (4H, d), 7.75 (3H, brs), 7.85 (4H, d), 9.3
(8H, s).
Example 13. N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamide
Intermediates (a) and (b) are the same as in Example 12. c) (4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-cyclohexyl)- carbamic acid tert-butyl esters
2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.428 g, 1.2 mmol) and (4-amino- cyclohexyl)-carbamic acid tert-butyl ester (0.282 g, 1.32 mmol) were coupled using the procedure of Example 5(c) to afford 0.51 g of the required product. Percentage purity (LCMS -ve mode): (M-I) = 553.2. 1U NMR (DMSOd6): δ 1.25 (4H, m), 1.40 (9H, s), 1.84 (4H, m), 2.74 (IH, s), 2.80 (IH, m), 3.22 (2H, m), 3.72 (IH, m), 6.78 (IH, d), 7.28 (IH, s), 7.35 (3H, d), 7.85 (4H, d), 7.95 (IH, s), 8.60 (IH, brs).
d) (4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl]- amino}cyclohexyl)carbamic acid tert-butyl esters
(4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-cyclohexyl)-carbamic acid tert-butyl esters (0.276 g, 0.70 mmol), hydroxylamine hydrochloride (0.208 g, 3.0 mmol) and DIPEA (0.387 g, 3.0 mmol) were used and the procedure of Example 2(d) was followed to afford 0.7 g of the required product. Percentage purity (LCMS): 47.3 %, (M+l) = 619.2.
e) (4- { [2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl] -amino }cyclohexyl)carbamic acid tert-butyl esters
(4- { [2,6-Bis-(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] - amino }cyclohexyl)carbamic acid tert-butyl esters 0.6 g (0.96 mmol) was acetylated with 0.2 g (2.0 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.65 g of the required product. Percentage purity (LCMS): 59.4 %, (M+l) = 703.2+1.
f) (4-{[2,6-Bis (4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl] amino} cyclo- hexyl)-carbamic acid tert-butyl esters (4- { [2,6-Bis-(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4-carbonyl] - amino }cyclohexyl)carbamic acid tert-butyl esters 0.65 g (0.92 mmol) was reduced by using the procedure of Example 2(f) to afford 0.56 g of required product. Percentage purity (LCMS): 60.2 %, (M+ 1) = 587.2+1.
g) N-(4-Amino-cyclohexyl)-2,6-bis-(4-carbamimidoyl-phenoxy)-isonicotinamide
The -Boc group was removed from (4-{[2,6-bis(4-carbamimidoyl-phenoxy)- pyridine-4-carbonyl]amino} cyclohexyl)-carbamic acid tert-butyl esters 0.55 g (0.93 mmol) using the procedure of Example 9(d) to afford 0.26 mg of the required product. Percentage purity (HPLC): 94.36 %, (LCMS): 96.21 %. 1H NMR (DMSOd6): δ 1.4 (3H, m), 2.0 (4H, m), 3.0 (2H, m), 3.75 (IH, m), 7.26 (2H, s), 7.4 (3H, d), 7.86 (3H, d), 8.0 (3H, brs), 8.72 (IH, m), 9.30 (6H, d).
Example 14.
N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxy-carbamimidoyl)-phenoxy]- isonicotinamide
Intermediates (a) to (d) are the same as in Example 13.
e) N-(4-aminocyclohexyl)-2,6-bis[4-(N-hydroxycarbamimidoyl)phenoxy]- isonicotinamide
The -Boc group was removed from (4-{[2,6-Bis-(4-(N-hydroxy-carbamimidoyl)- phenoxy)-pyridine-4-carbonyl]-amino}cyclohexyl)carbamic acid tert-butyl esters 0.25 g (0.41 mmol) using the procedure of Example 9(d) to afford 0.115 g of the required product. The crude product was purified by reverse-phase preparative HPLC to afford 0.115 g of the required product. Percentage purity (HPLC): 97.73 %, (LCMS): 94.78 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.75 (IH, m), 7.20 (2H, s), 7.36 (4H, d), 7.76 (4H, d), 7.9 (3H, brs), 8.5 (2H, m), 8.68 (IH, d). 11.0 (2H, s).
Example 15. N-[l-(4-amino butyiyl) piperidin-4-yl]-2,6-bis[4-carbamimidoylphenoxy]- isonicotinamide
Intermediates (a) and (b) are the same as in Example 12.
c) 4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}-piperidine-l- carboxylic acid tert-butyl ester
2,6-bis (4-Cyano phenoxy)-isonicotinic acid (0.220 g, 0.61 mmol) and 4-amino- piperidine-1-carboxylic acid tert-butyl ester (0.142 g, 0.71 mmol) were coupled using the procedure of Example 5(c) to afford 0.295 g of the required product. Percentage purity (LCMS): 59.4 %, (M+ 1) = 439.2+1 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 1.81 (4H, m), 2.86 (4H, m), 3.82 (IH, m), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.64 (IH, d).
d) 2,6-Bis (4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide
The -Boc group was removed from 4-{[2,6-Bis-(4-cyano-phenoxy)-pyridine-4- carbonyl] amino} -piperidine-1-carboxylic acid tert-butyl ester 0.29 g (0.53 mmol) using the procedure of Example 9(d) to afford 0.2 g of the required product. Percentage purity (LCMS): 88.3 %, (M+ 1) = 439.2+1. 1H NMR (DMSOd6): δ 1.62 (2H, m), 2.00 (3H, m), 3.02 (2H, m), 4.05 (2H, m), 7.30 (6H, m), 7.85 (4H, d), 8.32 (2H, brs), 8.88 (IH, d).
e) [3-(4-{[2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino}piperidin-l-yl)- propyl]carbamic acid tert-butyl ester
2,6-Bis (4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide 0.16 g (0.364 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester 0.12 g (0.50 mmol) and potassium carbonate 0.175 g (1.26 mmol) were used and the procedure of Example 1 l(e) was followed to afford 0.175 g of the required product. Percentage purity (LCMS): 80.4 %, (M+l) = 596.2+1. 1H NMR (DMSOd6): δ 1.40 (9H, s), 1.88 (9H, m), 2.95 (4H, m), 3.85 (2H, m), 6.86 (2H, brs), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.15 (2H, brs), 9.02 (IH, brs).
f) [3-(4-{[2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl]- amino } -piperidin- 1 -yl)-propyl] carbamic acid tert-butyl ester
[3 -(4- { [2,6-Bis(4-cyano-phenoxy)-pyridine-4-carbonyl]amino } piperidin- 1 -yl)- propyl] carbamic acid tert-butyl ester (0.17 g, 0.28 mmol), hydroxylamine hydrochloride (87.5 mg, 1.26 mmol) and DIPEA (162.8 mg, 1.26 mmol) were used and the procedure Example 2(d) was followed to afford 0.13 g of the required product. Percentage purity (LCMS): 42.4 %, (M+ 1) = 662.3+1.
g) [3-(4-{[2,6-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl] amino} -piperidin- l-yl)-propyl] carbamic acid tert-butyl ester
[3-(4- { [2,6-Bis(4-(N-hydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl]- amino}-piperidin-l-yl)-propyl]carbamic acid tert-butyl ester 0.13 g (0.19 mmol) was acetylated using 45 mg (0.4 mmol) of acetic anhydride following the procedure of Example 2(e) to afford 0.12 g of the required product. Percentage purity (LCMS): 66.9 %, (M+1) = 746.3+1.
h) [3-(4-{[2,6-Bis(4-carbamimidoyl-phenoxy)-pyridine-4-carbonyl]amino}- piperidin-l-yl)propyl] carbamic acid tert-butyl ester
[3-(4-{[2,6-Bis(4-(N-acetylhydroxy-carbamimidoyl)-phenoxy)-pyridine-4- carbonyl] amino} -piperidin- l-yl)-propyl] carbamic acid tert-butyl ester 0.13 g (0.17 mmol) was reduced using the procedure of Example 2(f) to afford 0.115 g of the required product. Percentage purity (LCMS): 81.1 %, (M+l) = 630.3+1.
i) N-[l-(4-amino butyryl) piperidin-4-yl]-2,6-bis-[4-carbamimidoyl phenoxy]-isonicotinamide The -Boc group was removed from [3-(4-{[2,6-bis(4-carbamimidoyl-phenoxy)- pyridine-4-carbonyl] amino }-piperidin-l-yl)propyl]carbamic acid tert-butyl ester 0.115 g (0.18 mmol) using the procedure of Example 9(d) to afford 28 mg of the required product. Percentage purity (HPLC): 97.58 %, (LCMS): 96.9 %. 1H NMR (DMSO-d6): δ 1.8 (2H, m), 2.0 (5H, m), 2.9 (2H, m), 3.15 (4H, m), 3.55 (IH, m), 4.1 (IH, m), 7.3 (2H, s), 7.4 (4H, d), 7.85 (6H, m), 8.9 (IH, d), 9.3 (6H, s), 10.05 (IH, brs).
Example 16.
4- { 4- [4-(2-aminoethyl)piperidine- 1 -carbonyl] -6-isopropoxypyridine-2-yloxy } - benzamidine
a) 2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester
2,6-Dihydroxyisonicatonic acid (2.0 g, 12.9 mmol) was dissolved in 20 ml of propane-2-ol at 0 °C. 2 ml of concentrated sulfuric acid was added to the stirred solution of dihydroxy acid at 0 0C over a period of 10 min and then the contents of the flask were refluxed overnight at 100 °C. The solvent was removed under reduced pressure and the crude residual mixture was dissolved in 250 ml of ethylacetate and washed with water. The organic phase was dried over anhydrous sodium sulphate, concentrated under reduced pressure and subjected to column chromatography, using chloroform : ethylacetate (8 : 2) as eluant to afford 0.5 g of required product. 1H NMR (CDCl3): δ 1.2 (6H, d), 1.35 (6H, d), 4.8 (IH, m), 5.25 (IH, m), 6.85 (IH, s), 6.95 (IH, s), 10.52 (IH, brs).
b) 2-(4-Cyano-phenoxy)-6-isopropoxy-isonicotinic acid isopropyl ester
2-Hydroxy-6-isopropoxy-isonicotinic acid isopropyl ester (0.5 g, 2.09 mmol) and 0.577 g (4.18 mmol) potassium carbonate was dissolved in 5 ml of dry DMF. 0.25 g (2.09 mmol) of 4-fluorobenzonitrile, dissolved in 5 ml of DMF, was added to the stirred solution of hydroxynicotinate over a period of 15 min and then the contents of the reaction flask were stirred overnight at 100 °C. Reaction mixture was concentrated and the residue was dissolved in 100 ml of ethylacetate and washed with water. Ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.3 g of required product which was used for the next step without further purification. 1H NMR (CDCl3): δ 1.2 (6H, d), 1.35 (6H, d), 4.8 (IH, m), 5.25 (IH, m), 7.2 (3H, m), 7.7 (3H, m).
c) 2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid
2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid isopropyl ester (0.3 g, 0.88 mmol) was deesterified using the procedure of Example 5(b) to afford 0.20 g of the required product. Percentage purity (LCMS): 96.71 %. 1H NMR (DMSOd6): δ 1.2 (6H, d), 4.8 (IH, m), 6.85 (IH, s), 6.9 (IH, s), 7.4 (2H, d), 7.98 (2H, m), 14.0 (IH, brs).
d) (2- { 1 -[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperidin-4- yl}ethyl)-carbamic acid tert-butyl ester
2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid (0.20 g, 0.67 mmol) and (2- piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.16 g, 0.7 mmol) were coupled using the procedure of Example 5(c) to afford 0.12 g of the required product. 1H NMR (DMSOd6): δ 1.12 (2H, m), 1.15 (6H, d), 1.4 (9H, s), 1.6 (2H, m), 1.75 (IH, m), 2.7 (IH, m), 2.98 (3H, m), 3.5 (IH, m), 4.45 (IH, m), 4.8 (IH, m), 6.48 (IH, s), 6.58 (IH, s), 6.8 (IH, brs), 7.38 (2H, d), 7.9 (2H, d).
e) 4- { 4- [4-(2- Amino-ethyl)-piperidine- 1 -carbonyl] -6-isopropoxy-pyridin-2-yloxy } - benzimidic acid ethyl ester
(2- { 1 -[2-(4-cyano-phenoxy)-6-isopropoxy-pyridine-4-carbonyl]piperidin-4- yl}ethyl)-carbamic acid tert-butyl ester (0.12 g, 0.23 mmol) was used and the procedure of Example l(d) was followed to afford 0.11 g of the required product. Percentage purity (LCMS): 51.13 %.
f) 4-{4-[4-(2-amino-ethyl)piperidine-l-carbonyl]-6-isopropoxy-pyridine-2-yloxy}- benzamidine 4- {4-[4-(2-Amino-ethyl)-piperidine- 1 -carbonyl]-6-isopropoxy-pyridin-2-yloxy } - benzimidic acid ethyl ester (0.11 g, 0.24 mmol) was used and the procedure of Example l(e) was followed to afford 50 mg of the required product. Percentage purity (HPLC): 99.46 %, (LCMS): 97.7 %. 1H NMR (DMSO-d6): δ 1.15 (6H, s), 1.5 (2H, m), 1.6 (2H, m), 1.75 (IH, m), 2.7 (IH, m), 2.85 (2H, m), 3.0 (IH, m), 3.2 (2H, s), 4.45 (IH, m), 4.85 (IH, m), 6.5 (IH, s), 6.6 (IH, s), 7.4 (2H, d), 7.75 (3H, brs), 7.9 (2H, d), 9.25 (2H, m), 9.35 (2H, s).
Example 17.
4-[5-[4-(2-aminoethyl)-piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzamidine
a) 2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester
96.7 mg (0.7 mmol) of potassium carbonate was added to a stirred solution of 2,6- dichloro nicotinic acid ethyl ester 0.15 g (0.7 mmol) in 10 ml of jV.iV-dimethyl- formamide (DMF) cooled to 5 °C.This was followed by dropwise addition (over a period of 10 min) of 4-cyano phenol 80 mg (0.68 mmol) dissolved in 2 ml of DMF. The reaction mixture was allowed to stir at RT for 2 h, concentrated under reduced pressure and the residue was dissolved in 100 ml of ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using hexane: ethylacetate (8:2) as eluants to afford 0.13 g of the required product. 1H NMR (DMSO- d6): δ 1.3 (3H, t), 4.3 (2H, q), 7.26 (IH, s), 7.38 (IH, s), 7.48 (2H, d), 7.96 (2H, d).
b) 6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
Potassium carbonate (60 mg, 0.43 mmol) was added to a stirred and cooled (0 °C) solution of 2-chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester 0.13 g (0.43 mmol) in 10 ml DMF and stirred for 10 min at the same temperature. This was followed by the addition of 76.5 mg (0.43 mmol) of 4-trifluoromethoxy phenol, dissolved in 2 ml of DMF, over a period of 10 min. After the addition was completed, the contents were allowed to stir at RT. This was followed by heating for 3 h at 80 °C. The reaction mixture was concentrated under reduced pressure, poured into ice-cold water and dissolved in 50 ml of ethyl acetate. Organic layer was then washed with brine solution followed by water and the crude product was purified by column chromatography using hexane: ethyl acetate (8:2) to afford 0.18 g of the required product. Percentage purity: LCMS (-ve mode): 20.12 %.
c) 6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid
6-(4-cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester (0.18 g, 0.40 mmol) was deesterified by using the procedure of Example 5(b) to afford 0.15 g of the required product. Percentage purity: LCMS (-ve mode): 41.96 %.
d) (2- { 1 - [6-(4-cyano phenoxy)-2-(4-trifiuoromethoxy phenoxy)pyridine-3 - carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
6-(4-Cyano phenoxy)-2-(4-trifluoromethoxy phenoxy) nicotinic acid (0.15 g, 0.36 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.082 g, 0.36 mmol) were coupled using the procedure of Example 5(c) to afford 0.15 g of the required product. Percentage purity (LCMS): 43.23 %.
e) 4-[5-[4-(2-Aminoethyl)piperidine- 1 -carbonyl]-6-(4-trifluoromethoxy- phenoxy)pyridine-2-yloxy]benzimidic acid ethyl ester
(2-{ l-[6-(4-cyano phenoxy)-2-(4-trifiuoromethoxy phenoxy)pyridine-3-carbonyl]- piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.15 g, 0.24 mmol) was used and the procedure of Example l(d) was followed to afford 0.20 g of the required product. Percentage purity: LCMS (+ve mode): 35.2 %.
f) 4-[5-[4-(2-aminoethyl)-piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzamidine 4-[5-[4-(2-Aminoethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzimidic acid ethyl ester (0.20 g, 0.34 mmol) was used and the procedure of Example l(e) was followed to afford 0.1 g of the required product. Percentage purity (HPLC): 89.68 %, (LCMS): 74.9 %. 1H NMR (DMSOd6): δ 1.05 (IH, m), 1.25 (IH, m), 1.65 (5H, m), 2.8 (4H, m), 3.2 (IH, m), 4.5 (IH, m), 6.85 (IH, d), 7.25 (2H, s), 7.35 (4H, m), 7.85 (4H, m), 7.9 (IH, m), 9.2 (2H, s), 9.3 (2H, s).
Example 18. 4-[5-[4-(2-amino-ethyl)piperidine- 1 -carbonyl]-6-(4-fluoro-phenoxy)pyridine-2- yloxy] -benzamidine
Intermediate (a) is the same as in Example 17.
b) 6-(4-Cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid ethyl ester
2-Chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester (0.25 g, 0.81 mmol) and 4- fluorophenol (0.09 g, 0.81 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 61.86 %.
c) 6-(4-cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid
6-(4-Cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid ethyl ester (0.23 g, 0.60 mmol) was deesterified using the procedure of Example 5(b) to afford 0.2 g of the required product. Percentage purity: LCMS (-ve mode): 57.29 %.
d) (2-{l-[6-(4-cyano phenoxy)-2-(4-fluoro phenoxy)pyridine-3-carbonyl]piperidin- 4-yl}ethyl)carbamic acid tert-butyl ester
6-(4-cyano phenoxy)-2-(4-fluoro phenoxy) nicotinic acid (0.2 g, 0.57 mmol) and (2- piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.13 g, 0.57 mmol) were coupled using the procedure of Example 5(c) to afford 0.25 g of the required product. Percentage purity: LCMS (-ve mode): 67.5 %.
e) 4-[5-[4-(2-Amino-ethyl)-piperidine- 1 -carbonyl]-6-(4-fIuoro-phenoxy)-pyridin-2- yloxyj-benzimidic acid ethyl ester
(2- { 1 - [6-(4-cyanophenoxy)-2-(4-fluorophenoxy)pyridine-3 -carbonyl] piperidin-4- yl}ethyl)carbamic acid tert-butyl ester (0.25 g, 0.44 mmol) was used and the procedure of Example l(d) was followed to afford 0.28 g of the required product. Percentage purity (LCMS): 51.02 %.
f) 4-[5-[4-(2-amino ethyl)piperidine-l -carbonyl] -6-(4-fluoro phenoxy)pyridine-2- yloxy] benzamidine
4-[5-[4-(2-Amino-ethyl)-piperidine-l-carbonyl]-6-(4-fluoro-phenoxy)-pyridin-2- yloxy]-benzimidic acid ethyl ester (0.28 g, 0.55 mmol) was used and the procedure of Example l(e) was followed to afford 0.12 g of the required product. Percentage purity (HPLC): 95.03 %, (LCMS): 90.18 %. 1H NMR (DMSO-d6): δ 1.05 (2H, m), 1.25 (IH, s), 1.5 (2H, m), 1.65 (2H, m), 1.75 (IH, m), 2.8 (2H, m), 3.05 (3H, m), 3.65 (IH, d), 4.5 (IH, d), 6.8 (IH, s), 7.18 (2H, d), 7.36 (2H, d), 7.68 (2H, brs), 7.82 (IH, d), 7.94 (IH, m), 8.98 (IH, s), 9.30 (IH, s).
Example 19.
4-[3-[4-(2-amino ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy phenoxy)pyridin-2-yloxy]benzamidine
a) 2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester
2,6-dichloronicotinic acid ethyl ester (0.22 g, 0.1 mmol) and 4-trifluoromethoxy- phenol (0.178 g, 0.1 mmol) were coupled using the procedure of Example 17(a) to afford 0.3 g of the required product. Percentage purity (LCMS): 64.0 %. b) 2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester (0.3 g, 0.83 mmol) and 4-cyanophenol (98.8 mg, 0.83 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 82.35 %.
c) 2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid ethyl ester
(0.23 g, 0.51 mmol) was deesterified using the procedure of Example 5(b) to afford 0.2 g of the required product. Percentage purity: LCMS (-ve mode): 66.14 %.
d) (2- { 1 - [2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3 -carbonyl] piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy) nicotinic acid (0.2 g, 0.48 mmol) and (2-Piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.11 g, 0.48 mmol) were coupled using the procedure of Example 5(c) to afford 0.21 g of the required product. Percentage purity (LCMS): 68.11 %.
e) 4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzimidic acid ethyl ester
(2- { 1 - [2-(4-cyanophenoxy)-6-(4-trifluoromethoxyphenoxy)pyridine-3 -carbonyl] piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (0.2 g, 0.319 mmol) was used and the procedure of Example l(d) was followed to afford 0.25 g of the required product. Percentage purity (LCMS): 52.44 %.
f) 4-[3-[4-(2-Amino-ethyl)piperidine- 1 -carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzamidine 4-[3-[4-(2-Amino-ethyl)piperidine-l-carbonyl]-6-(4-trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzimidic acid ethyl ester (0.25 g, 0.43 mmol) was used and the procedure of Example l(e) was followed to afford 0.050 g of the required product. Percentage purity (HPLC): 94.13 %, (LCMS): 91.76 %. 1H NMR (DMSOd6): δ 1.5 (2H, m), 1.65 (2H, m), 1.75 (IH, m), 2.3 (IH, m), 2.8 (4H, m), 3.1 (2H, m), 3.65 (IH, d), 4.5 (IH, d), 6.88 (IH, s), 7.26 (2H, m), 7.36 (3H, m), 7.82 (2H, d), 7.94 (2H, brs), 9.14 (2H, s), 9.34 (2H, s).
Example 20. 4-[5-[4-(2-amino-ethyl)piperidine-l -carbonyl]-3-fluoro-6-(3-trifluoromethoxy phenoxy)-pyridine-2-yloxy]benzamidine
a) 2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester
2,6-Dichloro-5-fluorq-nicotinic acid ethyl ester (3.5 g, 15.0 mmol) and 4-cyano- phenol (1.78 g, 15.0 mmol) were coupled using the procedure of Example 17(a) to afford 2.4 g of the required product. 1H NMR (DMSOd6): δ 1.35 (3H, t), 4.4 (2H, q), 7.58 (2H, d), 8.0 (2H, d), 8.4 (IH, d).
b) 6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)nicotinic acid ethyl ester
2-chloro-6-(4-cyano phenoxy)-5-fluoro nicotinic acid ethyl ester (2.4 g, 7.49 mmol) and 3-trifluoromethoxyphenol (1.33 g, 7.49 mmol) were coupled using the procedure of Example 17(b) to afford 1.8 g of the required product. 1H NMR (DMSOd6): δ 1.35 (3H, t), 4.4 (2H, q), 7.22 (2H, d), 7.3 (3H, d), 7.34 (IH, m), 7.54 (2H, d), 8.38 (IH, d).
c) 6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy) nicotinic acid
6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)nicotinic acid ethyl ester (1.8 g, 2.79 mmol) was deesterified using the procedure of Example 5(b) to afford 1.3 g of the required product. 1H NMR (DMSOd6): δ 7.22 (2H, d), 7.3 (4H, m), 7.74 (2H, d), 8.34 (IH, d), 13.2 (IH, brs).
d) (2-{ l-[6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy)pyridine-3- carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
6-(4-cyano phenoxy)-5-fluoro-2-(3-trifluoromethoxy phenoxy) nicotinic acid (1.3 g, 2.99 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.684 g, 3.0 mmol) were coupled using the procedure of Example 5(c) to afford 1.1 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (2H, m), 1.4 (9H, d), 1.5 (2H, m), 1.6 (2H, m), 2.2 (IH, m), 2.35 (IH, m), 3.0 (3H, m), 3.7 (IH, m), 4.45 (IH, m), 6.78 (IH, m), 7.18 (IH, m), 7.26 (2H, m), 7.32 (IH, s), 7.46 (IH, m), 7.76 (IH, m), 7.86 (IH, s), 8.1 (IH, m).
e) 4- [5 - [4-(2- Amino ethyl)piperidine- 1 -carbonyl] -3 -fluoro-6-(3 -trifluoromethoxy phenoxy)pyridine-2-yloxy]benzimidic acid ethyl ester
(2-{l-[6-(4-cyanophenoxy)-5-fluoro-2-(3-trifluoromethoxyphenoxy) pyridine-3- carbonyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester (1.1 g, 1.70 mmol) was used and the procedure of Example l(d) was followed to afford 1.0 g of the required product. Percentage purity (LCMS): 11.21 %.
f) 4-[5-[4-(2-Aminoethyl)piperidine- 1 -carbonyl-3-fiuoro-6-(3-trifiuoromethoxy phenoxy)pyridine-2-yloxy]benzamidine
4-[3-[4-(2-Amino-ethyl)piperidine- 1 -carbonyl] -6-(3 -trifluoromethoxy-phenoxy)- pyridine-2-yloxy]benzimidic acid ethyl ester (1.0 g, 1.69 mmol) was used and the procedure of Example l(e) was followed to afford 0.250 g of the required product. Percentage purity (HPLC): 98.16 %, (LCMS): 90.93 %. 1H NMR (DMSO-d6): δ 1.5 (3H, m), 1.6 (2H, m), 1.75 (2H, m), 2.0 (IH, m), 2.8 (4H, m), 4.5 (IH, m), 7.1 (2H, m), 7.25 (2H, m), 7.45 (2H, d), 8.0 (3H, m), 8.1 (2H, m), 9.20 (2H, s), 9.35 (2H, s).
Example 21. 2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-2-naphthalenesulfonamide
a) 1 ,5-Bis-(4-cyano-phenoxy)-2-nitrobenzene
4-cyanophenol 4.5 g (23.0 mmol), dissolved in 5 ml of DMF, was added to a stirred suspension of sodium hydride 0.92 g (23.0 mmol) in 5 ml of DMF cooled to 5 °C. The reaction flask was stirred for 10 min at the same temperature and this was followed by dropwise addition (over 15 min) of 2,4-dichloronitrobenzene 2.0 g (10.5 mmol) dissolved in 5 ml of DMF. The reaction mixture was stirred for 6 h at 70 °C. The reaction mass was poured into ice-cold water and extracted with 200 ml of ethylacetate. The organic phase was washed with 1 M Na2CO3 and saturated brine solution. The solution was dried over sodium sulphate and concentrated to afford an oily residue, which was purified by column chromatography using chlorofrom-ethyl acetate (10 : 2) to afford 2.5 g of the required product. 1H NMR (DMSOd6): δ 6.79 (IH, d), 6.93 (IH, d), 7.06 (2H, d), 7.18 (2H, d), 7.75 (4H, d), 8.16 (IH, d).
b) 1 ,5-Bis-(4-cyano-phenoxy)-2-aminobenzene
Zinc dust, 0.4 g (5.3 mmol) was added portionwise to a reaction flask containing a stirred mixture (10 min) of l,5-bis-(4-cyano-phenoxy)-2-nitrobenzene 1.5 g (4.2 mmol) and 0.085 g (0.08 mmol) of ammonium chloride dissolved in 25 ml of methanol. The reaction mixture was allowed to stir for 1 h at RT. Reaction mixture was filtered through celite and the filtrate was concentrated to afford a brown viscous residue which was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to afford an oily residue, which was purified by column chromatography using chloroform-ethyl acetate (10 : 1) to afford 1.3 g of the required product. 1H NMR (DMSO-d6): δ 5.10 (2H, brs), 6.85 (3H, m), 7.06 (4H, m), 7.80 (4H, m).
c) Naphthalene-2-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl] -amide l,5-Bis-(4-cyano-phenoxy)-2-aminobenzene 0.175 g (0.54 mmol), 2-naphthalene- sulfonyl chloride 0.148 g (0.65 mmol) and TV.iV-diisopropylethylamine (DIPEA) 0.85 g (0.65 mmol) were dissolved in 5 ml of dry toluene and refluxed for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate after the pH was adjusted to 2 with 6 N HCl. The organic phase was washed with 1 M Na2CO3 (5 x 100 ml) and saturated brine solution. The solution was dried over sodium sulphate and concentrated to afford an oily residue, which was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.19O g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 8.10 (2H, d), 8.35 (IH, s).
d) Naphthalene-2-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl]- amide
Using naphthalene-2-sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19 g, 0.36 mmol) and following the procedure of Example l(d) afforded 0.13 g of the required product. Percentage purity (LCMS): 69.6 %, (M+ 1) = (609.1+1).
e) Naphthalene-2-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]-amide
Using naphthalene-2-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)- phenyl] -amide (0.13 g, 0.21 mmol) and following the procedure of Example l(e) 0.033 g of the required product was obtained. Percentage purity (HPLC): 96.91 %, (LCMS): 96.74 %. 1U NMR (DMSO-d6): δ 6.5 (IH, s), 6.7 (3H, m), 6.95 (2H, m), 7.2 (3H, m), 7.3 (IH, s) 7.45 (IH, m), 7.55 (2H, d), 7.7 (2H, m), 7.75 (IH, m), 7.85 (2H, d), 7.95 (2H, m), 8.1 (IH, m), 8.3 (IH, s), 9.0 (3H, m), 9.15 (2H, s), 9.25 (2H.s).
Example 22.
4-Fluorobenzene-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]- amide
Intermediates (a) and (b) are the same as in Example 21. c)N-[2,4-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulfonamide
4-Fluorobenzene sulfonyl chloride (0.126 g, 0.65 mmol) was added to a stirred solution of 1 ,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with other reagents as mentioned in Example 20(c) to afford 0.18 g of the required product. 1H NMR (DMSO-d6): δ 6.86 (IH, brs), 6.95 (3H, m), 7.26 (2H, d), 7.34 (IH, d), 7.54 (3H, t), 7.82 (2H, d), 7.95 (2H, d), 7.95 (2H, m).
d) 4-Fluorobenzene-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)- phenyl] -amide
Using N-[2,4-bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzene sulfonamide (0.18 g, 0.37 mmol) and following the procedure of Example l(d) afforded 0.16 g of the required product. Percentage purity (LCMS): 62.0 %, (M+l) = (577.1+1).
e) 4-Fluorobenzene-sulfonic acid [2,4-bis-(4-carbamimidoyl-phenoxy)-phenyl]- amide
Using 4-fluorobenzene-sulfonic acid [2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)- phenyl]-amide (0.16 g, 0.27 mmol) and following the procedure of Example l(e) 0.033 g of the required product was obtained. Percentage purity (HPLC): 96.54 %, (LCMS): 95.4 %. 1H NMR (DMSOd6): δ 6.5 (IH, s), 6.75 (IH, s), 6.95 (3H, m), 7.2 (2H, d), 7.3 (2H, d) 7.4 (IH, d), 7.75 (3H, m), 7.85 (2H, d), 8.6 (IH, s), 8.95 (3H, brs), 9.25 (3H, brs), 10.2 (IH, brs).
Example 23.
2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl-l-naphthalenesulfonamide
Intermediates (a) and (b) are the same as in Example 21.
c) Naphthalene- 1 -sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl] -amide 1 -Naphthalene sulfonyl chloride (0.148 g, 0.65 mmol) was added to a stirred solution of l,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with other reagents as mentioned in Example 20(c) to afford 0.19 g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 7.85 (3H, m).
d) 2,4-Bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl- 1 -naphthalenesulfonamide
Using naphthalene- 1 -sulfonic acid [2,4-bis-(4-cyano-phenoxy)-phenyl]-amide (0.19 g, 0.36 mmol) and following the procedure of Example l(d) afforded 0.16 g of the required product. Percentage purity (LCMS): 55.3 %, (M+l) = (609.19+1H).
e) 2,4-Bis-(4-carbamimidoyl-phenoxy)-phenyl- 1 -naphthalenesulfonamide
Using 2,4-bis-(4-ethoxycarbonimidoyl-phenoxy)-phenyl- 1 -naphthalene sulfonamide (0.16 g, 0.26 mmol) and following the procedure of Example l(e) 0.035 g.of the required product was obtained. Percentage purity (HPLC): 94.73 %, (LCMS): 96.0 %. 1H NMR (DMSOd6): δ 6.55 (IH, s), 7.1 (2H, d), 7.3 (2H, m), 7.4 (2H, d), 7.75 (4H, m), 7.9 (4H, m), 8.2 (IH, d), 8.4 (IH, d), 8.5 (2H, brs), 9.1 (4H, d), 9.3 (4H, s).
Example 24.
N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzamide
a) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester
Potassium carbonate 2.1g (15.2 mmol) dissolved in DMF solution was added to 3,5-dihydroxy-benzoic acid ethyl ester 1.5 g (8.2 mmol) dissolved in 15 ml of DMF. This was followed by dropwise addition of 6-chloro-nicotinonitrile 2.1g (15.2 mmol) dissolved in 5 ml of DMF. After complete addition, the reaction mixture was stirred at 60 °C for 8-10 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated to afford a crude solid which was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 2.5 g of the required product. 1H NMR (DMSOd6): δ 1.30 (3H, t), 4.32 (2H, q), 7.35 (2H, d), 7.52 (IH, t), 7.68 (2H, d), 8.39 (2H, d), 8.69 (2H, s).
b) 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid
2.3 g (5.9 mmol) of 3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoic acid ethyl ester was hydrolysed by using the procedure of Example 5(b) to afford 1.8 g.of the required product. 1H NMR (DMSO-d6): δ 7.34 (2H, d), 7.48 (IH, t), 7.61 (2H, d), 8.38 (2H, dd), 8.70 (2H, d), 13.5 (IH, brs).
c) {4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)- benzoic acid 0.35 g (0.97 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.97 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.47 (9H, s), 1.72 (5H, m), 1.82 (3H, m), 3.20 (IH, m), 3.72 (IH, m), 6.74 (IH, m), 7.18 (IH, d), 7.32 (IH, s), 7.50 (IH, brs), 7.59 (IH, s), 8.08 (IH, brs), 8.30 (2H, dd), 8.39 (IH, dd), 8.67 (2H, d).
d) N-(4-Amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)- benzamide
Using {4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.13 g, 0.23 mmol) and following the procedure of Example l(d) afforded 0.12 g of the required product. Percentage purity (LCMS): 74.6 %, (M+l) = 546.2.
e) N-(4-Amino-cyclohexyl)-3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzamide Using N-(4-amino-cyclohexyl)-3,5-bis-(5-ethoxycarbonimidoyl-pyridin-2-yloxy)- benzamide (0.12 g, 0.21 mmol) and following the procedure of Example l(e) 0.044 g.of the required product was obtained. Percentage purity (HPLC): 98.4 %, (LCMS): 96.7 %. 1H NMR (DMSOd6): δ 1.8-2.0 (5H, m), 3.0 (2H, m), 3.7 (3H, m), 7.32 (2H, d), 7.40 (IH, s), 7.62 (2H, d), 7.88 (3H, brs), 8.30 (2H, dd), 8.42 (IH, m), 8.62 (2H, d), 9.24 (4H, s), 9.42 (3H, s).
Example 25.
4-amino- 1 -{4-[3 ,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin- 1 - yl } -butan- 1 -one
Intermediates (a) and (b) are the same as in Example 24.
c) 4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-l-carboxylic acid tert- butyl ester
Following the procedure of Example 5(c) 3,5-bis-(5-cyano-pyridin-2-yloxy)- benzoic acid 0.6 g (1.67 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 1.67 mmol) were used to afford 0.55 g of the required product. 1H NMR (DMSOd6): δ 1.42 (9H, s), 3.45 (6H, m), 3.56 (2H, m), 7.20 (2H, d), 7.27 (IH, t), 7.32 (2H, d), 8.37 (2H, dd), 8.70 (2H, d).
d) 4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine
Using 4-[3,5-bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazine-l-carboxylic acid tert-butyl ester (0.5 g, 0.94 mmol) and following the procedure of Example 9(d) afforded 0.4 g of the required product. 1H NMR (DMSOd6): δ 3.20 (4H, m), 3.46 (4H, m), 5.42 (IH, brs), 7.18 (2H, d), 7.25 (IH, t), 7.31 (2H, d), 8.41 (2H, dd), 8.75 (2H, d).
e) 4-{4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benκoyl]-piperazin-l-yl}-4-oxo-butyl)- carbamic acid tert-butyl ester Following the procedure of Example 5(c) 4-[3,5-bis-(5-cyano-pyridin-2-yloxy)- benzoylj-piperazine 0.4 g (0.93 mmol) and 4-tert-butoxycarbonylamino-butyric acid (0.19 g, 0.93 mmol) were used to afford 0.35 g of the required product. 1H NMR (DMSOd6): δ 1.39 (9H, s), 1.60 (2H, q), 2.32 (3H, m), 2.94 (2H, q), 3.50 (7H, m), 6.80 (IH, brs), 7.15 (IH, d), 7.28 (IH, t), 7.32 (2H, d), 8.37 (2H, dd), 8.72 (2H, d).
f) [4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl}- piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester
4-{4-[3,5-Bis-(5-cyano-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}-4-oxo-butyl)- carbamic acid tert-butyl ester 0.35 g (0.57 mmol), DIPEA 0.3 g (2.28 mmol) and 0.158 g (2.28 mmol) of hydroxylamine hydrochloride were used as described in Example 2(d) to afford 0.25 g of the required product. Percentage purity (LCMS): 86.1 %, (M+l) = 677.2 (with BOC). 1U NMR (DMSOd6): δ 1.40 (9H, s), 1.62 (2H, q), 2.33 (2H, m), 2.92 (3H, m), 3.18 (IH, m), 3.50 (4H, m), 3.62 (2H, m), 6.16 (3H, brs), 6.82 (2H, t), 7.08 (2H, s), 7.18 (3H, d), 8.14 (2H, dd), 8.48 (2H, s), 9.85 (2H, brs).
g) [4-(4-{3,5-Bis-[5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy]- benzoyl}-piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester
[4-(4-{3,5-Bis-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yloxy]-benzoyl}-piperazin- l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester 0.25 g (0.37 mmol) was acetylated with 0.08 g (0.8 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 0.25 g of the required product. Percentage purity (LCMS): 86.1 %, (M+l) = 761.2 (with BOC). 1H NMR (DMSO-d6): δ 1.36 (9H, s), 1.62 (2H, m), 2.14 (6H, s), 2.33 (3 H, m), 2.93 (3H, m), 3.55 (6H, brs), 6.82 (IH, brs), 6.95 (4H, brs), 7.18 (5H, m), 8.18 (2H, dd), 8.50 (2H, s).
h) (4-{4-[3,5-Bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}-4- oxo-butyl)-carbamic acid tert-butyl ester [4-(4-{3,5-Bis-[5-(N-(acetylhydroxy)-carbamimidoyl)-pyridin-2-yloxy]-benzoyl}- piperazin-l-yl)-4-oxo-butyl]-carbamic acid tert-butyl ester 0.25 g (0.32 mmol) was reduced using the procedure of Example 2(f) to afford 0.12 g of the required product. Percentage purity (LCMS): 68.7 %, (M+ 1) = 645.3+1.
i) 4-{4-[3,5-Bis-(5 -carbamimidoyl-pyridin-2-yloxy)-benzoyl] -piperazin- 1 -yl } -4- oxo-butanylamine
Using (4-{4-[3,5-bis-(5-carbamimidoyl-pyridin-2-yloxy)-benzoyl]-piperazin-l-yl}- 4-oxo-butyl)-carbamic acid tert-butyl ester (0.12 g, 0.18 mmol) and following the procedure of Example 9(d) afforded 0.05 g of the required product. Percentage purity (HPLC): 87.7%, (LCMS): 86.4%. 1H NMR (DMSOd6): δ 1.2 (2H, m), 1.75 (2H, m), 2.8 (2H, m), 3.2 (8H, m ), 4.2 (2H, brs), 7.22 (3H, m), 7.36 (2H, m), 7.80 (3H, brs), 8.30 (2H, m), 8.66 (2H, s), 9.22 (3H, s), 9.44 (3H, s).
Example 26. l-[(4-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-(4-carbamimidoyl-phenoxy)- benzene
a) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester
Potassium carbonate 0.61 Ig (4.4 mmol) was added to a stirred solution of 3,5- dihydroxy-benzoic acid ethyl ester 0.5 g (1.7 mmol) dissolved in 15 ml of DMF and stirred for 10 min. This was followed by dropwise addition of 4-fluorobenzonitrile 0.82 g (6.8 mmol), dissolved in 5 ml of DMF, and the contents of the flask were stirred at 80 °C for 4 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic phase was washed with Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated to afford an oily residue which was purified by column chromatography using hexane-ethyl acetate (10: 2) to afford 0.4 g of the required product. The yield was 0.6 g. 1H NMR (DMSO-d6): δ 1.30 (3 H, t), 4.30 (2H, q), 7.25 (2H, d), 7.32 (IH, t), 7.46 (2H, d), 7.90 (2H, d). b) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid
3,5-Bis-(4-cyano-phenoxy)-benzoic acid ethyl ester 0.6 g (1.56 mmol) was hydrolysed by using the procedure of Example 5(b) to afford 0.45 g of required product. 1H NMR (DMSOd6): δ 7.27 (3H, d), 7.40 (2H, d), 7.92 (2H, d), 13.5 (IH, brs).
c) 1 - [(4-Boc- Amino-ethyl)-piperidine- 1 -carbonyl] -3 ,5-bis-(4-cyano-phenoxy)- benzene
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.45 g (1.26 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.287 g, 1.26 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSOd6): δ 1.05 (2H, m), 1.30 (2H, m), 1.40 (9H, s), 1.45 (4H, m), 2.60 (IH, m), 2.94 (3H, m), 3.54 (IH, m), 4.38 (IH, m), 6.78 (IH, t), 6.75 (2H, d), 7.04 (IH, t), 7.25 (4H, d), 7.88 (2H, d).
d) 1 - [(4-Boc- Amino-ethyl)-piperidine- 1 -carbonyl] -3 ,5-bis- [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzene
Following the procedure of Example 2(d) 1 - [(4-boc-amino-ethyl)-piperidine- 1 - carbonyl]-3,5-bis-(4-cyano-phenoxy)-benzene 0.4 g (0.7 mmol) and other reagents were used to afford 0.35 g of the required product. Percentage purity (LCMS): 69.2 %, (M+l) = 632.2+1.
e) l-[(4-Boc-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-[4-(N-acetyl- hydroxycarbamimidoyl)-phenoxy]-benzene
Following the procedure of Example 2(e) l-[(4-boc-amino-ethyi)-piperidine-l- carbonyl]-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzene 0.35 g (0.55 mmol) was used to afford 0.3 g of the required product. Percentage purity (LCMS): 51.0 %, (M+l) = 716.3 (with BOC). f) l-[(4-Boc-Amino-ethyl)-piperidine-l-caτbonyl]-3,5-bis-(4- carbamimidoyl- phenoxy)-benzene
l-[(4-Boc-amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -benzene 0.3 g (0.41 mmol) was reduced using the procedure of Example 2(f) to afford 0.2 g of required product. Percentage purity (LCMS): 74.0 %, (M+ 1)= 600.3+1.
g) l-[(4-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-(4-carbamimidoyl-phenoxy)- benzene
Using l-[(4-boc-Amino-ethyl)-piperidine-l-carbonyl]-3,5-bis-(4- carbamimidoyl- phenoxy)-benzene (0.2 g, 0.33 mmol) and following the procedure of Example 9(d) afforded 0.06 g of the required product. Percentage purity (HPLC): 97.85 %, (LCMS): 94.26 %. 1H NMR (DMSOd6): δ 1.05 (2H, m), 1.4-1.8 (5H, m), 2.8 (3H, m), 3.0 (IH, m), 3.4 (IH, m), 4.4 (IH, m), 6.95 (3H, brs), 7.3 (3H, d), 7.9 (6H, d), 9.1-9.6 (7H, d).
Example 27.
N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) {4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert- butyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.27 g, 1.26 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSOd6): δ 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (IH, m), 3.68 (IH, m), 6.78 (IH, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.51 (2H, d, 3=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.35 (IH, d, J=7.5 Hz). d) (4- { 3 ,5 -Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3,5-bis-(4-cyano-phenoxy)- benzoylamino] -cyclohexyl}-carbamic acid tert-butyl ester 0.5 g (9 mmol) and other reagents were used to afford 0.4 g of the required product. Percentage purity (LCMS): 68.0 %, (M+l) = 618.2+1. 1H NMR (DMSOd6): δ 1.31 (4H, m), 1.45 (9H, s), 1.80 (4H, m), 3.22 (IH, m), 3.68 (IH, m), 6.78 (IH, d, J=7.8 Hz), 7.24 (2H, d, J=9.6 Hz), 7.42 (2H, d, J=2.1 Hz), 7.75 (2H, d, J=8.7 Hz), 7.92 (4H, brs), 8.35 (IH, d, J=7.5 Hz), 11.05 (2H, brs).
e) (4- { 3 , 5 -Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure as in Example 2(e) (4-{3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoylamino }-cyclohexyl)-carbamic acid tert-butyl ester 0.4 g (0.64 mmol) was used to afford 0.45 g of the required product. Percentage purity (LCMS): 89.0 %, (M+l) = 702.3+1. 1H NMR (DMSOd6): δ 1.28 (4H, m), 1.45 (9H, s), 1.75 (4H, m), 2.62 (6H, s), 3.31 (IH, m), 3.78 (IH, m), 6.81 (IH, d, J=7.8 Hz), 7.04 (2H, d, J=9.2 Hz), 7.31 (2H, d, J=I .9 Hz), 7.58 (2H, d, J=8.6 Hz), 8.30 (5H, brs).
f) {4-[3,5-Bis-(4-carbamimidoyl phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
(4-{3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexyl)-carbamic acid tert-butyl ester 0.45 g (0.64 mmol) was reduced using the procedure of Example 2(f) to afford 0.3 g of required product. Percentage purity (LCMS): 74.0 %, (M+l) = 586.2+1.
g) N-(4-Amino-cyclohexyl)-3,5-bis-(4-carbamimidoyl-phenoxy)-benzamide Using {4-[3,5-bis-(4-carbamimidoyl phenoxy) benzoylaminojcyclohexyl} carbamic acid tert-butyl ester (0.3 g, 0.51 mmol) and following the procedure of Example 9(d) afforded 0.06 g of the required product. Percentage purity (HPLC): 87.7 %, (LCMS): 94.5 %. 1H NMR (DMSO-d6): δ 1.44 (4H, m), 1.82 (4H, m), 3.05 (2H, m), 7.15 (IH, m), 7.35 (2H, d, J=9.4 Hz), 7.50 (2H, d, J=2.0 Hz), 7.88 (2H, d, J=8.6 Hz), 8.45 (IH, m), 9.11 (4H, brs), 9.25 (4H, brs).
Example 28.
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}- cyclohexylamine
Intermediates (a) to (d) are the same as in Example 27.
e) 4- { 3 ,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexylamine
Using (4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino }- cyclohexyl)-carbamic acid tert-butyl ester (0.3 g, 0.48 mmol) and following the procedure of Example 9(d) afforded 0.06 g of the required product. Percentage purity (HPLC): 96.2 %, (LCMS): 97.2 %. 1H NMR (DMSOd6): δ 1.38 (4H, m), 1.92 (4H, m), 3.02 (2H, m), 3.71 (2H, m), 7.04 (2H, brs), 7.23 (4H, d), 7.44 (2H, s), 7.78 (5H, d), 7.92 (3H, brs), 8.44 (2H, brs), 11.05 (2H, brs).
Example 29. 3-{4-[3,5-Bis-(4- carbamimidoyl -phenoxy)-benzoyl]-piperazin-l-yl}- propylamine
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-l-carboxylic acid tert-butyl ester Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSOd6): δ 1.40 (9H, sm), 3.35 (6H, m), 3.55 (2H, m) 7.02 (2H, d), 7.08 (IH, t), 7.26 (2H, d), 7.88 (2H, d).
d) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine
Following the procedure of Example 9(d) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 0.95 mmol) was used to afford 0.35 g of the required product. 1H NMR (DMSOd6): 5 3.15 (4H, m), 3.45 (4H, m), 7.06 (2H, d), 7.11 (IH, t), 7.26 (4H, d), 7.90 (4H, d), 8.25 (2H, brs).
e) (3 - {4-[3 ,5-Bis-(4-cyano-phenoxy)-benzoyl] -piperazin- 1 -yl } -propyl)-carbamic acid tert-butyl ester
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- piperazine 0.35 g (0.82 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.195 g, 0.82 mmol) were used to afford 0.35 g of the required product. 1H NMR (DMSOd6): δ 1.39 (9H, s), 1.52 (2H, m), 2.35 (8H, m), 2.95 (2H, m), 3.56 (2H, brs), 6.79 (IH, m), 6.90 (2H, d), 7.04 (IH, t), 7.25 (4H, d), 7.88 (4H, d).
f) 3-(4-{3,5-Bis- [4-(ethoxycarbonimidoyl)-phenoxy] -benzoyl } -piperazin- 1 -yl)- propylamine
Using (3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-propyl)-carbamic acid tert-butyl ester (0.35 g, 0.60 mmol) and following the procedure of Example l(d) afforded 0.15 g of the required product. Percentage purity (LCMS): 56.0 %, (M+l) = 573.3.
g) 3-(4-{3,5-Bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-piperazin-l-yl)- propylamine Using 3-(4-{3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl}-piperazin-l-yl)- propylamine (0.15 g, 0.26 mmol) and following the procedure of Example l(e) afforded 0.035 g of the required product. Percentage purity (HPLC): 90.82 %, (LCMS): 91.76 %. 1H NMR (DMSOd6): δ 1.9 (3H, m), 2.85 (3 H, m), 2.8-3.2 (6H, m), 4.4 (2H, m), 7.05 (3H, brs), 7.30 (4H, d), 7.90 (6H, d), 9.1 (3H, brs), 9.30 (4H, s).
Example 30.
3-{4-[3,5-Bis-(4- carbamimidoyl -phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo- propylamine
Intermediates (a) and (b) are the same as in Example 26. Intermediates (c) and (d) are the same as in Example 29.
e) (3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo-propyl)- carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and 4-[3,5-bis-(4- cyano-phenoxy)-benzoyl]-piperazine (0.5 g, 1.09 mmol) and other reagents as described in Example 9(e) were used to afford 0.5 g of the required product. 1H NMR (DMSOd6): δ 1.38 (9H, s), 2.45 (2H, m), 3.14 (2H, m), 3.52 (8H, m), 6.71 (IH, brs), 7.01 (2H, s), 7.08 (IH, t), 7.28 (4H, d), 7.89 (4H, d).
f) 3-{4-[3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoyl]-piperazin-l-yl}-3- oxo-propylamine
Using (3-{4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo-propyl)- carbamic acid tert-butyl ester (0.5 g, 0.83 mmol) and following the procedure of Example l(d) afforded 0.25 g of the required product. Percentage purity (LCMS): 33.3 %, (M+1) = 587.2+1.
g) 3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazin-l-yl}-3-oxo- propylamine Using 3-{4-[3,5-bis- [4-(ethoxycarbonimidoyl)-phenoxy] -benzoyl] -piperazin- 1 -yl } - 3-oxo-propylamine (0.25 g, 0.42 mmol) and following the procedure of Example l(e) afforded 0.06 g of the required product. Percentage purity (HPLC): 98.99 %, (LCMS): 91.36 %. 1H NMR (DMSO-d6): δ 2.1 (3H, m), 2.70 (IH, m), 3.0 (IH, m), 3.15 (3H, brs), 3.75 (3H, m), 7.0 (3H, m), 7.30 (4H, d), 7.8 (2H, m), 7.9 (4H, d), 9.1 (2H, brs), 9.30 (5H, s), 9.45 (IH, m).
Example 31. 2-{4-[3,5-Bis-(4- carbamimidoyl -phenoxy)-benzoyl] -piperazin- l-yl}-ethylamine
Intermediates (a) and (b) are the same as in Example 26. Intermediates (c) and (d) are the same as in Example 29.
e) (2-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-ethyl)-carbamic acid tert-butyl ester
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- piperazine 0.35 g (0.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.183 g, 0.82 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.39 (9H, s), 2.28 (6H, m), 3.04 (2H, m), 3.54 (2H, m), 6.65 (IH, brs), 6.98 (2H, d), 7.05 ( IH, t), 7.25 (4H, d), 7.88 (4H, d).
f) 2- {4- [3 ,5 -Bis- [4-(ethoxycarbonimidoyl)-phenoxy] -benzoyl] -piperazin- 1 -yl } - ethylamine
Using (2-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazin-l-yl}-ethyl)-carbamic acid tert-butyl ester (0.4 g, 0.70 mmol) and following the procedure of Example l(d) afforded 0.2 g of the required product. Percentage purity (LCMS): 79.3 %, (M+l) = 559.2+1.
g) 2- {4- [3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-benzoyl] -piperazin- 1 -yl } -ethylamine Using 2- { 4- [3 ,5 -bis- [4-(ethoxycarbonimidoyl)-phenoxy] -benzoyl] -piperazin- 1 -yl } - ethylamine (0.2 g, 0.35 mmol) and following the procedure of Example l(e) afforded 0.04 g of the required product. Percentage purity (HPLC): 87.99 %, (LCMS): 96.56 %. 1H NMR (DMSOd6): δ 1.1 (3H, t), 3.1 (8H, m), 7.0 (3H, s), 7.30 (4H, d), 7.9 (4H, d), 8.2 (2H, brs), 9.30 (8H, s).
Example 32.
N-[l-(3-Amino-propyl)-piperidin-4-yl]-3,5-bis-(4-carbamimidoyl-phenoxy)- benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid tert- butyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and 4-amino-piperidine-l-carboxylic acid tert-butyl ester (0.252 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSOd6): δ 1.40 (9H, s), 1.75 (2H, m), 2.82 (2H, m), 3.18 (2H, d), 3.92 (3H, m), 7.25 (5H, m), 7.54 (2H, d), 7.88 (4H, d), 38 (IH, brs).
d) 3,5-Bis-(4-cyano-phenoxy)-N-piperidin-4-yl-benzamide
Using 4-[3,5-bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid tert-butyl ester (0.5 g, 0.92 mmol) and following the procedure of Example 9(d) afforded 0.35 g of the required product. 1H NMR (DMSOd6): δ 1.60 (2H, m), 1.95 (2H, m), 3.05 (2H, m), 3.34 (2H, m), 4.08 (IH, brs), 7.24 (5H, d), 7.57 (2H, s), 7.90 (4H, d), 8.60 (IH, brs), 8.74 (IH, brs).
e) (3-{4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidin-l-yl}-propyl)- carbamic acid tert-butyl ester Following procedure of Example l l(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4- yl-benzamide 0.35 g (0.79 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (0.188 g, 0.79 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSOd6): δ 1.38 (9H, s), 1.52 (4H, m), 1.75 (2H, m), 1.90 (2H, m), 2.28 (2H, m), 2.82 (IH, m), 2.92 (2H, m), 3.74 (IH, brs), 3.68 (IH, m), 6.79 (IH, brs), 7.18 (IH, t), 7.26 (4H, d), 7.52 (2H, s), 7.88 (4H, d), 8.38 (IH, d).
f) 3 -(4- { 3 ,5-Bis- [4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino } -piperidin- 1 - yl)-propylamine
Using (3-{4-[3,5 -bis-(4-cyano-phenoxy)-benzoylamino] -piperidin- 1 -yl } -propyl)- carbamic acid tert-butyl ester (0.4 g, 0.67 mmol) and following the procedure of Example l(d) afforded 0.2 g of the required product. Percentage purity (LCMS): 99.0% (M+l) = 587.3+1.
g) 3 - {4- [3 ,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino] -piperidin- 1 -yl } - propylamine
Using 3-(4-{3,5-bis-[4-(ethoxycarbonimidoyl)-phenoxy]-benzoylamino}-piperidin- l-yl)-propylamine (0.2 g, 0.34 mmol) and following the procedure of Example l(e) afforded 0.04 g of the required product. Percentage purity (HPLC): 95.27 %, (LCMS): 95.15 %. 1H NMR (DMSOd6): δ 1.80 (2H, m), 2.0 (4H, m), 2.85 (2H, m), 3.1 (4H, m), 3.5 (2H, d), 4.0 (IH, m), 7.15 (IH, s), 7.30 (4H, d), 7.5 (2H, s), 7.9 (7H, d), 8.65 (IH, d), 9.25 (8H, d), 10.1 (IH, brs).
Example 33.
N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
Intermediates (a), (b) and (c) are the same as in Example 26. d) { 4- [3 ,5 -Bis-(4-aminomethyl-phenoxy)-benzoylamino] -cyclohexyl } -carbamic acid tert-butyl ester
0.05 g of Raney nickel was added to 0.3g (0.54 mmol) of {4-[3,5-bis-(4-cyano- phenoxy)-benzoylamino] -cyclohexyl} -carbamic acid tert-butyl ester stirred with 50 ml of 10 % NH3-methanol. The reaction mixture was stirred overnight on hydrogen gas pressure (50 psi) at 50 °C. The reaction mixture was filtered through celite and concentrated to afford 0.25 g of the required product which was used for the next step without further purification. Percentage purity (LCMS): 70.8 %, (M+l) = 560.2+1
e) N-(4-Amino-cyclohexyl)-3,5-bis-(4-aminomethyl-phenoxy)-benzamide
Using {4-[3,5-bis-(4-aminomethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.25 g, 0.44 mmol) and following the procedure of Example 9(d) afforded 0.03 g of the required product. Percentage purity (HPLC): 98.8 %, (LCMS): 96.0 %. 1H NMR (DMSO-d6): δ 1.37 (4H, m), 1.88 (4H, m), 2.96 (IH, m), 3.70 (IH, m), 4.02 (4H, s), 6.76 (IH, s),7.14 (4H, d), 7.25 (2H, s), 7.51 (4H, d), 7.82 (3H, brs), 8.18 (5H, brs), 8.42 (IH, brs).
Example 34.
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperazine- 1 -carboxylic acid ethyl ester
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperazine-l -carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1 -carboxylic acid tert-butyl ester (0.234 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSOd6): δ 1.18 (3H, t), 3.52 (8H, m), 4.15 (2H, q), 7.00 (2H, s), 7.07 (IH, s), 7.28 (2H, d), 7.88 (2H, d). d) 4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperazine-l- carboxylic acid ethyl ester
Following the procedure of Example 2(d) 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- piperazine-1-carboxylic acid ethyl ester 0.5 g (1.0 mmol) and other reagents were used to afford 0.4 g of the required product. Percentage purity (LCMS): 51.8 %, (M+l) = 562.2+1.
e) 4- { 3 ,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } -piperazine- 1 -carboxylic acid ethyl ester
Following the procedure of Example 2(e) 4-{3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoyl} -piperazine-1-carboxylic acid ethyl ester 0.4 g (0.71 mmol) was used to afford 0.4 g of the required product. Percentage purity (LCMS): 67.6 %, (M+l) = 646.2+1.
f) 4-{3,5-Bis-[4-carbamimidoyl-phenoxy]-benzoyl}-piperazine-l -carboxylic acid ethyl ester
4-{3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } -piperazine- 1 - carboxylic acid ethyl ester 0.4 g (0.61 mmol) was reduced by using the procedure of Example 2(f) to afford 0.15 g of required product. Percentage purity (HPLC): 94.1 %, (LCMS): 92.83 %. 1H NMR (DMSOd6): δ 1.2 (3H, t), 3.4 (8H, m), 4.05 (2H, q), 6.95 (2H, s), 7.35 (4H, d), 7.9 (4H, d), 9.06 (3H, brs), 9.3 (4H, s).
Example 35. l-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
Intermediates (a) and (b) are the same as in Example 26.
c) 1 -[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-quinoline Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and decahydro-quinoline (0.175 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.40 (6H, m), 1.62 (5H, m), 1.82 (IH, m), 3.10 (IH, m), 3.20 (IH, m), 3.91 (IH, m), 4.12 (IH, m), 6.88 (IH, s), 6.95 (IH, s), 7.02 (IH, t), 7.28 (2H, d), 7.88 (2H, d).
d) 1 -[3 ,5-Bis-((N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro-quinoline
Following the procedure of Example 2(d) l-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- nonahydro-quinoline 0.5 g (1.04 mmol) and other reagents were used to afford 0.52 g of the required product. Percentage purity (LCMS): 41.7 %, (M+ 1) = 543.2+1.
e) 1 - [3 , 5 -Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl] -nonahydro- quinoline
Following the procedure of Example 2(e) l-[3,5-bis-((N-hydroxycarbamimidoyl)- phenoxy)-benzoyl]-nonahydro-quinoline 0.5 g (0.91 mmol) was used to afford 0.45 g of the required product. Percentage purity (LCMS): 63.0 %, (M+l) = 627.2+1.
f) 1 -[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-quinoline
l-[3,5-Bis-((N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro- quinoline, 0.45 g (0.71 mmol) was reduced using the procedure of Example 2(f) to afford 0.2 g of required product. Percentage purity (HPLC): 95.37 %, (LCMS): 93.43 %. 1H NMR (DMSO-d6): δ 1.7 (1 IH, m), 1.85 (IH, m), 3.20 (2H, m), 3.9 (IH, m), 4.05 (IH, m), 6.84 (IH, brs), 6.9 (IH, brs), 7.0 (IH, s), 7.54 (4H, d), 7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 36. 3,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
Intermediates (a) and (b) are the same as in Example 26. c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and diisobutyl-amine (0.29 g, 2.24 mmol) were used to afford 0.74 g of the required product. 1H NMR (DMSOd6): δ 0.72 (6H, d), 0.88 (6H, d), 1.82 (IH, m), 2.00 (IH, m), 3.06 (2H, d), 3.24 (2H, d), 6.98 (2H, d), 7.04 (IH, t), 7.22 (4H, d), 7.89 (4H, d).
d) 3,5-Bis-[4-(ethoxycarbonimidoyl)-phenoxy]-N,N-diisobutyl-benzamide
Using 3,5-bis-(4-cyano-phenoxy)-N,N-diisobutyl-benzamide (0.74 g, 1.58 mmol) and following the procedure of Example l(d) afforded 0.8 g of the required product. Percentage purity (LCMS): 52.8 %, (M+l) = 559.3+1.
e) 3 ,5-Bis-(4-carbamimidoyl-phenoxy)-N,N-diisobutyl-benzamide
Using 3 , 5 -bis- [4-(ethoxycarbonimidoyl)-phenoxy] -N,N-diisobutyl-benzamide (0.8 g, 0.1.42 mmol) and following the procedure of Example l(e) afforded 0.36 g of the required product. Percentage purity (HPLC): 97.51 %, (LCMS): 97.48 %. 1H NMR
(DMSO-d6): δ 0.7 (6H, s), 0.80 (6H, s), 1.8 (IH, m), 2.0 (IH, m), 3.1 (2H, d), 3.2 (2H, d), 6.9 (2H, d), 7.0 (IH, s), 7.3 (4H, d), 7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 37. 2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
Intermediates (a) and (b) are the same as in Example 26.
c) 2-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-nonahydro-isoquinoline
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and decahydro-isoquinoline (0.467 g, 3.36 mmol) were used to afford 1.25 g of the required product. 1H NMR (DMS0-d6): δ 1.30 (5H, m), 1.62 (5H, m), 1.85 (IH, m), 3.05 (IH, m), 3.18 (IH, m), 3.51 (IH, m), 3.90 (IH, m), 4.12 (IH, m), 6.86 (IH, s), 6.95 (IH, s), 7.04 (IH, t), 7.26 (2H, d), 7.86 (2H, d).
d) 2-[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro- isoquinoline
Following the procedure of Example 2(d) 2-[3,5-bis-(4-cyano-phenoxy)-benzoyl]- nonahydro-isoquinoline 1.25 g (2.61 mmol) and other reagents were used to afford 1.3 g of the required product. Percentage purity (LCMS): 80.0 %, (M+l) = 543.2+1.
e) l-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro- isoquinoline
Following the procedure of Example 2(e) 2-[3,5-bis-(4-(N-hydroxycarbamimidoyl)- phenoxy)-benzoyl]-nonahydro-isoquinoline 1.3 g (2.39 mmol) was acetylated to afford 1.2 g of the required product. Percentage purity (LCMS): 70.0 %, (M+l) = 627.2+1.
f) 2-[3,5-Bis-(4-carbanimidoyl-phenoxy)-benzoyl]-nonahydro-isoquinoline
2-[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-benzoyl]-nonahydro- isoquinoline, 1.2 g (1.91 mmol) was reduced using the procedure of Example 2(f) to afford 0.4 g of required product. Percentage purity (HPLC): 95.37 %, (LCMS): 93.43 %. 1H NMR (DMSOd6): δ 1.7 (HH, m), 1.85 (IH, m), 3.20 (2H, m), 3.9 (IH, m), 4.05 (IH, m), 6.84 (IH, brs), 6.9 (IH, brs), 7.0 (IH, s), 7.54 (4H, d), 7.88 (4H, d), 9.12 (4H, s), 9.28 (4H, s).
Example 38.
3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-N,N-diethyl-benzamide
Intermediates (a) and (b) are same as in Example 26. c) 3,5-Bis-(4-cyano-phenoxy)-N,N-diethyl-benzamide
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and diethyl-amine (0.245 g, 3.36 mmol) were used to afford 1.0 g of the required product. 1H NMR (DMSO-d6): δ 1.15 (6H, m), 3.22 (2H, m), 3.40 (2H, m), 6.94 (2H, d), 7.05 (IH, t), 7.25 (2H, d), 7.88 (2H, d).
d) N,N-Diethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzamide
Following the procedure of Example 2(d) N,N-diethyl-3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzamide 1.0 g (2.43 mmol) and other reagents were used to afford 1.1 g of the required product. Percentage purity (LCMS): 80.0 %, (M+l) = 477.2+1.
e) N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamide
Following the procedure of Example 2(e) N,N-diethyl-3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzamide 1.1 g (2.3 mmol) was acetylated to afford 1.0 g of the required product. Percentage purity (LCMS): 77.0 %, (M+l) = 561.2+1.
f) 3,5-Bis-(4-carbonimidoyl-phenoxy)-N,N-diethyl-benzamide
N,N-Diethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamide, 1.0 g (1.78 mmol) was reduced using the procedure of Example 2(f) to afford 0.35 g of required product. Percentage purity (HPLC): 95.41 %, (LCMS): 93.34 %. 1H NMR (DMSOd6): δ 1.02 (6H, s), 3.2 (2H, m), 3.4 (2H, m), 6.9 (2H, d), 7.0 (IH, s), 7.3 (4H, d), 7.88 (4H, d), 9.24 (3H, s), 9.30 (3H, s).
Example 39. N-(3 - Amino-propyl)-3 ,5 -bis-(4-carbamimidoyl-phenoxy)-N-cyclopropyl- benzamide Intermediates (a) and (b) are the same as in Example 26.
c) (3-{[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-cyclopropyl-amino}-propyl)-carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and (3-cyclopropylamino-propyl)-carbamic acid tert-butyl ester (0.72 g, 3.36 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSOd6): δ 0.48 (IH, m), 0.65 (2H, m), 1.38 (9H, s), 1.42 (2H, m), 1.68 (2H, m), 2.95 (2H, m), 3.22 (2H, m), 6.80 (IH, brs), 6.95 (IH, s), 7.08 (2H, m), 7.25 (4H, m), 7.88 (4H, m).
d) [3 -( { 3 , 5 -Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoyl } -cyclopropyl- amino)-propyl]-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) (3-{[3,5-bis-(4-cyano-phenoxy)-benzoyl]- cyclopropyl-amino}-propyl)-carbamic acid tert-butyl ester 1.5 g (2.71 mmol) and other reagents were used to afford 1.3 g of the required product. Percentage purity (LCMS): 42.8.0 %, (M+l) = 618.2 (with BOC).
e) [3-({3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } - cyclopropyl-amino)-propyl]-carbamic acid tert-butyl ester
Following the procedure of Example 2(e) [3-({3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoyl } -cyclopropyl-amino)-propyl] -carbamic acid tert- butyl ester 1.3 g (2.1 mmol) was acetylated to afford 1.25 g of the required product. Percentage purity (LCMS): 83.0 %, (M+l) = 702.3.
f) [3-({3,5-Bis- [4-(carbamimidoyl)-phenoxy] -benzoyl } -cyclopropyl-amino)- propyl] -carbamic acid tert-butyl ester
[3-({3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } -cyclopropyl- amino)-propyl]-carbamic acid tert-butyl ester, 1.25 g (1.77 mmol) was reduced using the procedure of Example 2(f) to afford 0.85 g of the required product. Percentage purity (LCMS): 72.0 %, (M+l) = 486.3+1 (de-Boc mass; -100).
g) 3,5-Bis-(4-carbamimidoyl-phenoxy)-cyclohexa-l,5-dienecarboxylic acid (3- amino-propyl)-cyclopropyl-amide
Using [3-({3,5-bis-[4-(carbamimidoyl)-phenoxy]-benzoyl}-cyclopropyl-amino)- propyl]-carbamic acid tert-butyl ester (0.85 g, 1.44 mmol) and following the procedure of Example 9(d) afforded 0.2 g of the required product. Percentage purity (HPLC): 96.18 %, (LCMS): 94.22 %. 1H NMR (DMSOd6): δ 0.50 (2H, m), 0.65 (2H, m), 1.88 (2H, m), 2.85 (3 H, m), 3.49 (2H, m), 7.02 (IH, t), 7.14 (2H, s), 7.25 (4H, d), 7.80 (2H, brs), 7.88 (4H, d), 9.22 (3H, s), 9.28 (3H, s).
Example 40. [3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-dihydro-lH-quinoline
Intermediates (a) and (b) are the same as in Example 26.
c) [3 ,5-Bis-(4-cyano-phenoxy)-benzoyl]-3,4-dihydro- 1 H-quinoline
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and 1,2,3,4-tetrahydro-quinoline (0.44 g, 3.36 mmol) were used to afford 1.3 g of the required product. 1H NMR (DMSOd6): δ 1.92 (2H, t), 2.54 (2H, m), 3.75 (2H, t), 6.92 (2H, d), 7.08 (7H, m), 7.82 (4H, d).
d) [3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydro-lH- quinoline
Following the procedure of Example 2(d) [3,5-bis-(4-cyano-phenoxy)-benzoyl]-3,4- dihydro-1 H-quinoline 1.3 g (2.75mmol) and other reagents were used to afford 1.25 g of the required product. Percentage purity (LCMS): 66.1 %, (M+l) = 537.2.2+1. e) [3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoyl]-3,4-Dihydro- lH-quinoline
Following the procedure of Example 2(e) [3,5-bis-[4-(N-hydroxycarbamimidoyl)- phenoxy]-benzoyl]-3,4-Dihydro-lH-quinoline 1.25 g (2.32 mmol) was acetylated to afford 1.2 g of the required product. Percentage purity (LCMS): 65.5 %, (M+l) = 621.2+1.
f) [3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-3,4-Dihydro-lH-quinoline
[3 ,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl] -3 ,4-dihydro- 1 H- quinoline, 1.2 g (1.93 mmol) was reduced using the procedure of Example 2(f) to afford 0.75 g of required product. Percentage purity (HPLC): 99.56 %, (LCMS): 96.29 %. 1H NMR (DMSO-d6): δ 1.92 (2H, q), 2.74 (2H, t), 3.75 (2H, t), 6.85 (IH, brs), 6.90 (2H, d), 6.98 (IH, t), 7.15 (7H, m), 7.84 (4H, d), 9.14 (4H, s), 9.26 (4H, s).
Example 41.
[3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-carbamimidoyl-phenoxy)- benzene
Intermediates (a) and (b) are the same as in Example 26.
c) [3,4-Dihydro- 1 H-isoquinoline-2-carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benzene
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.8 g (2.24 mmol) and 1,2,3,4-tetrahydro-isoquinoline (0.3 g, 2.26 mmol) were used to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 2.82 (2H, m), 3.58 (IH, m), 3.80 (IH, m), 4.08 (IH, m), 4.74 (IH, m), 7.10 (3H, m), 7.20 (4H, m), 7.28 (4H, d), 7.90 (2H, d).
d) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-hydroxy- carbamimidoyl)-phenoxy)-benzene Following the procedure of Example 2(d) [3,4-dihydro-lH-isoquinoline-2- carbonyl]-3,5-Bis-(4-cyano-phenoxy)-benzene 0.9 g (1.9 mmol) and other reagents were used to afford 0.85 g of the required product. Percentage purity (LCMS): 38.9 %, (M+l) = 537.0+1.
e) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-(N-acetylhydroxy- carbamimidoyl)-phenoxy)-benzene
Following the procedure of Example 2(e) [3,4-dihydro-lH-isoquinoline-2- carbonyl]-3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-benzene 0.85 g (1.58 mmol) was acetylated to afford 0.8 g of the required product. Percentage purity (LCMS): 58.1 %, (M+l) = 621.2+1.
f) [3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-Bis-(4-carbamimidoyl-phenoxy)- benzene
[3,4-Dihydro-lH-isoquinoline-2-carbonyl]-3,5-bis-(4-(N-acetylhydroxy- carbamimidoyl)-phenoxy)-benzene, 0.8 g (1.28 mmol) was reduced using the procedure of Example 2(f) to afford 0.15 g of required product. Percentage purity (HPLC): 93.50 %, (LCMS): 94.20 %. 1H NMR (DMSOd6): δ 2.80 (2H, m), 3.60 (IH, m), 3.80 (IH, m), 4.67 (2H, m), 6.98 (2H, m), 7.05 (IH, s), 7.18 (4H, m), 7.35 (4H, d), 7.90 (4H, d), 9.10 (4H, brs), 9.28 (3H, brs).
Example 42.
N-(4-Amino cyclohexyl)-3-(3-carbamimidoyl benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
a) 3-(4-Cyano phenoxy)-5 -hydroxy benzoic acid ethyl ester
Potassium carbonate 6.7g(48.5mmol) followed by 4-fluoro benzonitrile 3.3 g (27.2 mmol) in 10 ml of DMF was added to a solution of 3,5-dihydroxy benzoic acid ethyl ester 5 g (27.4mmol) in 20 ml of DMF at 20 °C. The reaction mixture was allowed to attain RT and was then heated to 45 °C for 1O h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated. The crude compound was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 1.15 g of the required product. 1H NMR (DMSOd6): δ 1.3 (3H, t), 4.3 (2H, q), 6.76 (IH, s), 7.02 (IH, s), 7.36 (2H, d), 7.24 (IH, s), 7.88 (2H, d), 10.3 (IH, s).
b) 3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester
Potassium carbonate K2CO30.44 g(3.18mmol) followed by 3-cyano benzylbromide 0.31 g (1.58 mmol) in 2 ml of DMF were added to a solution of 3-(4-cyano phenoxy)-5- hydroxy benzoic acid ethyl ester 0.45 g (1.58 mmol) in 7 ml of DMF at 20 °C. The reaction mixture was allowed to attain RT and stirred overnight. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated to afford 0.51 g of a thick oily liquid. 1H NMR (CDCl3): δ 1.3 (3H, t), 4.3 (2H, q), 5.25 (2H, s), 6.88 (IH, s), 7.02 (2H, d), 7.34 (IH, s), 7.5 (2H, m), 7.66 (4H, m), 7.78 (IH, s).
c) 3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
1.6 g (4.01 mmol) of 3-(3-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 5.25 (2H, s), 7.16 (4H, m), 7.44 (IH, s), 7.64 (IH, m), 7.9 (5H, m), 13.4 (IH, brs).
d) {4-[3-(3-Cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}- carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(3-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.46 g (1.24 mmol) and (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (0.265 g, 1.24 mmol) were used to afford 0.52 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.25 (2H, s), 6.74 (IH, d), 7.02 (IH, s), 7.32 (2H, d), 7.22 (IH, s), 7.44 (IH, s), 7.64 (IH, m), 7.84 (4H, m), 7.95 (IH, s), 8.3 (IH, d).
e) 4-[3-(3 -ethoxycarbonimidoyl-benzyloxy)-5 -(4-ethoxycarbonimidoyl- phenoxy)benzoyl amino] cyclohexylamine
Using {4-[3-(3-cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}- carbamic acid tert-butyl ester (0.5 g, 0.88 mmol) and following the procedure of
Example l(d) afforded 0.3 g of the required product. Percentage purity (LCMS): 64.2 %, (M+1) = 558.2+1.
f) N-(4-Amino cyclohexyl)-3-(3-carbamimidoyl benzyloxy)-5-(4-carbamimidoyl- phenoxy) benzamide
Using 4-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl phenoxy)benzoyl amino] cyclohexylamine (0.3 g, 0.53 mmol) and following the procedure as in Example l(e) afforded 0.16 g of the required product. Percentage purity (HPLC): 96.67 %, (LCMS): 99.51 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 5.30 (2H, s), 7.0 (IH, s), 7.2 (3H, d), 7.45 (IH, s), 7.70 (IH, m), 7.8-8.0 (7H, m), 8.4 (IH, d), 9.25 (4H, d), 9.4 (4H, d).
Example 43. N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester Using 0.66 g (2.3 mmol) of 3-(4-cyano phenoxy)-5 -hydroxy benzoic acid ethyl ester and 4-cyanobenzylbromide (0.45 g, 2.3 mmol) and following the procedure of Example 42(b) afforded 0.72 g of the required product. 1H NMR (DMSOd6): δ 1.3 (3H, t), 4.3 (2H, q), 5.35 (2H, s), 7.16 (4H, m), 7.44 (IH, s), 7.66 (2H, s), 7.88 (4H, d).
c) 3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid
0.72 g (1.8 mmol) of 3-(4-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 0.55 g of the required product. 1H NMR (DMSOd6): δ 5.25 (2H, s), 7.10 (IH, m), 7.18 (3H, m), 7.42 (IH, s), 7.66 (2H, s), 7.88 (4H, d).
d) {4-[3-(4-Cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl} carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.55 g (1.48 mmol) and (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (0.316 g, 1.48 mmol) were used to afford 0.75 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.3 (2H, s), 6.74 (IH, d), 7.02 (IH, s), 7.1 (2H, s), 7.22 (IH, s), 7.44 (IH, s), 7.66 (2H, d), 7.88 (4H, m), 8.28 (IH, d).
e) 4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl-phenoxy)- benzoyl amino] cyclohexylamine
Using {4-[3-(4-cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino]- cyclohexyl} carbamic acid tert-butyl ester (0.75 g, 1.32 mmol) and following the procedure of Example l(d) afforded 0.35 g of the required product. Percentage purity (LCMS): 33.7 %, (M+l) = 558.2+1.
f) N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl- phenoxy) benzamide Using 4-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy carbonimidoyl- phenoxy)-benzoylamino]cyclohexylamine (0.35 g, 0.62 mmol) and following the procedure of Example l(e) afforded 0.12 g of the required product. Percentage purity (HPLC): 91.03 %, (LCMS): 96.32 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 5.30 (2H, s), 7.0 (IH, s), 7.2 (3H, d), 7.45 (IH, s), 7.70 (2H, d), 7.9 (6H, m), 8.4 (IH, m), 9.3 (7H, t).
Example 44. N-(4- Amino-cyclohexyl)-3 - [4-(N-hydroxycarbamimidoyl)-benzyloxy] -5 - [4-(N- hydroxycarbamimidoyl)-phenoxy]-benzamide
Intermediates (a) to (d) are the same as in Example 43.
e) (4-{3-[4-(N-Hydroxycarbamimidoyl)-benzyloxy]-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-cyano benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester 0.65 g (1.14 mmol) and other reagents were used to afford 0.52 g of the required product. Percentage purity (LCMS): 48.2 %, (M+l) = 632.3+1.
f) N-(4- Amino-cyclohexyl)-3 - [4-(N-hydroxycarbamimidoyl)-benzyloxy] -5 - [4-(N- hydroxycarbamimidoyl)-phenoxy]-benzamide
Using (4- { 3 - [4-(N-hydroxycarbamimidoyl)-benzyloxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.5 g, 0.8 mmol) and following the procedure of Example 9(d) afforded 0.28 g of the required product. Percentage purity (HPLC): 96.4 %, (LCMS): 96.7 %. 1H NMR (DMSO-d6): δ 1.48 (4H, m), 1.98 (4H, m), 3.04 (IH, m), 3.76 (IH, m), 5.42 (2H, s),
7.05 (IH, s), 7.24 (3H, m), 7.48 (2H, m), 7.70 (2H, d), 7.81 (4H, d), 7.91 (3H, brs), 8.42 (IH, d), 8.72 (2H, brs), 11.04 (2H, brs). Example 45.
N-(4-Aminocyclohexyl)-3-(4-aminomethyl benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester
Using 0.85 g (3.0 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and (4-bromomethyl-benzyl)-carbamic acid tert-butyl ester (0.9 g, 3.0 mmol) and following the procedure of Example 42(b) afforded 1.32 g of the required product. 1H NMR (CDCl3): δ 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d), 4.3 (2H, q), 5.25 (2H, s), 7.18 (4H, m), 7.26 (2H, d), 7.4 (4H, m), 7.88 (2H, d).
c) 3-(4-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid
1.3 g (2.58 mmol) of 3-(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4- cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.1 g.of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 4.15 (2H, d), 5.2 (2H, s), 7.08 (IH, m), 7.16 (3H, m), 7.26 (2H, d), 7.88 (2H, d), 13.2 (IH, brs)
d) {4-[3-(4-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid 1.1 g (2.31 mmol) and (4-amino- cyclohexyl)-carbamic acid tert-butyl ester (0.494 g, 2.31 mmol) were used to afford 1.24 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 4.1 (2H, d), 5.15 (2H, s), 6.74 (IH, d), 6.88 (IH, s), 7.12 (2H, d), 7.18 (IH, s), 7.26 (2H, d), 7.4 (4H, d), 7.86 (2H, d), 8.26 (IH, d).
e) 4- [3 -(4- Amino cyclohexylcarbamoyl)-5-(4-aminomethyl benzyloxy) phenoxyjbenzimidic acid ethyl ester
Using {4-[3-(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)benzoyl amino]cyclohexyl}carbamic acid tert-butyl ester (1.2 g, 1.78 mmol) and following the procedure of Example l(d) afforded 0.5 g of the required product. Percentage purity (LCMS): 52.0 %, (M+ 1) = 516.2 + 1.
f) N-(4-Aminocyclohexyl)-3-(4-aminomethylbenzyloxy)-5-(4-carbamimidoyl- phenoxy) benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-aminomethyl benzyloxy) phenoxyjbenzimidic acid ethyl ester (0.5 g, 0.96 mmol) and following the procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity (HPLC): 96.46 %, (LCMS): 98.41 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 3.0 (IH, m), 4.1 (3H, s), 5.20 (2H, s), 7.0 (IH, s), 7.2 (3H, m), 7.5 (5H, m), 7.85 (4H, m), 8.25 (2H, brs), 8.4 (IH, d), 9.2 (4H, s).
Example 46.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 45.
e) (4- { 3 - [4-(tert-Butoxycarbonylamino-methyl)-benzyloxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-(tert-butoxycarbonylamino- methyl)benzyloxy)-5-(4-cyanophenoxy)benzoylamino] cyclohexyl}carbamic acid tert- butyl ester 0.6 g (0.89 mmol) and other reagents were used to afford 0.55 g of the required product. Percentage purity (LCMS): 38.9 %, (M+l) = 703.3+1.
g) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzamide
Using (4-{3-[4-(tert-butoxycarbonylamino-methyl)-benzyloxy]-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.55 g, 0.78 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 96.9 %, (LCMS): 92.4 %. 1H NMR
(DMSOd6): δ 1.40 (4H, m), 1.90 (4H, m), 3.00 (IH, m), 3.71 (IH, m), 4.15 (2H, s), 5.18 (2H, s), 6.98 (IH, s), 7.16 (3H, m), 7.40 (IH, s), 7.50 (4H, m), 7.76 (2H, d), 7.90 (3H, brs), 8.30 (4H, brs), 8.65 (IH, brs), 11.25 (IH, brs).
Example 47.
N-(4- Aminocyclohexyl)-3 -(3 -aminomethyl benzyloxy)-5 -(4-carbamimidoyl phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(3-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid ethyl ester
Using 1.4 g (4.94 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and (3-bromomethyl-benzyl)-carbamic acid tert-butyl ester (1.48 g, 4.94 mmol) and following the procedure of Example 42(b) afforded 1.9 g of the required product. 1H NMR (DMSOd6): δ 1.3 (3H, t), 1.4 (9H, s), 4.15 (2H, d), 4.35 (2H, q), 5.25 (2H, s), 7.18 (5H, m), 7.32 (3H, m), 7.44 (2H, s), 7.88 (2H, d).
c) 3-(3-(tert-Butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid 1.9 g (3.78 mmol) of 3-(3-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4- cyano phenoxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.35 g of the required product. 1H NMR (DMSOd6): δ 1.4 (9H, s), 4.05 (2H, s), 5.2 (2H, s), 7.1 (5H, m), 7.3 (5H, m), 7.9 (2H, m), 13.2 (IH, brs)
d) {4-[3-(3-(tert-Butoxycarbonylaminomethyl)benzyloxy)-5-(4-cyano phenoxy)- benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(3-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.65 g (1.36 mmol) and (4-amino- cyclohexyl)-carbamic acid tert-butyl ester (0.29 g, 1.36 mmol) were used to afford 0.7 g of the required product. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 4.1 (2H, d), 5.15 (2H, s), 6.74 (IH, d), 6.9 (IH, s), 7.10 (2H, d), 7.2 (2H, m), 7.35 (3H, m), 7.45 (2H, m), 7.86 (2H, d), 8.26 (IH, d).
e) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(3-aminomethyl benzyloxy) phenoxy]benzimidic acid ethyl ester
Using {4-[3-(3-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy)benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester (0.7 g, 1.04 mmol) and following the procedure of Example l(d) afforded 0.3 g of the required product. Percentage purity (LCMS): 98.0 %, (M+l) = 703.3+1.
f) N-(4-Amino cyclohexyl)-3 -(3 -aminomethyl benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-aminomethyl benzyloxy) phenoxy] benzimidic acid ethyl ester (0.3 g, 0.58 mmol) and following the procedure of Example l(e) afforded 0.12 g of the required product. Percentage purity (HPLC): 97.76 %, (LCMS): 92.64 %. 1H NMR (DMSOd6): δ 1.35 (4H, m), 1.9 (4H, m), 3.0 (2H, m), 4.1 (2H, d), 5.20 (2H, s), 7.0 (IH, s), 7.2 (3H, m), 7.45 (3H, m), 7.55 (IH, s), 7.85 (4H, m), 8.2 (2H, brs), 8.35 (IH, d), 9.0 (2H, s), 9.25 (2H, s). Example 48.
N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 47.
e) (4- { 3 - [3 -(tert-Butoxycarbonylamino-methyl)-benzyloxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(3-(tert-butoxycarbonylamino- methyl)benzyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl} carbamic acid tert- butyl ester 0.65 g (0.97 mmol) and other reagents were used to afford 0.6 g of the required product. Percentage purity (LCMS): 38.9 %, (M+l) = 503.3+1 (de-Boc; 2 x 100).
f) N-(4-Amino-cyclohexyl)-3-(3-aminomethyl-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Using (4- { 3 - [3 -(tert-butoxycarbonylamino-methyl)-benzyloxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 0.85 mmol) and following the procedure of Example 9(d) afforded 0.2 g of the required product. Percentage purity (HPLC) : 98.8 %, (LCMS) : 94.1 %. 1H NMR (DMSOd6): δ 1.4 (4H, m), 1.82 (4H, m), 3.03 (IH, m), 3.65 (IH, m), 4.10 (3H, brs), 5.18 (2H, s), 6.98 (IH, s), 7.18 (3H, d), 7.4 (IH, s), 7.46 (3H, m), 7.55 (IH, s), 7.76 (2H, d), 7.88 (3H, brs), 8.25 (3H, brs), 8.38 (IH, d), 11.10 (IH, brs).
Example 49.
N-(4-Amino cyclohexyl)-3-(3-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediate (a) is the same as in Example 42. b) 3-(4-Cyano phenoxy)-5 -hydroxy benzoic acid
1.2 g (4.23 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester was hydro lysed using the procedure of Example 5(b) to afford 0.95 g of the required product. 1H NMR (DMSOd6): δ 6.75 (IH, s), 7.0 (IH, s), 7.15 (2H, d), 7.25 (IH, s), 7.85 (2H, d), 10.2 (IH, s), 13.2 (lH, brs).
c) {4-[3-(4-Cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 3.52 mmol) were used to afford 0.6 g of the required product. H NMR (DMSOd6): δ 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.15 (IH, m), 3.7 (IH, m), 6.62 (IH, s), 6.76 (IH, d), 7.04 (IH, s), 7.16 (3H, m), 7.86 (2H, m), 8.2 (IH, d), 10.0 (IH, s).
d) {4-[3-(3 -bromo-benzyloxy)-5 -(4-cyano-phenoxy)benzoylamino] -cyclohexyl } - carbamic acid tert-butyl ester
Using 0.6 g (1.32 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl} carbamic acid tert-butyl ester and l-bromo-3-bromomethyl-benzene (0.33 g, 1.32 mmol) and following the procedure of Example 42(b) afforded 0.7 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.2 (2H, s), 6.76 (IH, d), 7.0 (IH, s), 7.12 (2H, d), 7.2 (IH, s), 7.44 (3H, m), 7.56 (IH, d), 7.68 (IH, s), 7.84 (2H, d), 8.3 (IH, d).
e) 4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy)phenoxy]- benzimidic acid ethyl ester
Using {4-[3-(3-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino]- cyclohexyl} -carbamic acid tert-butyl ester (0.7 g, 1.12 mmol) and following the procedure of Example l(d) afforded 0.35 g of the required product. Percentage purity (LCMS): 59.0 %, (M+l) = 503.3+1.
f) N-(4-Amino cyclohexyl)-3-(3-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexyl-carbamoyl)-5-(3-bromobenzyloxy) phenoxy]- benzimidic acid ethyl ester (0.35 g, 0.61 mmol) and following the procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity (HPLC): 98.8 %, (LCMS): 96.6 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.92 (4H, m), 3.02 (IH, m), 3.71 (IH, m), 5.20 (2H, s), 7.02 (IH, s), 7.14 (IH, s), 7.21 (2H, d), 7.42 (3H, m), 7.58 (IH, d), 7.68 (IH, s), 7.88 (4H, d), 8.35 (IH, d), 9.12 (2H, brs), 9.26 (2H, brs).
Example 50. N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 49.
e) (4-{3-(3 -Bromo-benzyloxy)-5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(3-bromo-benzyloxy)-5-(4-cyano- phenoxy)benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.58 g (0.93 mmol) and other reagents were used to afford 0.6 g of the required product. Percentage purity (LCMS): 48.2 %, (M+l) = 653.2+1.
f) N-(4-Amino-cyclohexyl)-3-(3-bromo-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Using (4- { 3 -(3 -bromo-benzyloxy)-5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] - benzoylarnino}-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 0.91 mmol) and following the procedure of Example 9(d) afforded 0.35 g of the required product. Percentage purity (HPLC): 98.4 %, (LCMS): 97.2 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.90 (4H, m), 3.00 (IH, m), 3.70 (IH, m), 5.18 (2H, s), 6.98 (IH, m), 7.11 (IH, s), 7.18 (2H, d), 7.42 (3H, m), 7.52 (IH, d), 7.68 (IH, s), 7.78 (2H, d), 7.90 (3H, brs), 8.36 (IH, d), 8.85 (IH, brs), 11.15 (IH, brs).
Example 51.
N-(4- Amino cyclohexyl)-3-(4-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) { 4- [3 -(4-bromo-benzyloxy)-5 -(4-cyano-phenoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester
Using 1.3 g (2.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl} carbamic acid tert-butyl ester and l-bromo-4-bromomethyl-benzene (0.72 g, 2.88 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the required product. 1H NMR (DMSOd6): δ 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.2 (2H, s), 6.78 (IH, d), 6.88 (IH, s), 7.12 (2H, d), 7.2 (IH, s), 7.4 (3H, s), 7.6 (2H, d), 7.86 (2H, d), 8.28 (IH, d).
e) 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromo benzyloxy)phenoxy]- benzimidic acid ethyl ester
Using {4-[3-(4-bromo-benzyloxy)-5-(4-cyano-phenoxy)benzoylamino] cyclohexyl} -carbamic acid tert-butyl ester (0.85 g, 1.36 mmol) and following the procedure of Example l(d) afforded 0.7 g of the required product. Percentage purity (LCMS): 68.08 %, (M+l) = 565.1+1.
f) N-(4-Amino cyclohexyl)-3-(4-bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzamide Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromo benzyloxy) phenoxy]- benzimidic acid ethyl ester (0.7 g, 1.23 mmol) and following the procedure of Example l(e) afforded 0.32 g of the required product. Percentage purity (HPLC): 98.39 %, (LCMS): 99.72 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.85(2H, m), 1.95 (2H, m), 3.0 (IH, m), 3.70 (IH, m), 5.20 (2H, s), 7.0 (IH, s), 7.2 (3H, s), 7.45 (3H, d), 7.6 (2H, d), 7.9 (5H, m), 8.36 (IH, d), 9.26 (4H, d).
Example 52. N-(4-Amino-cyclohexyl)-3-(4-bromo-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) to (d) are the same as in Example 51.
e) (4-{3-(4-Bromo-benzyloxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]- benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-bromo-benzyloxy)-5-(4-cyano- phenoxy)benzoylamino]cyclohexyl}-carbamic acid tert-butyl ester 0.6 g (0.96 mmol) and other reagents were used to afford 0.45 g of the required product. Percentage purity (LCMS): 38.9 %, (M+l) = 652.2+1.
f) N-(4-Amino-cyclohexyl)-3-(4-bromo-benzyloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Using (4- { 3 -(4-bromo-benzyloxy)-5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.45 g, 0.68 mmol) and following the procedure of Example 9(d) afforded 0.21 g of the required product.
Percentage purity (HPLC): 97.9 %, (LCMS): 98.5 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.92 (4H, m), 3.00 (IH, m), 3.70 (IH, m), 5.18 (2H, s), 6.96 (IH, m), 7.18 (3H, m),
7.42 (3H, d), 7.61 (2H, d), 7.76 (2H, d), 7.90 (3H, brs), 8.36 (IH, d), 8.85 (2H, brs),
11.14 (IH, brs). Example 53.
N-(4-Amino cyclohexyl)-3-(6-bromo pyridine-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(6-bromopyridine-3-ylmethoxy)-5-(4-cyanophenoxy)benzoylamino]- cyclohexyl}carbamic acid tert-butyl ester
Using 1.4 g (3.1 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester and 2-bromo-5-bromomethyl-pyridine (0.77 g, 3.1 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the required product. 1H NMR (DMSOd6): δ 1.20 (4H, m), 1.40 (9H, s), 1.80 (4H, m), 3.2 (IH, m), 3.70 (IH, m), 5.25 (2H, s), 6.75 (IH, d), 7.0 (IH, s), 7.15 (2H, d), 7.22 (IH, s), 7.45 (IH, s), 7.7 (IH, d), 7.85 (3H, m), 8.3 (IH, d), 8.5 (IH, s).
e) 4-[3-(4-aminocyclohexylcarbamoyl)-5-(6-bromopyridine-3-ylmethoxy) phenoxy] benzimidic acid ethyl ester
Using {4-[3-(6-bromopyridine-3-ylmethoxy)-5-(4-cyanophenoxy)benzoyl amino]- cyclohexyl}carbamic acid tert-butyl ester (0.9 g, 1.44 mmol) and following the procedure of Example l(d) afforded 0.54 g of the required product. Percentage purity (LCMS): 68.08 % (M+l) = 566.1+1.
f) N-(4-Amino cyclohexyl)-3-(6-bromo pyridine-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-bromo benzyloxy) phenoxy]- benzimidic acid ethyl ester (0.54 g, 0.95 mmol) and following the procedure of Example l(e) afforded 0.14 g of the required product. Percentage purity (HPLC): 95.76 %, (LCMS): 99.15 %. 1H NMR (DMSO-d6): δ 1.40 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 5.2 (2H, s), 7.0 (IH, s), 7.2 (3H, m), 7.4 (IH, s), 7.7 (IH, d), 7.9 (5H, m), 8.4 (IH, d), 8.5 (IH, d), 9.2 (2H, s), 9.3 (2H, s).
Example 54. N-(4-Amino cyclohexyl)-3-(6-amino pyridin-3-ylmethoxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {5-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester and (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.76 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 1.42 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (27H, s), 1.8 (4H, m), 3.20 (IH, m), 3.75 (IH, m), 5.25 (2H,s), 6.75 (IH, d), 7.05 (IH, s), 7.15 (2H, d), 7.2 (IH, s), 7.45 (2H, m), 7.85 (2H, d), 7.95 (IH, d), 8.25 (IH, d), 8.5 (IH, s).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)- phenoxyj-benzimidic acid ethyl ester
Using {5-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxymethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (1.4 g, 2.12 mmol) and following the procedure of Example l(d) afforded 0.64 g of the required product. Percentage purity (LCMS): 83.8 %, (M+l) = 566.1+1.
f) N-(4-Amino cyclohexyl)-3-(6- amino pyridine-3-ylmethoxy)-5-(4- carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(6-amino-pyridin-3-ylmethoxy)- phenoxy]-benzimidic acid ethyl ester (0.64 g, 1.27 mmol) and following the procedure of Example l(e) afforded 0.14 g of the required product. Percentage purity (HPLC): 96.58 %, (LCMS): 94.17 %. 1H NMR (DMSOd6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 5.05 (2H, s), 7.0 (2H, m), 7.2 (2H, d), 7.4 (IH, s), 7.86 (5H, m), 8.0 (IH, d), 8.1 (2H, s), 8.36 (IH, d), 9.08 (2H, s), 9.26 (2H,s).
Example 55.
4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy- methyl] -benzoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49.
d) 4-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)- phenoxy methyljbenzoic acid ethyl ester
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester and 4-bromomethyl -benzoic acid ethyl ester (0.644 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 1.32 g of the required product. Percentage purity (LCMS): 84.4 %, (M+l) = 613.2+1.
e) 4-[3-(4- Amino cyclohexyl carbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxymethyl] benzoic acid ethyl ester
Using 4-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxy methyljbenzoic acid ethyl ester (1.32 g, 2.12 mmol) and following the procedure of Example l(d) afforded 0.54 g of the required product. Percentage purity (LCMS): 68.7 %, (M+l) = 559.2+1.
f) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy) phenoxymethyl] -benzoic acid ethyl ester
Using 4-[3-(4- amino cyclohexyl carbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxymethyl]benzoic acid ethyl ester (0.54 g, 0.96 mmol) and following the procedure of Example l(e) afforded 0.23 g of the required product. Percentage purity (HPLC): 97.37 %, (LCMS): 97.15%. 1H NMR (DMSOd6): δ 1.35 (3H, t), 1.4 (4H, m), 1.95 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 4.35 (2H, q), 5.3 (2H, s) 7.0 (IH, s), 7.2 (3H, m), 7.42 (IH, s), 7.60 (2H, d), 7.82 (4H, m), 8.0 (2H, d), 8.38 (IH, d), 9.08 (2H, s), 9.26 (2H, s).
Example 56.
4-{3-[4-(2-amino ethyl)piperidine-l-carbonyl]-5-phenethyloxy phenoxy}- benzamidine
Intermediate (a) is the same as in Example 42.
b) 3-(4- Cyano phenoxy)-5-phenethyloxy benzoic acid ethyl ester
Using 1.0 g (3.53 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and (2-bromo-ethyl)-benzene (0.65 g, 3.53 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (CDCl3): δ 1.35 (3H, t), 3.1 (2H, t), 4.2 (2H, t), 4.35 (2H, q), 6.78 (IH, t), 7.0 (2H, s), 7.22 (IH, m) 7.32 (5H, m), 7.42 (IH, m), 7.62 (2H, s).
c) 3 -(4- Cyano phenoxy)-5-phenethyloxy benzoic acid
0.95 g (2.45 mmol) of 3-(4- cyano phenoxy)-5-phenethyloxy benzoic acid ethyl ester was hydro lysed using the procedure of Example 5(b) to afford 0.6 g.of the required product. 1H NMR (DMSOd6): δ 3.02 (2H, t), 4.26 (2H, t), 7.0 (IH, t), 7.18 (3H, m), 7.24 (IH, m) 7.32 (5H, m), 7.88 (2H, s), 13.4 (IH, brs).
d) (2-{ l-[3-(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)- carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4- cyano phenoxy)-5-phenethyloxy benzoic acid 0.6 g (1.66 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.378 g, 1.66 mmol) were used to afford 0.55 g of the required product. 1H NMR (DMSOd6): δ 1.05 (3H, m), 1.4 (9H, s), 1.55 (2H, m), 1.7 (IH, m), 2.1 (5H, s), 3.0 (5H, m), 4.2 (2H, t), 4.4 (IH, m), 6.62 (IH, s), 6.78 (2H, s), 7.14 (2H, d), 7.24 (IH, m), 7.3 (4H, d), 7.88 (2H, d).
e) 4- { 3 - [4-(2-aminoethyl)piperidine- 1 -carbonyl] -5 -phenethyloxyphenoxy } - benzimidic acid ethyl ester
Using (2-{ l-[3-(4-cyanophenoxy)-5-phenethyloxybenzoyl]piperidin-4-yl}ethyl)- carbamic acid tert-butyl ester (0.55 g, 0.96 mmol) and following the procedure of
Example l(d) afforded 0.28 g of the required product. Percentage purity (LCMS): 56.4 %, (M+1) = 515.2+1
f) 4- { 3 - [4-(2-aminoethyl)piperidine- 1 -carbonyl] -5 -phenethyloxyphenoxy } - benzamidine
Using 4-{3-[4-(2-aminoethyl)piperidine-l-carbonyl]-5-phenethyloxy phenoxy}- benzimidic acid ethyl ester (0.28 g, 0.54 mmol) and following the procedure of Example l(e) afforded 0.06 g of the required product. Percentage purity (HPLC): 87.23 %, (LCMS): 76.08 %. 1H NMR (DMSO-d6): δ 1.10 (3H, t), 1.50 (2H, m), 1.60 (2H, m), 1.75 (IH, m), 2.70 (IH, m), 2.85 (2H, m), 3.05 (3H, m), 3.6 (IH, m), 4.25 (2H, t), 4.45 (IH, m), 6.6 (s), 6.8 (2H, m), 7.25 (2H, m), 7.35 (3H, s), 7.7 (2H, brs), 7.9 (2H, s), 9.05 (2H, s), 9.25 (2H, s).
Example 57.
2-{ l-[3-(3-Carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl]- piperidin-4-yl } -ethylamine
Intermediates (a) - (c) are the same as in Example 42.
d) (2- { 1 - [3 -(3 -cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl } ethyl)- carbamic acid tert-butyl ester Following the procedure of Example 5(c) 3-(3-cyano-benzyloxy)-5-(4-cyano- phenoxy)-benzoic acid 0.75 g (2.02 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.46 g, 2.02 mmol) were used to afford 0.7 g of the required product. Percentage purity (LCMS): 62.3 %, (M+l) = 480.2+1 (de-Boc mass, -100).
e) 2-{l-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl- phenoxy)benzoyl]piperidin-4-yl } ethylamine
Using (2-{ l-[3-(3-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl] piperidin-4- yl}ethyl)-carbamic acid tert-butyl ester (0.7 g, 1.2 mmol) and following the procedure of Example l(d) afforded 0.43 g of the required product. Percentage purity (LCMS): 49.2 %, (M+l) = 572.3+1.
f) 2-{l-[3-(3-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)-benzoyl]- piperidin-4-yl } ethylamine
Using 2-{ l-[3-(3-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy carbonimidoyl- phenoxy)benzoyl]piperidin-4-yl} ethylamine (0.43 g, 0.54 mmol) and following the procedure of Example l(e) afforded 0.16 g of the required product. Percentage purity (HPLC): 98.59 %, (LCMS): 98.49 %. 1H NMR (DMSO-d6): δ 1.10 (2H, m), 1.50 (2H, m), 1.60 (2H, m), 1.75 (IH, m), 2.80 (3H, m), 3.0 (2H, m), 4.45 (IH, m), 5.2 (2H, s), 6.65 (IH, s), 6.9 (2H, s), 7.25 (2H, s), 7.65 (IH, m), 7.7 - 7.85 (5H, m), 7.9 (3H, s), 9.1 (2H, s), 9.25 (3H, d), 9.4 (2H, s).
Example 58.
2-{l-[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]- piperidin-4-yl } ethylamine
Intermediates (a) - (c) are the same as in Example 43. d) (2-{ 1 -[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin-4-yl}ethyl)- carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano-benzyloxy)-5-(4-cyano- phenoxy)-benzoic acid 0.8 g (2.16 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.16 mmol) were used to afford 0.92 g of the required product. 1H NMR (DMSOd6): δ 1.10 (2H, m), 1.30 (2H, m), 1.4 (9H, s), 1.50 (2H, m), 1.75 (IH, m), 2.70 (IH, m), 2.8 (3H, m), 3.5 (IH, m), 4.4 (IH, m), 5.2 (2H, s), 6.65 (IH, s), 6.78 (IH, m), 6.88 (2H, m), 7.16 (2H, s), 7.64 (2H, d), 7.88 (4H, m).
e) 2-{l-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxycarbonimidoyl- phenoxy)benzoyl]piperidin-4-yl } ethylamine
Using (2-{ l-[3-(4-cyanobenzyloxy)-5-(4-cyanophenoxy)benzoyl]piperidin -4- yl}ethyl)-carbamic acid tert-butyl ester (0.92 g, 1.58 mmol) and following the procedure of Example l(d) afforded 0.54 g of the required product. Percentage purity (LCMS): 30.4 %, (M+1) = 572.3+1.
f) 2- { 1 -[3-(4-carbamimidoyl-benzyloxy)-5-(4-carbamimidoyl-phenoxy)benzoyl]- piperidin-4-yl} ethylamine
Using 2-{ l-[3-(4-ethoxycarbonimidoyl-benzyloxy)-5-(4-ethoxy carbonimidoyl- phenoxy)benzoyl]piperidin-4-yl} ethylamine (0.54 g, 0.94 mmol) and following the procedure of Example l(e) afforded 0.32 g of the required product. Percentage purity (HPLC): 98.97 %, (LCMS): 93.02 %. 1H NMR (DMSO-d6): δ 1.10 (2H, m), 1.50 (2H, m), 1.60 (2H, m), 1.75 (IH, m), 2.85 (4H, m), 3.0 (IH, m), 4.45 (IH, m), 5.3 (2H, s), 6.65 (IH, s), 6.9 (2H, s), 7.2 (2H, d), 7.7 (2H, d), 7.8 (2H, brs), 7.9 (4H, t), 9.3 (6H, t).
Example 59. 4-[3-(4-aminomethyl benzyloxy)-5-(4-carbamimidoyl phenoxy)benzoyl]- piperazine-1-carboxylic acid ethyl ester Intermediate (a) is the same as in Example 42. Intermediates (b) and (c) are the same as in Example 45.
d) 4- [3 - [4-(tert-butoxycarbonylaminomethyl)benzyloxy] -5 -(4-cyanophenoxy)- benzoyl] piperazine-1-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3-(4-(tert-butoxycarbonyl aminomethyl) benzyloxy)-5-(4-cyano phenoxy) benzoic acid 0.85 g (1.79 mmol) and piperazine-1- carboxylic acid ethyl ester (0.283 g, 1.79 mmol) were used to afford 0.91 g of the required product. 1H NMR (DMSOd6): δ 1.20 (3H, t), 1.40 (9H, s), 3.3 (2H, m), 3.6 (6H, m), 4.05 (2H, q), 4.15 (2H, d), 5.1 (2H, s), 6.7 (IH, s), 6.9 (2H, s), 7.18 (2H, d), 7.26 (2H, d), 7.4 (3H, d), 7.86 (2H, d), 7.86 (2H, s).
e) 4-[3-(4-aminomethyl benzyloxy)-5-(4-ethoxy carbonimidoyl phenoxy) benzoyl]piperazine-l-carboxylic acid ethyl ester
Using 4-[3-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-5-(4-cyanophenoxy)- benzoyl] piperazine-1-carboxylic acid ethyl ester (0.91 g, 1.48 mmol) and following the procedure of Example l(d) afforded 0.34 g of the required product. Percentage purity (LCMS): 73.3 %, (M+l) = 560.2+1.
f) 4- [3 -(4- Aminomethylbenzyloxy)-5 -(4-carbamimidoylphenoxy)benzoyl] - piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-aminomethyl benzyloxy)-5-(4-ethoxy carbonimidoyl phenoxy)- benzoyl]piperazine-l-carboxylic acid ethyl ester (0.34 g, 0.6 mmol) and following the procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity (HPLC): 93.79 %, (LCMS): 95.27 %. 1H NMR (DMSO-d6): δ 1.2 (3H, t), 3.4 (2H, m), 3.6 (2H, m), 3.75 (6H, m), 4.1 (2H, q), 5.2 (2H, s), 6.66 (IH, s), 6.9 (2H, s), 7.22 (2H, d), 7.5 (3H, s), 7.88 (2H, d), 8.2 (2H, brs), 9.06 (2H, s), 9.25 (2H, s). Example 60.
4- [3 -(4-Carbamimidoylphenoxy)-5 -(4-ethoxycarbonylbenzyloxy)-benzoyl] - piperazine-1-carboxylic acid ethyl ester
Intermediates (a) and (b) are the same as in Example 49.
c) 4-[3-(4-Cyano phenoxy)-5 -hydroxy benzoyl]piperazine-l-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5 -hydroxy benzoic acid 0.9 g (3.52 mmol) and piperazine-1-carboxylic acid ethyl ester (0.556 g, 3.52 mmol) were used to afford 0.52 g of the required product. Percentage purity (LCMS): 90.2 %, (M+l) = 395.1+1.
d) 4-[3-(4-Cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine-l- carboxylic acid ethyl ester
Using 0.52 g (1.31 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]- piperazine-1-carboxylic acid ethyl ester and 4-bromomethyl-benzoic acid ethyl ester (0.318 g, 1.31 mmol) and following the procedure of Example 42(b) affored 0.61 g of the required product. Percentage purity (LCMS): 60.0 % (M+ 1) = 557.2+1.
e) 4-[3-(4-Ethoxycarbonimidoyl phenoxy)-5-(4-ethoxycarbonyl benzyloxy)- benzoyl]piperazine-l-carboxylic acid ethyl ester
Using 4-[3-(4-cyanophenoxy)-5-(4-ethoxycarbonyl-benzyloxy)-benzoyl]piperazine- 1-carboxylic acid ethyl ester (0.6 g, 1.07 mmol) and following the procedure of Example l(d) afforded 0.32 g of the required product. Percentage purity (LCMS): 42.2 %, (M+l) = 603.2+1.
f) 4-[3-(4-Carbamimidoylphenoxy)-5-(4-ethoxycarbonylbenzyloxy)-benzoyl]- piperazine-1-carboxylic acid ethyl ester Using 4-[3-(4-ethoxycarbonimidoyl phenoxy)-5-(4-ethoxycarbonyl benzyloxy)- benzoyl]piperazine-l-carboxylic acid ethyl ester (0.32 g, 0.53 mmol) and following the procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity (HPLC): 94.77 %, (LCMS): 99.8 %. 1H NMR (DMSOd6): δ 1.2 (3H, t), 1.35 (3H, t), 3.3 (2H, m), 3.4 (2H, m), 3.6 (4H, m), 4.1 (2H, q), 4.4 (2H, q), 5.3 (2H, s), 6.7 (IH, s), 6.9 (2H, d), 7.25 (2H, d), 7.6 (2H, d), 7.85 (2H, d), 8.0 (2H, d), 9.0 (2H, s), 9.25 (2H, s).
Example 61. 4-[3-(4-Bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzoyl]piperazine-l- carboxylic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 60.
d) 4-[3-(4-Bromo benzyloxy)-5-(4-cyano phenoxy)benzoyl]piperazine-l-carboxylic acid ethyl ester
Using 0.75 g (1.89 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]- piperazine-1-carboxylic acid ethyl ester and l-bromo-4-bromomethyl-benzene (0.472 g, 1.89 mmol) and following the procedure of Example 42(b) afforded 0.85 g of the required product. Percentage purity (LCMS): 75.2 %, (M+l) = 563.1+1.
e) 4-[3-(4-Bromobenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy)benzoyl]- piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-bromobenzyloxy)-5-(4-cyano phenoxy)benzoyl]piperazine-l- carboxylic acid ethyl ester (0.85 g, 1.5 mmol) and following the procedure of Example l(d) afforded 0.37 g of the required product. Percentage purity (LCMS): 43.1 %, (M+l) = 609.1+1. f) 4-[3-(4-Bromo benzyloxy)-5-(4-carbamimidoyl phenoxy) benzoyl]piperazine-l- carboxylic acid ethyl ester
Using 4-[3-(4-bromobenzyloxy)-5-(4-ethoxycarbonimidoylphenoxy) benzoyl]- piperazine-1-carboxylic acid ethyl ester (0.37 g, 0.6 mmol) and following the procedure of Example l(e) afforded 0.15 g of the required product. Percentage purity (HPLC): 98.96 %, (LCMS): 91.78 %. 1H NMR (DMSOd6): δ 1.2 (3H, t), 3.35 (6H, m), 3.6 (2H, m), 3.6 (4H, m), 4.1 (2H, q), 5.2 (2H, s), 6.68 (IH, s), 6.7 (2H, m), 7.24 (2H, d), 7.4 (2H, d), 7.6 (2H, d), 7.86 (2H, d), 8.9 (2H, s), 9.25 (2H, s).
Example 62.
3-(3-Amino benzyloxy)-N-(4-amino cyclohexyl)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(4-Cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid ethyl ester
Using 1.2 g (4.23 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and l-bromomethyl-3-nitro-benzene (0.913 g, 4.23 mmol) and following the procedure of Example 42(b) afforded 1.43 g of the required product. 1H NMR (DMSOd6): δ 1.3 (3H, t), 4.3 (2H, q), 5.4 (2H, s), 7.2 (4H, m), 7.45 (IH, s), 7.72 (IH, t), 7.9 (3H, m), 8.25 (IH, d), 8.35 (IH, s).
c) 3-(4-Cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid
1.43 g (3.41 mmol) of 3-(4-cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.1 g of the required product. 1H NMR (DMSOd6): δ 5.4 (2H, s), 7.16 (4H, d), 7.45 (IH, s), 7.5 (IH, t), 7.9 (3H, d), 8.22 (IH, d), 8.34 (IH, s), 13.4 (IH, brs) d) { 4- [3 -(4-cyanophenoxy)-5 -(3 -nitrobenzyloxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-(3-nitro benzyloxy) benzoic acid 1.1 g (2.81 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 2.81 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.35 (2H, s), 6.78 (IH, d), 7.04 (IH, s), 7.12 (2H, d), 7.22 (IH, s), 7.46 (IH, s), 7.72 (IH, t), 7.9 (3H, d), 8.2 (IH, d), 8.34 (2H, m).
e) {4-[3-(3-amino benzyloxy)-5-(4-cyano phenoxy)benzoylamino] cyclohexyl} carbamic acid tert-butyl ester
1.2 g (2.04 mmol) of {4-[3-(4- cyano phenoxy)-5-(3-nitro benzyloxy)benzoyl aminojcyclohexyl} carbamic acid tert-butyl ester, dissolved in 10 ml of THF, 0.455 g (8.16 mmol) of iron powder and 0.436 g (8.16 mmol) OfNH4Cl solution (5 ml water) were mixed. The resulting reaction mixture was refluxed overnight. After completion of reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. 100 ml water was added to the concentrated mixture and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed with water followed by saturated brine, dried over anhydrous sodium sulphate and concentrated to afford crude compound which was purified by column chromatography using hexane-ethylacetate (10 : 2) to afford 0.75 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.0 (2H, s), 5.15 (2H, s), 6.5 (2H, m), 6.62 (IH, s), 6.78 (IH, d), 6.94 (IH, s), 7.0 (IH, t), 7.12 (3H, m), 7.4 (IH, s), 7.82 (2H, d), 8.26 (IH, d).
f) 4-[3-(3-amino benzyloxy)-5-(4- aminocyclohexyl carbamoyl) phenoxy] benzimidic acid ethyl ester
Using {4-[3-(3-aminobenzyloxy)-5-(4-cyano phenoxy)benzoylamino] cyclohexyl} carbamic acid tert-butyl ester (0.65 g, 1.16 mmol) and following the procedure of Example l(d) afforded 0.23 g of the required product. Percentage purity (LCMS): 98.0 %, (M+ 1) - 502.2+1.
g) 3-(3-Aminobenzyloxy)-N-(4-aminocyclohexyl)-5-(4-carbamimidoylphenoxy) benzamide
Using 4-[3-(3-amino benzyloxy)-5-(4- aminocyclohexyl carbamoyl) phenoxy] benzimidic acid ethyl ester (0.23 g, 0.45 mmol) and following the procedure of Example l(e) afforded 0.04 g of the required product. Percentage purity (HPLC): 97.77 %, (LCMS): 94.67 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 5.10 (2H, s), 6.85 (3H, m), 6.95 (IH, s), 7.20 (4H, m), 7.40 (IH, s), 7.85 (5H, s), 8.35 (IH, d), 9.1 (2H, brs), 9.25 (2H, s).
Example 63. N-(4- Amino cyclohexyl)-3-[3-(3-amino propionylamino)benzyloxy]-5-(4- carbamimidoyl phenoxy) benzamide
Intermediates (a) - (e) are the same as in Example 62.
f) {4-[3-[3-(3 -tert-butoxycarbonylaminopropionylamino)benzyloxy] -5 -(4-cyano phenoxy)-benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and {4-[3-(3- amino benzyloxy)-5 -(4-cyano phenoxy)benzoylamino]cyclohexyl} carbamic acid tert- butyl ester (0.6 g, 1.09 mmol) and other reagents as described in Example 9(e) were used to afford 0.45 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 2.45 (2H, m), 3.1 (3H, m), 3.7 (2H, m), 5.15 (2H, s), 6.74 (IH, d), 6.88 (IH, m), 6.98 IH, s), 7.12 (3H, d), 7.2 (IH, s), 7.3 (IH, t), 7.42 (IH, s), 7.54 (IH, d), 7.72 (IH, s), 7.86 (2H, d), 8.26 (IH, d).
g) 4-{3-(4-Amino cyclohexyl carbamoyl)-5-[3-(3-amino propionylamino) benzyloxy]phenoxy}benzimidic acid ethyl ester Using { 4- [3 - [3 -(3 -tert-butoxycarbonylaminopropionylamino)benzyloxy] -5 -(4-cyano phenoxy)-benzoyl amino] cyclohexyl}carbamic acid tert-butyl ester (0.45 g, 0.61 mmol) and following the procedure of Example l(d) afforded 0.15 g of the required product. Percentage purity (LCMS): 51.2 %, (M+l) = 573.3+1.
h) N-(4-Aminocyclohexyl)-3-[3-(3-aminopropionylamino)benzyloxy]-5-(4- carbamimidoyl phenoxy) benzamide
Using 4- { 3 -(4-amino cyclohexyl carbamoyl)-5 - [3 -(3 -amino propionylamino)- benzyloxy]phenoxy}benzimidic acid ethyl ester (0.15 g, 0.26 mmol) and following the procedure of Example l(e) afforded 0.03 g of the required product. Percentage purity (HPLC): 91.6 %, (LCMS): 92.3 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.92 (4H, m), 2.72 (2H, t), 3.0 (IH, m), 3.10 (2H, q), 3.72 (IH, m), 5.14 (2H, s), 6.98 (IH, s), 7.14 (IH, s), 7.20 (2H, d), 7.35 (IH, t), 7.40 (IH, s), 7.72 (IH, s), 7.81 (3H, brs), 7.88 (6H, d), 8.35 (IH, d), 9.14 (2H, brs), 9.25 (2H, s), 10.24 (IH, brs).
Example 64.
N-(4-Aminocyclohexyl)-3-(4-carbamimidoylphenoxy)-5-(3-carbamimidoyl- propoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-cyanophenoxy)-5-(3-cyano propoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester
Using 0.75 g (1.66 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl} carbamic acid tert-butyl ester and 4-bromo-butyronitrile (0.245 g, 1.66 mmol) and following the procedure of Example 42(b) afforded 0.82 g of the required product. 1H NMR (DMSOd6): δ 1.20 (3H, m), 1.4 (9H, s), 1.8 (4H, m), 2.05 (3H, m), 2.65 (2H, m), 3.2 (IH, m), 3.7 (IH, m), 4.1 (2H, m), 6.76 (IH, d), 6.92 (IH, s), 7.14 (2H, d), 7.2 (IH, s), 7.34 (IH, s), 7.86 (2H, d), 8.28 (IH, d) e) 4- [3 -(4- Aminocyclohexylcarbamoyl)^ -(3 -ethoxycarbonimidoylpropoxy) phenoxy]benzimidic acid ethyl ester
Using {4-[3-(4-cyanophenoxy)-5-(3-cyano propoxy)benzoylamino] cyclohexyl}- carbamic acid tert-butyl ester (0.82 g, 1.58 mmol) and following the procedure of Example l(d) afforded 0.43 g of the required product. Percentage purity (LCMS): 62.1 %, (M+1) = 510.2+1.
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoylphenoxy)-5-(3-carbamimidoyl proρoxy)benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(3-ethoxycarbonimidoyl propoxy)- phenoxy]benzimidic acid ethyl ester (0.43 g, 0.84 mmol) and following the procedure of Example l(e) afforded 0.14 g of the required product. Percentage purity (HPLC): 98.11
O %y , (LCMS): 99.32 %. 1H NMR (DMSO-d6): δ 1.40 (4H, m), 1.9 (4H, m), 2.1 (2H, m), 2.6 (2H, m), 3.0 (2H, m), 4.1 (2H, m), 6.90 (IH, s), 7.20 (3H, m), 7.35(1H, s), 7.85 (5H, s), 8.35 (IH, d), 8.7 (2H, brs), 8.95 (2H, s), 9.1 (2H, brs), 9.25 (2H, s).
Example 65.
N-(4-Aminocyclohexyl)-3-(4-carbamirnidoylbutoxy)-5-(4-carbamimidoyl- phenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-cyanobutoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbamic acid tert-butyl ester
Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyljcarbamic acid tert-butyl ester and 5-bromo-pentanenitrile (0.304 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.0 g of the required product. 1H NMR (DMSOd6): δ 1.25 (3H, m), 1.4 (9H, s), 1 8 (7H, m), 2.6 (3H, m), 3.2 (IH, m), 3.7 (IH, m), 4.2 (2H, m), 6.76 (IH, d), 6.92 (IH, s), 7.14 (3H, m), 7.34 (IH, s), 7.88 (2H, d), 8.28 (IH, d).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)- phenoxyj-benzimidic acid ethyl ester
Using { 4- [3 -(4-cyanobutoxy)-5 -(4-cyanophenoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester (1.0 g, 1.87 mmol) and following the procedure of Example l(d) afforded 0.52 g of the required product. Percentage purity (LCMS): 64.4 %, (M+l) = 524.3+1
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoylbutoxy)-5-(4-carbamimidoyl phenoxy)benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-butoxy)- phenoxyj-benzimidic acid ethyl ester (0.52 g, 0.99 mmol) and following the procedure of Example l(e) afforded 0.23 g of the required product. Percentage purity (HPLC): 97.4 %, (LCMS): 92.3 %. 1H NMR (DMSOd6): δ 1.41 (4H, m), 1.72 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 2.44 (2H, t), 3.00 (IH, m), 3.82 (IH, m), 4.08 (2H, m), 6.89 (IH, s), 7.12 (IH, s), 7.20 (2H, d), 7.32 (IH, s), 7.86 (4H, d), 8.34 (IH, d), 8.68 (2H, brs), 8.92 (2H, brs), 9.14 (2H, brs), 9.26 (2H, brs).
Example 66.
N-(4-Aminocyclohexyl)-3-(5-carbamimidoylpentyloxy)-5-(4-carbamimidoyl- phenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(5-cyanopentyloxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}- carbamic acid tert-butyl ester Using 0.85 g (1.88 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexanenitrile (0.33 g, 1.88 mmol) and following the procedure of Example 42(b) afforded 1.15 g of the required product. 1H NMR (DMSOd6): δ 1.25 (3 H, m), 1.4 (9H, s), 1.6 (4H, m), 1.8 (6H, m), 3.2 (IH, m), 3.7 (IH, m), 4.05 (2H, m), 6.75 (IH, d), 6.90 (IH, s), 7.14 (3H, m), 7.34 (IH, s), 7.88 (2H, d), 8.28 (IH, d).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbonimidoyl-pentyloxy)- phenoxy]-benzimidic acid ethyl ester
Using {4- [3 -(5 -cyanopentyloxy)-5 -(4-cyanophenoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester (1.15 g, 2.1 mmol) and following the procedure of Example l(d) afforded 0.61 g of the required product. Percentage purity (LCMS): 70.5 %, (M+1) = 538.3+1.
f) N-(4-Amino cyclohexyl)-3-(5-carbamimidoyl pentyloxy)-5-(4-carbamimidoyl phenoxy)benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(5-ethoxycarbonimidoyl-pentyloxy)- phenoxyj-benzimidic acid ethyl ester (0.61 g, 1.13 mmol) and following the procedure of Example l(e) afforded 0.25 g of the required product. Percentage purity (HPLC): 98.2 %, (LCMS): 90.6 %. 1H NMR (DMSOd6): δ 1.42 (4H, m), 1.72 (4H, m), 1.86 (2H, m), 1.98 (2H, m), 2.42 (2H, t), 3.00 (IH, m), 3.72 (IH, m), 4.06 (2H, t), 6.89 (IH, s), 7.12 (IH, s), 7.20 (2H, d), 7.32 (IH, s), 7.88 (4H, d), 8.32 (IH, d), 8.68 (2H, brs), 8.90 (2H, brs), 9.14 (2H, brs), 9.26 (2H, brs).
Example 67.
5-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]- pentanoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49. d) 5-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano phenoxy) phenoxyjpentanoic acid ethyl ester
Using 0.63 g (1.39 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanoic acid ethyl ester (0.29 g, 1.39 mmol) and following the procedure of Example 42(b) afforded 0.71 g of the required product. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.25 (2H, m), 1.4 (9H, s), 1.75 (9H, m), 2.35 (2H, m) 3.2 (IH, m), 3.7 (IH, m), 4.05 (4H, m), 6.75 (IH, d), 6.9 (IH, s), 7.15 (3H, d), 7.35 (IH, s), 7.85 (2H, d), 8.25 (IH, d).
e) 5-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxy]pentanoic acid ethyl ester
Using 5-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano- phenoxy)phenoxy]pentanoic acid ethyl ester (0.71 g, 1.22 mmol) and following the procedure of Example l(d) afforded 0.36 g of the required product. Percentage purity (LCMS): 90.9 %, (M+ 1) = 525.2+1.
f) 5 - [3 -(4- Aminocyclohexylcarbamoyl)^ -(4-carbamimidoylphenoxy)phenoxy] - pentanoic acid ethyl ester
Using 5-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxyjpentanoic acid ethyl ester (0.36 g, 0.68 mmol) and following the procedure of Example l(e) afforded 0.18 g of the required product. Percentage purity (HPLC): 96.9 %, (LCMS): 95.1 %. 1H NMR (DMSOd6): δ 1.18 (3H, t), 1.40 (4H, m), 1.72 (4H, m), 1.92 (4H, m), 2.38 (2H, t), 3.02 (IH, m), 3.72 (IH, m), 4.05 (4H, m), 6.88 (IH, s), 7.12 (IH, s), 7.21 (2H, d), 7.30 (IH, s), 7.88 (4H, d), 8.34 (IH, d), 9.14 (2H, brs), 9.26 (2H, brs).
Example 68.
6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]- hexanoic acid ethyl ester Intermediate (a) - (c) are the same as in Example 49.
d) 6-[3-(4-tert-Butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyanophenoxy)- phenoxy]hexanoic acid ethyl ester
Using 0.84 g (1.86 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino] cyclohexyl}carbamic acid tert-butyl ester and 6-bromo-hexaanoic acid ethyl ester (0.41 g, 1.86 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (DMSOd6): δ 1.15 (3H, t), 1.25 (2H, m), 1.4 (9H, s), 1.45 (3H, m), 1.6 (2H, m) 1.7 (2H, m), 1.8 (4H, m), 2.3 (2H, t), 3.2 (IH, m), 3.7 (IH, m),
4.05 (4H, m), 6.72 (IH, d), 6.88 (IH, s), 7.12 (3H, m), 7.3 (IH, s), 7.84 (2H, d), 8.24 (IH, d).
e) 6-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxy]hexanoic acid ethyl ester
Using 6-[3-(4-tert-butoxycarbonylaminocyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxy]hexanoic acid ethyl ester (0.95 g, 1.6 mmol) and following the procedure of Example l(d) afforded 0.45 g of the required product. Percentage purity (LCMS): 90.08 %, (M+ 1) = 539.3+1.
f) 6-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-carbamimidoylphenoxy)phenoxy]- hexanoic acid ethyl ester
Using 6-[3-(4-amino cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy) phenoxy]hexanoic acid ethyl ester (0.45 g, 0.83 mmol) and following the procedure of Example l(e) afforded 0.17 g of the required product. Percentage purity (HPLC): 95.7 %, (LCMS): 95.0 %. 1H NMR (DMSOd6): δ 1.18 (3H, t), 1.42 (6H, m), 1.60 (2H, m), 1.74 (2H, m), 1.78 (2H, brs), 1.98 (2H, brs), 2.32 (2H, t), 3.02 (IH, m), 3.70 (IH, m),
4.06 (4H, m), 6.90 (IH, s), 7.12 (IH, s), 7.22 (2H, d), 7.32 (IH, s), 7.88 (4H, d), 8.35 (IH, d), 9.14 (2H, brs), 9.28 (2H, brs). Example 69.
N-(4- Amino cyclohexyl)-3-(4-carbamimidoyl-2-chloro phenoxy)-5-(4- carbamimidoyl phenoxy)benzamide
Intermediate (a) is the same as in Example 42.
b) 3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester
To 1.2 g (4.23 mmol) of 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester, dissolved in 10 ml of DMF, potassium carbonate 1.17g (8.46 mmol) was added and stirred for 30 min at RT. 1.31 g (8.46 mmol) of 3-chloro-4-fluoro-benzonitrile, dissolved in 5 ml of DMF, was added dropwise to the reaction mixture during 15 min and final contents were stirred at 80 0C overnight. The reaction mixture was concentrated, residue was dissolved in 200 ml of ethyl acetate and partitioned with water. The organic layer was washed with brine followed by of water. Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was subjected to column chromatography, using silica-gel and eluted with hexane : ethyl acetate (8 :2) to afford 1.4 g of pure product. 1H NMR (DMSOd6): δ 1.3 (3H, t), 4.3 (2H, q), 7.2-7.36 (4H, m), 7.44 (2H, dd), 7.88 (3H, m), 8.26 (IH, d).
c) 3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid
3-(2-Chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester, 1.4 g (3.34 mmol), was hydrolysed using the procedure of Example 5(b) to afford 1.05 g of required product. 1H NMR (DMSOd6): δ 7.2-7.42 (6H, m), 7.88 (3H, m) 8.26 (IH, s), 13.8 (lH, brs).
d) {4-[3-(2-Chloro-4-cyanophenoxy)-5-(4-cyano phenoxy)benzoylamino] cyclohexyl}carbamic acid tert-butyl ester Following the procedure of Example 5(c) 3-(2-chloro-4-cyano phenoxy)-5-(4-cyano phenoxy)benzoic acid 1.0 g (2.55 mmol) and (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (0.54 g, 2.55 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.38 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.68 (IH, m), 6.76 (IH, d), 7.22 (4H, m), 7.5 (2H, s), 7.88 (3H, m), 8.26 (IH, d), 8.38 (IH, d).
e) 4-[3-(4-Aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoylphenoxy)- phenoxy]-3-chloro benzimidic acid ethyl ester
Using {4-[3-(2-chloro-4-cyanophenoxy)-5-(4-cyano phenoxy)benzoyl amino]- cyclohexyl}carbamic acid tert-butyl ester (1.2 g, 2.04 mmol) and following the procedure of Example l(d) afforded 0.64 g of the required product. Percentage purity (LCMS): 44.3 %, (M+l) = 539.3+1.
f) N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-2-chlorophenoxy)-5-(4- carbamimidoyl phenoxy)benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl phenoxy)- phenoxy]-3-chloro benzimidic acid ethyl ester (0.64 g, 1.1 mmol) and following the procedure of Example 1 (e) afforded 0.16 g of the required product. Percentage purity
(HPLC): 99.16 %, (LCMS): 92.13 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, s), 3.7 (IH, m) 7.16 (IH, s), 7.32 (3H, m), 7.48 (2H, s), 7.82 (IH, dd), 7.9 (4H, m), 8.14 (IH, d), 8.46 (IH, d), 9.2 (2H, s), 9.3 (2H, s), 9.38 (3H, s).
Example 70.
4- [3 - [4-(2- Amino ethyl)piperidine- 1 -carbonyl] -5 -(3 -amino propoxy)phenoxy] benzamidine
Intermediate (a) is the same as in Example 42.
b) 3-(3-tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester Following the procedure of Example 69(b) 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester 0.9 g (3.17 mmol) and (3-bromo-propyl)-carbamic acid tert-butyl ester (1.5 g, 6.34 mmol) were used to afford 0.95 g of the required product. 1H NMR (DMSO-d6): δ 2.05 (4H, m), 3.35 (2H, m), 3.90 (3H, s), 4.08 (2H, t), 4.72 (IH, brs), 6.78 (IH, t), 7.02 (2H, d), 7.28 (IH, s), 7.41 (IH, s), 7.62 (2H, d), 8.05 (IH, brs).
c) 3-(3- tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid
3 -(3 -tert-Butoxycarbonylamino propoxy)-5-(4-cyano phenoxy)benzoic acid ethyl ester, 0.95 g (2.15 mmol) was hydrolysed by using the procedure of Example 5(b) to afford 0.7 g of required product. 1H NMR (DMSOd6): δ 1.85 (2H, t), 3.12 (2H, m), 4.02 (2H, t), 6.85 (IH, s), 6.95 (IH, s), 7.15 (3H, m), 7.32 (IH, s), 7.85 (2H, d), 13.22 (IH, brs).
d) { 3 - [3 - [4-(2-tert-Butoxycarbonylaminoethyl)piperidine- 1 -carbonyl] -5 -(4-cyano phenoxy)phenoxy]propyl}carbamic acid tert-butyl ester
Following the procedure of Example 5(c) 3r(3- tert-butoxycarbonylamino propoxy)- 5-(4-cyano phenoxy)benzoic acid 0.7 g (1.69 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.38 g, 1.69 mmol) were used to afford 0.72 g of the required product. Percentage purity (LCMS): 47.0 %, (M+l) = 422.3+1 (de bisboc mass -200).
e) 4-[3-[4-(2-amino ethyl)piperidine-l-carbonyl]-5-(3-amino propoxy)phenoxy] benzimidic acid ethyl ester
Using {3-[3-[4-(2-tert-butoxycarbonylaminoethyl)piperidine-l-carbonyl]-5-(4- cyano phenoxy)phenoxy]propyl}carbamic acid tert-butyl ester (0.72 g, 1.15 mmol) and following the procedure of Example l(d) afforded 0.25 g of the required product. Percentage purity (LCMS): 63.9 %, (M+l) = 468.2+1.
f) 4-[3-[4-(2-Amino ethyl)piperidine-l -carbonyl] -5 -(3 -amino propoxy)phenoxy] benzamidine
Using 4-[3-[4-(2-amino ethyl)piperidine-l-carbonyl]-5-(3-amino propoxy) phenoxyjbenzimidic acid ethyl ester (0.25 g, 0.53 mniol) and following the procedure of Example l(e) afforded 0.065 g of the required product. Percentage purity (HPLC): 97.13 %, (LCMS): 89.6 %. 1H NMR (DMSOd6): δ 1.10 (2H, m), 1.50 (2H, m), 1.60-1.80 (3H, m), 2.0 (2H, m), 2.70 (IH, m), 2.8 (2H, m), 3.0 (3H, m), 4.1 (2H, t), 4.5 (IH, s), 6.60 (IH, s), 6.8 (2H, s), 7.20 (2H, d), 7.80 (3H, brs), 7.9 (4H, d), 9.3 (3H, s).
Example 71.
N-(4-Aminocyclohexyl)-3-(6-aminopyridine-3-yloxy)-5-(4-carbamimidoyl- phenoxy)-benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-Cyanophenoxy)-5-(6-nitropyridine-3-yloxy)benzoylamino]-cyclo- hexyl}carbamic acid tert-butyl ester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy- benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.65 mmol) and 5- chloro-2-nitro-pyridine (0.84 g, 5.31 mmol) were used to afford 1.2 g of the required product. 1H NMR (DMSOd6): δ 1.28 (3H, m), 1.4 (1OH, s), 1.8 (5H, m), 3.20 (IH, m), 3.7 (IH, m), 6.75 (IH, d), 7.25 (2H, d), 7.35 (IH, d), 7.5 (2H, s), 7.8 (IH, dd), 7.9 (2H, d), 8.35 (2H, d), 8.5 (IH, s).
e) {4-[3-(6-Aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoylamino]- cyclohexyl}carbamic acid tert-butyl ester
Following the procedure of Example 62(e) {4-[3-(4-cyanophenoxy)-5-(6-nitro- pyridine-3-yloxy)benzoylamino]-cyclohexyl}carbamic acid tert-butyl ester 1.2 g (2.09 mmol) was used to afford 0.45 g of the required product. 1H NMR (DMSOd6): δ 1.28 (4H, m), 1.4 (1OH, s), 1.8 (4H, m), 3.20 (IH, m), 3.7 (IH, m), 5.9 (2H, s), 6.5 (IH, d), 6.75 (IH, d), 6.85 (2H, s), 7.15 (3H, d), 7.3 (3H, m), 7.85 (3H, d), 8.3 (IH, m).
f) 4- [3 -(4- Amino cyclohexylcarbamoyl)-5-(6-amino pyridine-3-yloxy) phenoxyjbenzimidic acid ethyl ester
Using {4-[3-(6-aminopyridine-3-yloxy)-5-(4-cyanophenoxy)benzoyl amino]- cyclohexyl}carbamic acid tert-butyl ester (0.45 g, 0.82 mmol) and following the procedure of Example l(d) afforded 0.21 g of the required product. Percentage purity (LCMS): 93.0 %, (M+ 1) = 489.2+1.
g) N-(4-Amino cyclohexyl)-3-(6-amino pyridine-3-yloxy)-5-(4-carbamimidoyl phenoxy)benzamide
Using 4-[3-(4-amino cyclohexylcarbamoyl)-5-(6-amino pyridine-3-yloxy)- phenoxyjbenzimidic acid ethyl ester (0.21 g, 0.42 mmol) and following the procedure of Example l(e) afforded 0.065 g of the required product. Percentage purity (HPLC): 95.3 %, (LCMS): 90.3 %. 1H NMR (DMSO-d6): δ 1.39 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 6.88 (IH, d), 7.02 (IH, s), 7.24 (2H, d), 7.36 (2H, d), 7.72 (IH, d), 7.86 (5H, d), 7.96 (IH, s), 8.42 (IH, d), 9.23 (4H, d).
Example 72.
N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-carbamimidoylphenoxy)- benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) { 4- [3 -(4-Cyanophenoxy)-5 -(4-nitro phenoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy- benzoylamino] cyclohexyl} carbamic acid tert-butyl ester 1.1 g (2.43 mmol) and 1- chloro-4-nitro-benzene (0.765 g, 4.86 mmol) were used to afford 0.94 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 6.7 (IH, d), 7.25 (5H, m), 7.55 (2H, m), 7.8 (2H, d), 8.3 (2H, d), 8.4 (IH, d).
e) {4-[3-(4-Aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}- carbamic acid tert-butyl ester
Following the procedure of Example 62(e) {4-[3-(4-cyanophenoxy)-5-(4-nitro phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.94 g (1.64 mmol) was used to afford 0.39 g of the required product. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.40 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 5.1 (2H, s), 6.6 (2H, d), 6.76 (2H, m), 6.82 (2H, d), 7.14 (2H, d), 7.26 (2H, s), 7.86 (2H, d), 8.28 (IH, d).
f) 4- [3 -(4- Aminocyclohexylcarbamoyl)-5 -(4-aminophenoxy)phenoxy] -benzimidic acid ethyl ester
Using { 4- [3 -(4-aminophenoxy)-5 -(4-cyanophenoxy)benzoylamino] cyclohexyl } - carbamic acid tert-butyl ester (0.39 g, 0.71 mmol) and following the procedure of Example l(d) afforded 0.16 g of the required product. Percentage purity (LCMS): 80.0 %, (M+l) = 488.2+1
g) N-(4-Aminocyclohexyl)-3-(4-aminophenoxy)-5-(4-carbamimidoylphenoxy)- benzamide
Using 4-[3-(4-aminocyclohexylcarbamoyl)-5-(4-aminophenoxy) phenoxy]- benzimidic acid ethyl ester (0.16 g, 0.32 mmol) and following the procedure of Example l(e) afforded 0.05 g of the required product. Percentage purity (HPLC): 97.05 %, (LCMS): 96.25 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 6.85 (IH, s), 7.0 (4H, s), 7.3 (4H, d), 7.85 (5H, d), 8.4 (IH, d), 9.2 (2H, s), 9.3 (2H, d).
Example 73. N-(4- Aminocyclohexyl)-3 - [4-(3 -aminopropionylamino)phenoxy] -5 -(4- carbamimidoyl phenoxy)benzamide
Intermediates (a) - (e) are the same as in Example 72.
f) {4-[3τ[4-(3-tert-Butoxycarbonyl amino propionylamino)phenoxy]-5-(4-cyano phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester
3-tert-Butoxycarbonylamino-propionic acid (0.31 g, 1.63 mmol) and {4-[3-(4- aminophenoxy)-5-(4-cyanophenoxy)benzoylamino]cyclohexyl}-carbamic acid tert-butyl ester (0.884 g, 1.63 mmol) and other reagents as described in Example 9(e) were used to afford 0.75 g.of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 2.4 (2H, m), 3.2 (3H, m), 3.7 (IH, m), 6.72 (IH, d), 6.88 (2H, m), 7.06 (2H, d), 7.16 (2H, d), 7.32 (2H, s), 7.64 (2H, d), 7.86 (2H, d), 8.3 (IH, d).
g) 4-{3-(4-Amino cyclohexylcarbamoyl)-5-[4-(3-amino propionylamino) phenoxy] phenoxy}benzimidic acid ethyl ester
Using {4-[3-[4-(3-tert-butoxycarbonyl amino propionylamino)phenoxy]-5-(4-cyano phenoxy)benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (0.75 g, 1.05 mmol) and following the procedure of Example l(d) afforded 0.34 g of the required product. Percentage purity (LCMS): 85.9 %, (M+ 1) = 559.2+1.
h) N-(4- Aminocyclohexyl)-3 - [4-(3 -aminopropionylamino)phenoxy] -5 -(4- carbamimidoyl phenoxy)benzamide
Using 4-{3-(4-aminocyclohexylcarbamoyl)-5-[4-(3-amino propionyl amino) phenoxy] phenoxy }benzimidic acid ethyl ester (0.34 g, 0.60 mmol) and following the procedure of Example l(e) afforded 0.14 g of the required product. Percentage purity (HPLC): 96.79 %, (LCMS): 92.82 %. 1H NMR (DMSOd6): δ 1.35 (4H, m), 1.9 (4H, m), 2.7 (2H, t), 2.95 (2H, m), 3.1 (2H, m), 6.9 (IH, s), 7.1 (2H, d), 7.3 (4H, d), 7.65 (2H, d), 7.85 (8H, m), 8.4 (IH, d), 9.1 (2H, s), 9.25 (2H, s), 10.35 (lH,s). Example 74.
N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-3-methylphenoxy)-5-(4- carbamimidoyl phenoxy)benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) {4-[3-(4-Cyano-3-methyl phenoxy)-5-(4-cyano phenoxy)benzoylamino] cyclohexyl}carbamic acid tert-butylester
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy- benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.85 g (1.88 mmol) and 4- fluoro-2-methyl-benzonitrile (0.508 g, 3.76 mmol) were used to afford 0.76 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 2.45 (3H, s), 3.15 (IH, m), 3.7 (IH, m), 6.72 (IH, d), 7.02 (IH, d), 7.2 (4H, m), 7.5 (2H, s), 7.8 (IH, d), 7.88 (2H, d), 8.34 (IH, d).
e) (4-{3-[4-(N-Hydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy- carbamimidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid tert-butylester
Following the procedure of Example 2(d) {4-[3-(4-cyano-3-methyl phenoxy)-5-(4- cyano phenoxy)benzoylamino]cyclohexyl} carbamic acid tert-butylester 0.76 g (1.34 mmol) and other aproperiate reagents were used to afford 0.64 g of the required product. Percentage purity (LCMS): 44.5 %, (M+ 1) = 632.3+1.
f) (4-{3-[4-(N-Acetylhydroxycarbamimidoyl)-3-methylphenoxy]-5-[4-(N-hydroxy- carbamimidoyl)phenoxy]benzoylamino}cyclohexyl) carbamic acid tert-butylester
Following the procedure of Example 2(e) (4-{3-[4-(N-hydroxycarbamimidoyl)-3- methylphenoxy]-5-[4-(N-hydroxy-carbamimidoyl)phenoxy] benzoylamino}cyclohexyl) carbamic acid tert-butylester 0.64 g (1.01 mmol) was used to afford 0.52 g of the required product. Percentage purity (LCMS): 49.7 %, (M+l) = 716.3. g) {4-[3-(4-Carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)- benzoylamino]cyclohexyl} carbamic acid tert-butylester
(4- { 3 - [4-(N- Acetylhydroxycarbamimidoyl)-3 -methylphenoxy] -5 - [4-(N-acetyl- hydroxy-carbamimidoy^phenoxyjbenzoylaminojcyclohexyl) carbamic acid tert- butylester 0.52 g (0.72 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of required product. Percentage purity (LCMS): 44.5 %, (M+l) = 600.3+1.
h) N-(4-Aminocyclohexyl)-3-(4-carbamimidoyl-3-methylphenoxy)-5-(4- carbamimidoyl phenoxy)benzamide
Using {4-[3-(4-carbamimidoyl-3-methylphenoxy)-5-(4-carbamimidoylphenoxy)- benzoylamino]cyclohexyl} carbamic acid tert-butylester (0.25 g, 0.41 mmol) and following the procedure of Example 9(d) afforded 0.05 g of the required product. Percentage purity (HPLC): 97.87 %, (LCMS): 97.27 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 2.4 (3H, s), 3.0 (IH, s), 3.7 (IH, m) 7.0 (IH, s), 7.1 (IH, d), 7.18 (IH, s), 7.28 (2H, d), 7.46 (2H, s), 7.54 (IH, s), 7.88 (5H, m), 8.44 (IH, d), 9.14 (2H, s), 9.28 (6H, s).
Example 75.
N-(4-Amino cyclohexyl)-3,5-bis-(4-carbamimidoyl benzyloxy)benzamide
a) 3, 5 -Bis (4-cyano phenoxy)benzoic acid ethyl ester
To a solution of 3,5-dihydroxy benzoic acid ethyl ester 1.2 g (6.58 mmol), dissolved in 10 ml DMF, was added K2CO3 3.63 g (26.32mmol) followed by 4-bromomethyl- benzonitrile 5.16 g (26.32mmol) in 5 ml of DMF at 20 °C. The reaction mixture was allowed to attain RT and then heated to 35 °C for 8 h. The solvent was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with brine and water. Organic phase was dried over anhydrous sodium sulphate and solvent was removed under reduced pressure. The crude product was subjected to column chromatography and eluted using hexane : ethyl acetate (8:2) to afford 2.1 g of purified product. 1H NMR (DMSO-d6): 1.3 (3H, t), 4.3 (2H, q), 5.3 (4H, s), 7.0 (IH, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
b) 3, 5 -Bis (4-cyano phenoxy)benzoic acid
2.1 g (5.46 mmol) of 3,5-bis (4-cyano phenoxy)benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.65 g of the required product. 1H NMR (DMSOd6): 5.2 (4H, s), 6.8 (IH, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
c) {4-[3,5-Bis (4-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert- butyl ester
3,5-Bis (4-cyano phenoxy)benzoic acid (0.75 g, 2.1 mmol) and (4-amino-cyclo- hexyl)-carbamic acid tert-butyl ester (0.45 g, 2.1 mmol) and other reagents as described in Example 9(e) were used to afford 0.82 g.of the required product. 1H NMR (DMSO- d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.70 (2H, m), 5.25 (4H, s), 6.72 (IH, m), 6.84 (IH, s), 7.12 (2H, s), 7.64 (4H, d), 7.86 (4H, d), 8.18 (IH, m).
d) N-(4-Aminocyclohexyl)-3,5-bis-(4-ethoxycarbonimidoyl benzyloxy)benzamide
Using {4-[3,5-Bis(4-cyanobenzyloxy)benzoylamino]cyclohexyl} carbamic acid tert- butyl ester (0.82 g, 1.41 mmol) and following the procedure of Example l(d) afforded 0.32 g of the required product. Percentage purity (LCMS): 49.4 %, (M+l) = 572.3+1.
e) N-(4-Amino cyclohexyl)-3,5-bis-(4-carbamimidoyl benzyloxy)benzamide
Using N-(4-aminocyclohexyl)-3 ,5-bis-(4-ethoxycarbonimidoyl benzyloxy)- benzamide (0.32 g, 0.55 mmol) and following the procedure of Example l(e) afforded 0.07 g of the required product. Percentage purity (HPLC): 98.01 %, (LCMS): 99.73 %. 1H NMR (DMSOd6): δ 1.4 (4H, m), 1.8 (2H, m), 2.0 (2H, m), 3.0 (IH, m), 3.70 (IH, m), 5.3 (4H, s), 6.9 (IH, s), 7.15 (2H, d), 7.7 (4H, d), 7.85 (4H, s), 7.9 (3H, m), 8.3 (IH, m), 9.3 (8H, s).
Example 76. 2-{l-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}- ethylamine
Intermediates (a) and (b) are the same as in Example 75.
c) (2-{l-[3,5-Bis-(4-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid tert-butyl ester
3,5-Bis (4-cyano phenoxy)benzoic acid (0.64 g, 1.79 mmol) and (2-piperidin-4-yl- ethyl)-carbamic acid tert-butyl ester (0.408 g, 1.79 mmol) and other reagents as described in Example 9(e) were used to afford 0.72 g of the required product.
Percentage purity (LCMS): 88.39 %. 1H NMR (DMSOd6): δ 1.3 (2H, m), 1.35 (9H, m), 1.5 (3H, m), 1.7 (IH, m), 2.98 (2H, m), 3.45 (2H, m), 5.25 (4H, s), 6.58 (2H, s), 6.76 (2H, m), 7.65 (4H, d), 7.88 (4H, d).
d) 2-{ l-[3,5-Bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl]piperidine-4-yl}- ethylamine
Using (2-{l-[3,5-bis-(4-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid tert-butyl ester (0.72 g, 1.21 mmol) and following the procedure of Example l(d) afforded 0.34 g of the required product. Percentage purity (LCMS): 49.9 %, (M+l) = 586.3+1.
e) 2- { 1 - [3 ,5-Bis-(4-ethoxycarbamimidoylbenzyloxy)benzoyl]piperidine-4-yl } - ethylamine
Using 2-{ l-[3,5-bis-(4-ethoxycarbonimidoylbenzyloxy)benzoyl] piperidine-4-yl}- ethylamine (0.34 g, 0.58 mmol) and following the procedure of Example l(e) afforded 0.17 g of the required product. Percentage purity (HPLC): 96.25 %, (LCMS): 97.96 %. 1H NMR (DMSOd6): δ 1.05 (2H, m), 1.50-1.8 (5H, m), 2.8 (4H, m), 3.5 (IH, m), 4.4 (IH, m), 5.25 (4H, s), 6.60 (2H, s), 6.8 (IH, brs), 7.65 (4H, d), 7.85 (6H, d), 9.4 (7H, s).
Example 77.
N-(4- Amino cyclohexyl)-3,5-bis-(3-carbamimidoyl benzyloxy)benzamide
a) 3,5-Bis (3-cyano phenoxy)benzoic acid ethyl ester
3,5-Dihydroxy benzoic acid ethyl ester (1.45 g, 7.95 mmol) and 3-bromomethyl- benzonitrile (6.23 g, 31.8 mmol) and other reagents as described in Example 75(a) were used to afford 2.3 g of the required product. 1H NMR (DMSO-d6): 1.15 (3H, t), 4.15 (2H, q), 5.3 (4H, s), 7.0 (IH, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
b) 3,5-Bis (3-cyano phenoxy)benzoic acid
2.3 g (5.98 mmol) of 3,5-bis (3-cyano phenoxy)benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 1.85 g. of the required product. 1H NMR (DMSO-d6): 6.86 (IH, s), 7.2 (2H, d), 7.62 (2H, s), 7.82 (4H, m), 7.94 (2H, s).
c) {4-[3,5-Bis (3-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert- butyl ester
3,5-Bis (3-cyano phenoxy)benzoic acid (1.2 g, 3.36 mmol) and (4-amino-cyclo- hexyl)-carbamic acid tert-butyl ester (0.72 g, 3.36 mmol) and other reagents as described in Example 9(e) were used to afford 1.33 g of the required product. 1H NMR (DMSO- d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.20 (IH, m), 3.70 (IH, m), 5.25 (4H, s), 6.74 (IH, m), 6.86 (IH, s), 7.16 (2H, s), 7.64 (2H, t), 7.82 (4H, t), 7.94 (2H, s), 8.22 (IH, d)
d) 4-[3,5-Bis (3-ethoxycarbonimidoyl benzyloxy)benzoylamino]cyclohexylamine Using {4-[3,5-bis(3-cyano benzyloxy)benzoylamino]cyclohexyl}carbamic acid tert- butyl ester (1.33 g, 2.3 mmol) and following the procedure of Example l(d) afforded 0.91 g of the required product. Percentage purity (LCMS): 14.8 %, (M+ 1) = 572.3+1.
e) N-(4-Amino cyclohexyl)-3,5-bis-(3-carbamimidoyl benzyloxy)benzamide
Using 4- [3, 5 -Bis (3-ethoxycarbonimidoyl benzyloxy)benzoylamino] cyclohexyl- amine (0.91 g, 1.58 mmol) and following the procedure of Example l(e) afforded 0.16 g of the required product. Percentage purity (HPLC): 98.81 %, (LCMS) 97.40 %. 1H NMR (DMSO-d6): δ 1.4 (4H, m), 1.9 (4H, m), 3.0 (IH, m), 3.70 (IH, m), 5.25 (4H, s), 6.9 (IH, s), 7.15 (2H, d), 7.7 (2H, t), 7.80 (4H, t), 7.9 (5H, s), 8.3 (IH, m), 9.4 (8H, s).
Example 78.
2- { 1 - [3 ,5 -Bis-(3 -carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } -ethyl- amine
Intermediates (a) and (b) are the same as in Example 77.
c) (2-{l-[3,5-Bis-(3-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid tert-butyl ester
3,5-Bis (3-cyano phenoxy)benzoic acid (0.6 g, 1.68 mmol) and (2-piperidin-4-yl- ethyl)-carbamic acid tert-butyl ester (0.383 g, 1.68 mmol) and other reagents as described in Example 9(e) were used to afford 0.65 g of the required product. 1H NMR (DMSOd6): δ 1.25 (2H, m), 1.4 (9H, s), 1.5 (3 H, m), 1.7 (2H, m), 2.7 (2H, m), 2.9 (3H, m), 4.4 (IH, m), 5.25 (4H, s), 6.6 (2H, s), 6.80 (2H, brs), 7.62 (2H, t), 7.82 (4H, m), 7.94 (2H, s).
d) 2-{l-[3,5-Bis-(3 -ethoxycarbonimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } - ethylamine Using (2-{ l-[3,5-bis-(3-cyano benzyloxy)benzoyl]piperidine-4-yl}ethyl)carbamic acid tert-butyl ester (0.65 g, 1.09 mmol) and following the procedure of Example l(d) afforded 0.43 g of the required product. Percentage purity (LCMS): 36.1 %, (M+l) = 586.3+1.
e) 2-{l-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}- ethylamine
Using 2-{l-[3,5-bis-(3 -ethoxycarbonimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } - ethylamine (0.43 g, 0.73 mmol) and following the procedure of Example l(e) afforded 0.081 g of the required product. Percentage purity (HPLC): 97.84 %, (LCMS): 98.96 %. 1H NMR (DMSOd6): δ 1.0 (2H, m), 1.50-1.6 (4H, m), 1.75 (IH, m), 2.7 (IH, m), 2.8- 3.0 (4H, m), 4.45 (IH, m), 5.4 (4H, s), 6.6 (2H, s), 6.8 (IH, brs), 7.65 (2H, m), 7.75 (6H, brs), 7.9 (2H, s), 9.45 (8H, s).
Example 79.
N-(4-Amino cyclohexyl)-2,4-bis-(4-carbamimidoyl benzyloxy)benzamide
a) [4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester
2,4-Dihydroxy benzoic acid (1.6 g, 10.38 mmol) and (4-amino-cyclohexyl)- carbamic acid tert-butyl ester (2.22 g, 10.38 mmol) and other reagents as described in Example 9(e) were used to afford 0.95 g of the required product. 1H NMR (DMSOd6): δ 1.20 (4H, m), 1.4 (9H, m), 2.1 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 6.2 (2H, d), 6.74 (IH, s), 7.7 (IH, s), 8.26 (IH, s), 10.0 (IH, brs), 13.0 (IH, brs).
b) {4-[2,4-Bis-(4-cyano benzyloxy) benzoylamino]cyclohexyl}carbamic acid tert- butyl ester
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.95 g,
2.71 mmol) and 4-bromomethyl-benzonitrile (2.12 g, 10.84 mmol) and other reagents as described in Example 75 (a) were used to afford 1.2 g of the required product. 1H NMR (DMSOd6): δ 1.20 (5H, m), 1.4 (9H, m), 1.75 (4H, m), 3.6 (IH, m), 5.3 (4H, s), 6.7 (IH, s), 6.85 (IH, s), 7.35 (2H, d), 7.5 (IH, s), 7.75 (4H, d), 7.9 (4H, s).
c) 4-[2,4-Bis-(4-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
Using {4-[2,4-bis-(4-cyanobenzyloxy) benzoylaminojcyclohexyl} carbamic acid tert-butyl ester (1.2 g, 2.06 mmol) and following the procedure of Example l(d) afforded 0.61 g of the required product. Percentage purity (LCMS): 56.9 %, (M+ 1) = 572.3+1.
d) 4-[2,4-Bis-(4-carbamimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
Using 4-[2,4-bis-(4-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl- amine (0.61 g, 1.06 mmol) and following the procedure of Example l(e) afforded 0.24 g of the required product. Percentage purity (HPLC): 97.52 %, (LCMS): 96.14 %. 1H NMR (DMSOd6): δ 1.10 (2H, m), 1.35 (2H, m), 2.85 (4H, m), 2.9 (IH, m), 3.6 (IH, m), 5.3 (4H, d), 6.75 (IH, d), 6.9 (IH, s), 7.7 (3H, m), 7.75 - 8.0 (8H, m), 8.35 (IH, d), 8.7 (2H, brs), 8.95 (2H, s), 9.1 (2H, brs), 9.2-9.5 (7H, s).
Example 80.
2- { 1 - [2,4-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } -ethyl- amine
a) {2-[l-(2, 4-Dihydroxy benzoyl)piperidin-4-yl] ethyl} carbamic acid tert-butyl ester
2,4-Dihydroxy benzoic acid (1.25 g, 8.11 mmol) and (2-piperidin-4-yl-ethyl)- carbamic acid tert-butyl ester (1.85 g, 8.11 mmol) and other reagents as described in Example 9(e) were used to afford 1.13 g of the required product. 1H NMR (DMS Od6): δ 1.05 (2H, m), 1.25 (2H, m), 1.4 (9H, s), 1.65 (2H, m), 2.75 (2H, m), 2.95 (2H, m), 3.15 (IH, m), 4.0 (2H, m), 6.24 (2H, m), 6.78 (IH, m), 6.9 (IH, d), 9.6 (2H, brs). b) (2-{ l-[2,4-Bis-(4-cyano-benzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
{2-[l-(2, 4-Dihydroxy benzoyl)piperidin-4-yl] ethyl }carbamic acid tert-butyl ester (1.13 g, 3.1 mmol) and 4-bromomethyl-benzonitrile (2.43 g, 12.4 mmol) and other reagents as described in Example 75(a) were used to afford 1.3 g of the required product. 1H NMR (DMSOd6): δ 1.35 (8H, s), 2.1 (4H, s), 2.9 (3H, m), 4.55 (4H, d), 5.25 (3H, s), 5.5 (2H, t), 6.8 (IH, m), 7.3 (IH, d), 7.4 (IH, d), 7.5 (4H, d), 7.66 (IH, d), 7.8 (3H, m), 7.86 (2H, m).
c) 2- { 1 - [2,4-Bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl } - ethylamine
Using (2-{ l-[2,4-bis-(4-cyano-benzyloxy)benzoyl]piperidin-4-yl}ethyl) carbamic acid tert-butyl ester (1.3 g, 2.18 mmol) and following the procedure of Example l(d) afforded 0.52 g of the required product. Percentage purity (LCMS): 71.2 %, (M+l) = 586.3+1.
d) 2-{ 1 -[2,4-Bis-(4-carbamimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}-ethyl- amine
Using 2-{l-[2,4-bis-(4-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}- ethylamine (0.52 g, 0.88 mmol) and following the procedure of Example l(e) afforded 0.19 g of the required product. Percentage purity (HPLC): 90.96 %, (LCMS): 98.53 %. 1H NMR (DMSOd6): δ 1.0 (IH, m), 1.30 (IH, m), 1.5 (3H, m), 1.7 (IH, m), 2.7 (4H, m), 2.9 (IH, m), 3.4 (IH, m), 4.5 (IH, m), 5.30 (4H, d), 6.65 (IH, d), 6.8 (IH, s), 7.15 (IH, m), 7.7 (7H, m), 7.85 (4H, d) 9.2 (4H, s), 9.35 (4H, s).
Example 81. N-(4-Amino cyclohexyl)-2.4-bis (3-carbamimidoyl benzyloxy)benzamide
Intermediate (a) is the same as in Example 79(a). b) {4-[2,4-Bis-(3-cyano benzyloxy) benzoylamino]cyclohexyl}carbamic acid tert- butyl ester
[4-(2,4-Dihydroxy benzoylamino)cyclohexyl]carbamic acid tert-butyl ester (0.85 g,
2.42 mmol) and 3-bromomethyl-benzonitrile (1.89 g, 9.68 mmol) and other reagents as described in Example 75(a) were used to afford 0.75 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.75 (4H, m), 3.15 (IH, m), 3.65 (2H, m), 4.55 (IH, m), 5.25 (4H, s), 6.72 (2H, m), 6.9 (IH, s), 7.7 (6H, m), 7.85 (4H, m), 7.94 (IH, s), 8.04 (IH, s).
c) 4-[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
Using {4-[2,4-bis-(3-cyanobenzyloxy) benzoylaminojcyclohexyl} carbamic acid tert-butyl ester (0.75 g, 1.29 mmol) and following the procedure of Example l(d) afforded 0.32 g of the required product. Percentage purity (LCMS): 90.7 %, (M+l) = 572.3+1.
d) 4-[2,4-Bis-(3-carbamimidoyl-benzyloxy)benzoylamino]-cyclohexyl-amine
Using 4-[2,4-bis-(3-ethoxycarbonimidoyl-benzyloxy)benzoylamino]-cyclohexyl- amine (0.32 g, 0.55 mmol) and following the procedure of Example l(e) afforded 0.08 g of the required product. Percentage purity (HPLC): 95.22 %, (LCMS): 93.7 %. 1H NMR (DMSOd6): δ 1.2 (2H, m), 1.40 (2H, m), 1.9 (4H, m), 2.95 (IH, m), 3.7 (IH, m), 5.35 (4H, d), 6.75 (IH, d), 6.9 (IH, s), 7.7 (5H, m), 7.85 (7H, m), 9.1-9.4 (8H, s).
Example 82.
2- { 1 - [2,4-Bis-(3 -carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } - ethylamine
Intermediate (a) is the same as in Example 80(a). b) (2-{ l-[2,4-Bis(3-cyano benzyloxy)benzoyl]piperidin-4-yl}ethyl)carbamic acid tert-butyl ester
{2-[l-(2, 4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester (1.05 g, 2.88 mmol) and 3-bromomethyl-benzonitrile (2.25 g, 11.5 mmol) and other reagents as described in Example 75(a) were used to afford 1.15 g of the required product. 1H NMR (DMSOd6): δ 1.4 (9H, s), 2.1 (2H, d), 2.6 (IH, m), 2.95 (4H, m), 3.45 (IH, m), 4.5 (2H, m), 5.2 (4H, s), 6.7 (2H, d), 6.84 (IH, d), 7.14 (IH, dd), 7.52 (IH, m), 7.62 (3H, d), 7.7 (2H, d), 7.8 (5H, m), 7.95 (IH, s).
c) 2-{l-[2,4-Bis-(3-ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl}- ethylamine
Using (2-{ l-[2,4-Bis(3-cyanobenzyloxy)benzoyl]piperidin-4-yl}ethyl) carbamic acid tert-butyl ester (1.15 g, 1.93 mmol) and following the procedure of Example l(d) afforded 0.41 g of the required product. Percentage purity (LCMS): 62.5 %, (M+l) = 586.3+1.
d) 2-{ l-[2,4-Bis-(3 -carbamimidoyl-benzyloxy)-benzoyl] -piperidin-4-yl } -ethyl- amine
Using 2- { 1 - [2,4-bis-(3 -ethoxycarbonimidoyl-benzyloxy)-benzoyl]-piperidin-4-yl } - ethylamine (0.41 g, 0.69 mmol) and following the procedure of Example l(e) afforded 0.16 g of the required product. Percentage purity (HPLC): 91.53 %, (LCMS) 95.59 %. 1H NMR (DMSO-d6): δ 0.9 (2H, m), 1.25 (2H, m), 1.5 (3H, m), 1.75 (IH, m), 2.8 (3H, m), 2.9 (IH, m), 3.4 (2H, m), 4.5 (IH, m), 5.25 (3H, d), 6.55 (IH, s), 6.7 (IH, d), 6.9 (IH, d), 7.3 (IH, m), 7.8 (8H, m) 7.9 (IH, s), 9.25 (3H, d), 9.4 (3H, s).
Example 83. 4-[3-(4-Aminomethyl phenoxy)-5-(4-carbamimidoyl phenoxy)benzoyl]-l- carboxylic acid ethyl ester Intermediates (a) - (c) are the same as in Example 62.
d) 4-[3-(4-Aminomethyl phenoxy)-5-hydroxy benzoyl]piperazine-l-carboxylic acid ethyl ester
Raney nickel ( 0.1 g, 1.7 mmols) was added to a stirred solution of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]piperazine-l-carboxylic acid ethyl ester (0.5 g, 1.26 mmols) dissolved in methanolic ammonia (50 ml) and the reaction mixture was heated to 50 °C in Paar apparatus under 50 Psi hydrogen gas pressure for 3 h. The reaction mixture was cooled and filtered through celite pad. The filtrate was concentrated to afford 0.4 g of the required product which was used for the next step without further purification. Percentage purity (LCMS): 74.3 %, (M+l) = 399.1+1.
e) 4- [3 -(4-(tert-Butoxycarbonylaminomethyl)-phenoxy)-5 -hydroxybenzoyl] - piperazine-1-carboxylic acid ethyl ester
(Boc)2O (0.24 g, 1.1 mmols) was added slowly with stirring to 4-[3-(4-aminomethyl phenoxy)-5-hydroxy benzoyl]piperazine-l-carboxylic acid ethyl ester (0.4 g, 1.0 mmols) in 1,4-dioxane and water ( 1 :1) and stirring was continued for 3 h at RT. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with water followed by brine and dried over anhydrous sodium sulphate and concentrated to afford 0.3 g of the required product. 1H NMR (DMSOd6): δ 1.20 (3H, t), 1.4 (9H, s), 3.5 (8H, ms), 4.2 (4H, m), 6.38 (2H, d), 6.48 (IH, s), 7.02 (2H, d), 7.28 (2H, d), 7.4 (IH, m), 9.8 (IH, s).
f) 4-[3-[4-(teit-Butoxycarbonylaminomethyl)-phenoxy]-5-(4-cyano-phenoxy)- benzoyl] piperazine-1-carboxylic acid ethyl ester
Using 0.3 g (0.6 mmol) of 4-[3-(4-cyano phenoxy)-5-hydroxy benzoyl]piperazine- 1-carboxylic acid ethyl ester and 4-fluorobenzonitrile (0.19 g, 1.5 mmol) and following the procedure of Example 42(b) afforded 0.38 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (3H, t), 1.4 (9H, s), 3.3 (2H, m), 3.4 (4H, m), 3.55 (2H, m), 4.05 (2H, q), 4.15 (2H, m), 6.84 (3H, m), 7.1 (2H, d), 7.26 (4H, d), 7.4 (IH, m), 7.88 (2H, s).
g) 4-[3-(4-Aminomethyl phenoxy)-5-(4-ethoxycarbonimidoyl phenoxy)benzoyl] piperazine-1-carboxylic acid ethyl ester
Using 4-[3-[4-(tert-butoxycarbonylaminomethyl)-phenoxy]-5-(4-cyano-phenoxy)- benzoyl] piperazine-1-carboxylic acid ethyl ester (0.38 g, 0.63 mmol) and following the procedure of Example l(d) afforded 0.17 g of the required product. Percentage purity (LCMS): 81.7 %, (M+l) = 546.2+1.
h) 4-[3-(4-Aminomethylphenoxy)-5-(4-carbamimidoyl phenoxy)benzoyl]- piperazine-1-carboxylic acid ethyl ester
Using 4-[3-(4-aminomethyl phenoxy)-5-(4-ethoxycarbonimidoyl phenoxy)- benzoyl]piperazine-l-carboxylic acid ethyl ester (0.17 g, 0.31 mmol) and following the procedure of Example l(e) afforded 0.07 g of the required product. Percentage purity (HPLC): 97.62 %, (LCMS): 94.31 %. 1H NMR (DMSOd6): δ 1.2 (3 H, t), 3.35 (2H, m), 3.55 (2H, m), 3.9 (6H, m), 4.1 (2H, q), 6.8 (IH, s), 6.85 (2H, m), 7.20 (2H, d), 7.3 (2H, d), 7.5 (2H, d), 7.9 (2H, d), 8.2 (3H, brs), 9.1 (2H, s), 9.3 (2H, s).
Example 84.
N-(4-Amino cyclohexyl)-3-(4-aminomethyl phenoxy)-5-(4-carbamimidoyl phenoxy) benzamide
Intermediates (a) - (c) are the same as in Example 49.
d) { 4- [3 - [4- Aminomethylphenoxy] -5 -hydroxybenzoylamino] cyclohexyl } carbamic acid tert-butyl ester
Using { 4- [3 -(4-cyano-phenoxy)-5 -hydroxy-benzoylamino] -cyclohexyl } -carbamic acid tert-butyl ester (2.0 g, 4.43 mmol) and following the procedure of Example 83(d) afforded 1.5 g of the required product. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (3H, m), 6.48 (IH, s), 6.78 (IH, d), 6.9 (IH, s), 7.0 (2H, m), 7.38 (IH, m), 8.18 (IH, d).
e) {4-[3- [4-tert-Butoxycarbonylaminomethylphenoxy] -5 -hydroxybenzoylamino] - cyclohexyl} carbamic acid tert-butyl ester
Using 1.5 g (3.29 mmol) of {4-[3-[4-aminomethylphenoxy]-5-hydroxybenzoyl- amino] cyclohexyl} carbamic acid tert-butyl ester and boc-anhydride (0.787 g, 3.61 mmol) and following the procedure of Example 83 (e) afforded 1.4 g of the required product. 1H NMR (DMSOd6): δ 1.2 (3H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (2H, m), 3.7 (IH, m), 4.15 (2H, d), 6.45 (IH, s), 6.7 (IH, d), 6.9 (IH, s), 7.0 (3H, d), 7.25 (2H, d), 7.4 (IH, brs), 8.15 (IH, d), 9.8 (IH, s).
f) {4-[3-[4-(tert-Butoxycarbonylamino methyl)phenoxy]-5-(4-cyano phenoxy) benzoylamino] cyclohexyl} carbamic acid tert-butyl ester
Using 1.4 g (2.51 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5- hydroxybenzoylamino] -cyclohexyl} carbamic acid tert-butyl ester and 4-fluoro- benzonitrile (0.76 g, 6.27 mmol) and following the procedure of Example 42(b) afforded 1.53 g of the required product. 1H NMR (DMSOd6): δ 1.3 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (IH, m), 3.7 (IH, m), 4.15 (2H, d), 6.72 (IH, d), 7.20 (IH, s), 7.06 (2H, d), 7.18 (2H, d), 7.28 (2H, d), 7.38 (3H, d), 7.86 (2H, s), 8.3 (IH, d).
g) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy]- benzimidic acid ethyl ester
Using {4-[3-[4-(tert-butoxycarbonylamino methyl)phenoxy]-5-(4-cyano phenoxy) benzoylamino] cyclohexyl} carbamic acid tert-butyl ester (1.53 g, 2.32 mmol) and following the procedure of Example l(d) afforded 1.15 g of the required product. Percentage purity (LCMS): 33.53 %, (M+l) - 502.2+1. h) N-(4-Aminocyclohexyl)-3-(4-aminomethylphenoxy)-5-(4-carbamimidoyl phenoxy) benzamide
Using 4-[3-(4-amino-cyclohexylcarbamoyl)-5-(4-aminomethyl-phenoxy)-phenoxy]- benzimidic acid ethyl ester (1.15 g, 2.28 mmol) and following the procedure of Example l(e) afforded 0.75 g of the required product. Percentage purity (HPLC): 96.64 %, (LCMS): 96.88 %. 1H NMR (DMSOd6): δ 1.45 (4H, t), 1.90 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 4.05 (2H, d), 6.9 (IH, s), 7.18 (2H, d), 7.26 (2H, d), 7.38 (2H, s), 7.52 (2H, d), 7.88 (4H, d), 8.22 (2H, brs), 8.42 (IH, d), 9.2 (2H, brs), 9.3 (2H, s).
Example 85.
(4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)- phenoxy] -phenoxy} -benzyl)-carbamic acid ethyl ester
Intermediates (a) to (d) are the same as in Example 84.
e) (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoylamino}- cyclohexyl)-carbamic acid tert-butyl ester
To 1.0 g (2.19 mmol) of {4-[3-(4-aminomethyl-phenoxy)-5-hydroxy-benzoyl- amino]-cyclohexyl}-carbamic acid tert-butyl ester, dissolved in 5 ml of THF, 0.13 g (5.47 mmol) of sodium hydride was added at 0 °C and the mixture was stirred for 15 min at same temperature. 0.26 g (2.40 mmol) of ethylchloroformate, dissolved in 2 ml of THF, was added dropwise to the stirred solution during 10 min and then the reaction mixture was stirred at RT for 6 h. After raction completion, solvent was removed under reduced pressure and the obtained residue was dissolved in 200 ml of ethyl acetate. Organic layer was washed with (3 x 100 ml) of brine followed by water (2 x 100 ml). Organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.56 g of required product which was used for the next step witout further purification. Percentage purity (LCMS): 59.7 %, (M+l) = 527.2+1. f) (4- { 3 -(4-Cyano-phenoxy)-5- [4-(ethoxycarbonylamino-methyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Using 0.56 g (1.06 mmol) of (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5- hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester and 4-fluoro- benzonitrile (0.32 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 0.61 g of the required product. Percentage purity (LCMS): 45.2 %, (M+ 1) = 628.3+1.
g) (4-{3-[4-(Ethoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(d) (4-{3-(4-cyano-phenoxy)-5-[4-(ethoxy- carbonylamino-methyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester 0.61 g (0.97 mmol) and other reagents were used to afford 0.68 g of the required product. Percentage purity (LCMS): 38.9 %, (M+ 1) = 661.3+1.
h) (4-{3-(4-Amino-cyclohexylcarbamoyl)-5-[4-(N-hydroxycarbamimidoyl)- phenoxy]-phenoxy}-benzyl)-carbamic acid ethyl ester
Using (4- { 3 - [4-(ethoxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-hydroxy carbamimidoyl)-phenoxy] -benzoylamino }-cyclohexyl)-carbamic acid tert-butyl ester (0.68 g, 1.02 mmol) and following the procedure of Example 9(d) afforded 0.28 g of the required product. Percentage purity (HPLC): 97.5 %, (LCMS): 96.6 %. 1H NMR (DMSO-d6): δ 1.24 (3H, t), 1.38 (4H, m), 1.92 (4H, m), 3.0 (IH, m), 3.8 (IH, m), 4.00 (2H, q), 4.20 (2H, d), 6.88 (IH, s), 7.06 (2H, d), 7.22 (2H, d), 7.32 (4H, m), 7.65 (2H, m), 7.78 (5H, m), 8.18 (IH, d), 11.0 (IH, brs).
Example 86. 4- [3 -(4- Aminomethylphenoxy)-5 -(octahydroquinoline- 1 -carbonyl)-phenoxy] - benzmidine Intermediates (a) and (b) are the same as in Example 49.
c) 4-[3-Hydroxy-5-(octahydro quinoline- 1 -carbonyl)phenoxy]benzonitrile
3-(4-Cyano-phenoxy)-5-hydroxy-benzoic acid (1.5 g, 5.87 mmol) and decahydro- quinoline (0.89 g, 6.45 mmol) and other reagents as described in Example 9(e) were used to afford 1.6 g of the required product. 1H NMR (DMSOd6): δ 1.35 (6H, m), 1.80 (7H, m), 3.0 (IH, m), 3.6 (IH, m), 4.5 (IH, m), 6.44 (IH, s), 6.54 (2H, m), 7.16 (2H, d), 7.88 (2H, d), 10.1 (lH, brs).
d) [3-(4-amino methyl phenoxy)-5-hydroxy phenyl] -(octahydro quinolin-1- yl)methanone
Using 4-[3-hydroxy-5-(octahydro quinoline- l-carbonyl)phenoxy] benzonitrile (1.6 g, 4.27 mmol) and following the procedure of Example 83(d) afforded 1.2 g of the required product. Percentage purity (LCMS): 94.5 %, (M+ 1) = 661.3+1.
e) {4-[3-hydroxy-5-(octahydro quinoline- 1 -carbonyl)phenoxy] benzyl }carbamic acid tert-butyl ester
Using 1.2 g (3.17 mmol) of [3-(4-amino methyl phenoxy)-5-hydroxy phenyl]-
(octahydro quinolin-l-yl)methanone and boc-anhydride (0.76 g, 3.48 mmol) and following the procedure of Example 83(e) afforded 1.34 g of the required product.
1H NMR (DMSO-d6):.δ 1.30 (8H, m), 1.40 (9H, s), 1.55 (2H, m), 1.75 (4H, m), 3.0 (IH, m), 3.55(1H, m), 4.1 (2H, d), 6.24 (IH, s), 6.42 (2H, s), 7.0 (2H, d), 7.26 (2H, d), 7.4
(IH, t), 9.8 (IH, s).
f) {4-[3-(4-Cyanophenoxy)-5-(octahydroquinoline-l-carbonyl)phenoxy]benzyl}- carbamic acid tert-butyl ester
Using 1.34 g (2.79 mmol) of {4-[3-hydroxy-5-(octahydroquinoline-l-carbonyl) phenoxy] benzyl }carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.84 g, 6.97 mmol) and following the procedure of Example 42(b) afforded 1.6 g of the required product. 1H NMR (DMSOd6): δ 1.30 (8H, m), 1.40 (9H, s), 1.8 (8H, m), 4.1 (2H, d), 6.68 (IH, s), 6.82 (2H, s), 7.08 (2H, d), 7.22 (2H, d), 7.28 (2H, d), 7.4 (IH, t), 7.88 (2H, d).
g) {4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-l- carbonyl)-phenoxy] benzyl} carbamic acid tert-butyl ester
Following the procedure of Example 2(d) {4-[3-(4-cyanophenoxy)-5-(octahydro- quinoline-l-carbonyl)phenoxy] benzyl} -carbamic acid tert-butyl ester 1.6 g (2.76 mmol) and other reagents were used to afford 1.43 g of the required product. Percentage purity (LCMS): 54.6 %, (M+l) = 612.3+1.
h) { 4- [3 - [4-(N-acetylhydroxycarbamimidoyl)phenoxy] -5 -(octahydro quinoline- 1 - carbonyl)phenoxy]benzyl} carbamic acid tert-butyl ester
{4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-l-carbonyl)- phenoxy] benzyl} carbamic acid tert-butyl ester, 1.4 g (2.28 mmol) was acetylated with 0.26 g (2.5 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 1.04 g of the required product. Percentage purity (LCMS): 36.1 %, (M+l) = 654.3+1.
i) 4-[3-(4-Aminomethylphenoxy)-5-(octahydroquinoline- 1 -carbonyl)phenoxy] benzmidine
1.0 g (1.52 mmol) of {4-[3-[4-(N-acetylhydroxycarbamimidoyl)phenoxy]-5-
(octahydro quinoline-l-carbonyl)phenoxy]benzyl} carbamic acid tert-butyl ester was reduced using the procedure of Example 2(f) to afford 0.43 g of the required product. Percentage purity (HPLC): 83.4 %, (LCMS): 96.26 %. 1H NMR (DMSO-d6): δ 1.3 (5H, m), 1.55 (2H, m), 1.75 (5H, m), 2.7 (IH, m), 3.05 (IH, m), 4.0 (2H, d), 4.25 (IH, m), 4.45 (IH, m), 6.75 (4H, m), 7.2 (2H, d), 7.3 (2H, d), 7.55 (2H, d), 7.9 (2H, d), 8.4 (3H, brs), 9.1 (2H, s), 9.4 (2H, s) Example 87.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6- difluoro-phenoxy)-benzamide
Intermediates (a) and (e) are the same as in Example 84.
f) { 4- [3 - [4-(tert-Butoxycarbonylamino-methyl)-phenoxy] -5 -(4-cyano-2,6-difluoro- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using 0.5 g (0.89 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5- hydroxybenzoylaminoj-cyclohexyl} carbamic acid tert-butyl ester and 3,4,5-trifluoro- benzonitrile (0.34 g, 2.22 mmol) and following the procedure of Example 42(b) afforded 0.4 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.38 (18H, d), 1.78 (4H, m), 3.18 (IH, m), 3.64 (IH, m), 4.12 (2H, d), 6.74 (IH, d), 6.90 (IH, s), 7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40 (IH, m), 8.08 (2H, d), 8.32 (IH, d).
g) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N- hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2,6- difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.4 g, 0.57 mmol) and following the procedure of Example 2(d) afforded 0.45 g of the required product. Percentage purity (LCMS): 83.53 %, (M+l) = 525.2+1 (de-bis BOC product mass).
h) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N- acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexy l)-carbamic acid tert- butyl ester
Using (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N- hydroxycarbamimidoy l)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester (0.45 g, 0.62 mmol) and following the procedure of Example 2(e) afforded 0.5 g of the required product. Percentage purity (LCMS): 81.00 %, (M+ 1) = 667.2+1 (de-BOC product mass).
i) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2,6- difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2,6-difluoro-4-(N- acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert- butyl ester 0.5 g (0.65 mmol) was reduced using the procedure of Example 2(f) to afford 0.3 g of the required product. Percentage purity (LCMS): 85.0 %, (M+l) = 709.3+1.
j) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2,6- difluoro-phenoxy)-benzamide
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl- 2,6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.3 g, 0.42 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 97.83 %, (LCMS): 92.22 %. 1H NMR (DMSOd6): δ 1.44 (4H, m), 1.88 (4H, m), 3.02 (IH, m), 3.48 (IH, m), 4.05 (2H, d), 6.92 (IH, s), 7.14 (2H, d), 7.25 (2H, d), 7.50 (2H, d), 7.90 (5H, m), 8.25 (3H, brs), 8.44 (IH, d), 9.52 (4H, d).
Example 88.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2- trifluoromethyl-phenoxy)-benzamide
Intermediates (a) and (e) are the same as in Example 84.
g) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2- trifluoromethyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester Using 0.46 g (0.82 mmol) of {4-[3-[4-tert-butoxycarbonylaminomethylphenoxy]-5- hydroxybenzoylamino]-cyclohexyl} carbamic acid tert-butyl ester and 4-fluoro-3-tri- fluoromethylbenzonitrile (0.313 g, 1.65 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.38 (18H, d), 1.8 (4H, m), 3.18 (IH, m), 3.64 (IH, m), 4.12 (2H, d), 6.75 (IH, d), 7.02 (IH, s), 7.08 (2H, d), 7.20 (IH, d), 7.28 (2H, d), 7.41 (3H, m), 8.1 (IH, m), 8.38 (2H, m).
h) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4- (N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert- butyl ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-2-tri- fluoromethyl-phenoxy)-benzoylamino]-cyclohexyl} -carbamic acid tert-butyl ester (0.3 g, 0.41 mmol) and following the procedure of Example 2(d) afforded 0.3 g of the required product. Percentage purity (LCMS): 75.8 %, (M+ 1) = 557.2+1 (de-bis BOC product mass).
i) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4- (N-acetylhydroxycarbamimidoyty-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester
Using (4- { 3 - [4-(tert-Butoxycarbonylamino-methyl)-phenoxy] -5 - [2-trifiuoromethyl- 4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert- butyl ester (0.3 g, 0.39 mmol) and following the procedure of Example 2(e) afforded 0.35 g of the required product. Percentage purity (LCMS): 59.00 %, (M+ 1) = 699.2+1 (de-BOC product mass).
j) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-2- trifluoromethyl-phenoxy)-benzoylamino]-cyclohexyl} -carbamic acid tert-butyl ester (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[2-trifluoromethyl-4-(N- acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert- butyl ester 0.35 g (0.47 mmol) was reduced using the procedure of Example 2(f) to afford 0.2 g of the required product. Percentage purity (LCMS): 70.0 %, (M+l) = 741.3+1.
k) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(4-carbamimidoyl-2- trifluoromethyl-phenoxy)-benzamide
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-
2,6-difluoro-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.3 g, 0.42 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 99.55 %, (LCMS): 96.52 %. 1H NMR (DMSOd6): δ 1.44 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 3.0 (IH, m), 3.6 (IH, m), 4.05 (2H, d), 7.08 (IH, s), 7.22 (2H, d), 7.30 (IH, d), 7.42 (2H, d), 7.52 (2H, d), 7.88 (3H, brs), 8.08 (IH, d), 8.22 (2H, brs), 8.28 (IH, s), 8.48 (IH, d), 9.45 (4H, d).
Example 89.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-2,6-difluoro-phenoxy)-5-(4- carbamimidoyl-phenoxy)-benzamide
a) 3-(4-Cyano-2,6-difluoro-phenoxy)-5-hydroxy-benzoic acid ethyl ester
Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a) afforded 1.2 g of the required product. 1H NMR (DMSOd6): δ 1.28 (3H, t), 4.27 (2H, q), 6.67 (IH, t), 6.92 (IH, s), 7.18 (IH, s), 8.08 (2H, d), 10.20 (IH, brs).
b) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-hydroxy- benzoic acid ethyl ester 0.9 g (2.82 mmol) of 3 -(4-cyano-2,6-difluoro-phenoxy)-5 -hydroxy-benzoic acid ethyl ester was dissolved in 50 ml of methanol and 1.23 g (5.64 mmol) of di-tert-butyl dicarbonate was slowly added at 0 0C. Nickel chloride (60.0 mg, 0.28 mmol) and sodium borohydride (0.75 g, 19.74 mmol) were added at 0 °C at 10 min interval each. After complete addition the reaction mixture was stirred at RT for 30 min. Then 0.3 g (3.22 mmol) of diethylenetriamine was added during 15 min and finally reaction . mixture was stirred for 2 h at RT. Reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with 2 x 100 ml solution of saturated sodium bicarbonate solution and then with 2 x 100 ml of saturated brine solution, dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography using hexane-ethyl acetate (10 : 2) to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (3 H, t), 1.40 (9H, s), 4.18 (2H, d), 4.28 (2H, q) 6.60 (IH, s), 6.84 (IH, s), 7.10 (IH, s), 7.18 (2H, d), 7.54 (IH, t), 10.2 (IH, brs).
c) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano- phenoxy)-benzoic acid ethyl ester
Using 0.5 g (1.18 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro- phenoxy]-5-hydroxy-benzoic acid ethyl ester and 4-fluorobenzonitrile (0.21 g, 1.77 mmol) and following the procedure of Example 42(b) afforded 0.3 g of the required product. 1H NMR (DMSOd6): δ 1.25 (3H, t), 1.42 (9H, s), 4.2 (2H, d), 4.28 (2H, q), 7.22 (6H, m), 7.32 (IH, s), 7.54 (IH, t), 7.90 (2H, d).
d) 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano- phenoxy)-benzoic acid
1.1 g (2.09 mmol) of 3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro- phenoxy]-5-(4-cyano-phenoxy)-benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 0.8 g of the required product. 1H NMR (DMSO- Cl6): δ 1.42 (9H, s), 4.22 (2H, d), 7.25 (7H, m), 7.52 (IH, m), 7.90 (2H, s), 12.4 (IH, brs).
e) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difIuoro-phenoxy]-5-(4-cyano- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano- phenoxy)-benzoic acid (0.6 g, 1.2 mmol) and (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (0.28 g, 1.3 mmol) and other reagents as described in Example 9(e) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.42 (18H, s), 1.8 (4H, m), 3.18 (IH, m), 3.64 (IH, m), 4.20 (2H, d), 6.74 (IH, d), 7.0 (IH, s), 7.16 (4H, m), 7.24 (IH, s), 7.38 (IH, s), 7.54 (IH, t), 7.88 (2H, d), 36 (IH, d).
f) (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N- hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4- cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.53 g, 0.76 mmol) and following the procedure of Example 2(d) afforded 0.6 g of the required product. Percentage purity (LCMS): 74.23 %, (M+l) = 725.3+1.
g) (4- { 3 - [4-(tert-Butoxycarbonylamino-methyl)-2 ,6-difluoro-phenoxy] -5 - [4-(N- acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert- butyl ester
Using (4-{3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N- hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester (0.6 g, 0.82 mmol) and following the procedure of Example 2(e) afforded 0.6 g of the required product. Percentage purity (LCMS): 21.0 %, (M+l) = 667.2+1 (de-BOC product mass). h) {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difiuoro-phenoxy]-5-(4- carbamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
(4-{3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-[4-(N- acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert- butyl ester 0.6 g (0.78 mmol) was reduced using the procedure of Example 2(f) to afford 0.35 g of the required product. Percentage purity (LCMS): 75.0 %, (M+ 1) = 709.3+1.
i) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-2,6-difluoro-phenoxy)-5-(4- carbamimidoyl-phenoxy)-benzamide
Using {4-[3-[4-(tert-Butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4- carbamimidoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.35 g, 0.49 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 98.72 %, (LCMS): 96.32 %. 1H NMR (DMSOd6): δ 1.38 (4H, m), 1.85 (2H, m), 1.95 (2H, m), 2.98 (IH, m), 3.65 (IH, m), 4.14 (2H, d), 6.98 (IH, t), 7.22 (3H, m), 7.38 (IH, s), 7.50 (2H, d), 7.90 (5H, m), 8.45 (3H, m), 9.30 (4H, d).
Example 90.
1 -[3 ,5-Bis-(4-carbamimidoyl-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
Intermediates (a) and (b) are the same as in Example 26.
c) l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid ethyl ester
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.6 g (1.68 mmol) and piperidine-4-carboxylic acid ethyl ester (0.31 g, 2.02 mmol) were used to afford 0.54 g of the required product. 1H NMR (DMSOd6): δ 1.18 (3 H, t), 1. 5 (2H, m), 1.82 (2H, m), 2.6 (IH, m), 2.90 (IH, m), 3.12 (IH, m), 3.52 (IH, m), 4.08 (2H, q), 4.25 (IH, m), 6.96 (2H, d), 7.06 (IH, t), 7.26 (4H, d), 7.88 (4H, d). d) 1 -[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid
0.48 g (0.96 mmol) of l-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4- carboxylic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 0.4 g of the required product. 1H NMR (DMSOd6): δ 1.28 (2H, m), 1.5 (2H, m), 1.82 (2H, m), 3.10 (IH, m), 3.58 (IH, m), 4.24 (IH, m), 6.98 (IH, d), 7.16 (2H, m), 7.25 (4H, m), 7.88 (4H, m), 12.5 (IH, brs).
e) l-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidine-4- carboxylic acid
Using l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidine-4-carboxylic acid (0.4 g, 0.85 mmol) and following the procedure of Example 2(d) afforded 0.4 g of the required product. Percentage purity (LCMS): 95.0 %, (M+ 1) = 531.0+1.
f) l-IS^-Bis-^-^arbamimidoy^-phenoxyJ-benzoylJ-piperidine^-carboxylic acid
l-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidine-4- carboxylic acid 0.4 g (0.74 mmol) was reduced using the procedure of Example 2(f) to afford 0.1 g of the required product. Percentage purity (HPLC): 95.33 %, (LCMS):
98.43 %. 1H NMR (DMSO-d6): δ 1.48 (2H, m), 1.85 (2H, m), 2.92 (IH, m), 3.10 (IH, m), 3.58 (IH, m), 4.25 (2H, m), 6.92 (2H, d), 7.0 (IH, t), 7.32 (4H, d), 7.88 (4H, d), 9.12 (4H, brs), 9.28 (4H, brs).
Example 91.
4- { 1 - [3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-benzoyl] -piperidin-4-yl } -butyric acid
Intermediates (a) and (b) are the same as in Example 26.
c) 4-{l -[3, 5 -Bis-(4-cyano-phenoxy)-benzoyl] -piperidin-4-yl} -butyric acid ethyl ester Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.37 mmol) and 4-piperidin-4-yl-butyric acid ethyl ester (0.68 g, 3.7 mmol) were used to afford 0.9 g of the required product. 1H NMR (DMSOd6): δ 1.20 (4H, m), 1. 52 (5H, m), 1.70 (IH, m), 2.3 (2H, t), 2.68 (IH, m), 3.6 (3H, s), 4.4 (2H, q), 4.25 (IH, m), 6.95 (2H, d), 7.04 (IH, t), 7.25 (4H, d), 7.88 (4H, d).
d) 4-(l-{3,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoyl } -piperidin-4-yl)- butyric acid ethyl ester
Using 4-{ l-[3,5-Bis-(4-cyano-phenoxy)-benzoyl]-piperidin-4-yl}-butyric acid ethyl ester (1.0 g, 1.91 mmol) and following the procedure of Example 2(d) afforded 1.1 g of the required product. Percentage purity (LCMS): 28.2 %, (M+ 1) = 589.2+1.
e) 4-(l-{3,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } - piperidin-4-yl)-butyric acid ethyl ester
Using 4-( 1 - { 3 ,5-bis- [4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoyl } -piperidin-4- yl)-butyric acid ethyl ester (1.0 g, 1.65 mmol) and following the procedure of Example 2(e) afforded 0.6 g of the required product. Percentage purity (LCMS): 38.0 %, (M+l) = 673.2+1.
f) 4-( 1 - { 3 ,5-Bis-[4-(carbamimidoyl)-phenoxy] -benzoyl } -piperidin-4-yl)-butyric acid ethyl ester
4-(l-{3 ,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoyl } -piperidin-4- yl)-butyric acid ethyl ester 0.6 g (0.87 mmol) was reduced using the procedure of Example 2(f) to afford 0.14 g of the required product. Percentage purity (HPLC): 90.04 %, (LCMS): 81.94 %. 1H NMR (DMSOd6): δ 1.20 (2H, m), 1. 52 (4H, m), 1.70 (IH, m), 2.30 (2H, t), 2.7 (2H, m), 3.0 (IH, m), 3.6 (3H, s), 4.4 (2H, m), 6.9 (2H, s), 7.0 (IH, s), 7.32 (4H, d), 7.88 (4H, d), 9.25 (8H, brs).
Example 92. 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]- benzoic acid
Intermediates (a) - (c) are the same as in Example 49.
d) { 4- [3 -(4-Cyano-phenoxy)-5 -(4-formyl-phenoxy)-benzoylamino] -cyclohexyl } - carbamic acid tert-butyl ester
Using 3.0 g (6.6 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]- cyclohexyl} -carbamic acid tert-butyl ester and 4-fluorobenzaldehyde (1.66 g, 13.3 mmol) and following the procedure of Example 42(b) afforded 2.2 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (IH, m), 3.68 (IH, m), 6.75 (IH, d), 7.25 (4H, m), 7.50 (2H, s), 7.82 (2H, d), 7.95 (2H, d), 8.38 (IH, d), 9.94 (IH, s).
e) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)- phenoxy] -benzoic acid
0.5 g (0.9 mmol) of {4-[3-(4-cyano-phenoxy)-5-(4-formyl-phenoxy)-benzoyl- amino] -cyclohexyl} -carbamic acid tert-butyl ester was dissolved in 15 ml of THF and 0.43 g (2.7 mmol) of potassium permanganate, dissolved in 8 ml of water, was added to THF solution at 10 °C during 10 min. The reaction mixture stirred over night at RT. Reaction progress was monitored by TLC. Reaction mixture was filtered through celite and washed with THF and thus obtained mother liquor was concentrated under vacuo. Product was crystallized with ethyl acetate to afford 0.25 g of the required product. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.36 (9H, s), 1.78 (4H, m), 3.18 (IH, m), 3.66 (IH, m), 6.75 (IH, d), 6.94 (3H, m), 7.18 (2H, d), 7.36 (2H, s), 7.86 (4H, d), 8.38 (IH, d).
f) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-pherioxy)- phenoxy] -benzoic acid benzyl ester 0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4- cyano-phenoxy)-phenoxy] -benzoic acid was dissolved in 5 ml of DMF. At 0 °C 50 mg (0.35 mmol) of potassium carbonate followed by 45 mg (0.26 mmol) benzylbromide were added and the reaction mixture was stirred for 4 h at RT. Reaction progress was monitored by TLC. Upon completion of the reaction the contents were diluted with 50 ml of ice- water and extarted with 3 x 50 ml of ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude residue was purified by column chromatography using 60-120 mesh silica-gel and eluted with ethylacetate : hexane (1 : 9) to give 0.38 mg of the required product. 1H NMR (DMSO- d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (IH, m), 3.66 (IH, m), 5.36 (2H, s), 6.76 (IH, d), 7.22 (5H, m), 7.46 (7H, m), 7.88 (2H, d), 8.05 (2H, d), 8.36 (IH, d).
g) 4- { 3 -(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5 - [4-(N- hydroxycarbamimidoyl)-phenoxy]-phenoxy} -benzoic acid benzyl ester
Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxy] -benzoic acid benzyl ester (0.4 g, 0.61 mmol) and following the procedure of Example 2(d) afforded 0.39 g of the required product. Percentage purity (LCMS): 52.0 %, (M+ 1) = 694.3+1.
h) 4-{3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-acetyl- hydroxycarbamimidoyl)-phenoxy]-phenoxy} -benzoic acid benzyl ester
Using 4- { 3 -(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5 - [4-(N- hydroxycarbamimidoyl)-phenoxy]-phenoxy} -benzoic acid benzyl ester (0.39 g, 0.56 mmol) and following the procedure of Example 2(e) afforded 0.41 g of the required product. Percentage purity (LCMS): 53.0 %, (M+ 1) = 680.5+1 (Boc-acid mass).
i) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl- phenoxy)-phenoxy] -benzoic acid 4-{3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-phenoxy} -benzoic acid benzyl ester 0.41 g (0.56 mmol) was reduced using the procedure of Example 2(f) to afford 0.13 g of the required product. Percentage purity (LCMS): 74.1 %, (M+ 1) = 587.1+1.
j ) N-(4- Amino-cyclohexyl)-3 ,5 -bis-(4-carbamimidoyl-phenoxy)-benzamide
Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-carbam- imidoyl-phenoxy)-phenoxy]-benzoic acid (0.13 g, 0.22 mmol) and following the procedure of Example 9(d) afforded 35 mg of the required product. Percentage purity (HPLC): 97.00 %, (LCMS): 93.86 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.92 (4H, m), 3.02 (IH, m), 3.70 (IH, m), 7.02 (IH, s), 7.15 (2H, d), 7.35 (2H, d), 7.45 (2H, d), 7.76 (IH, brs), 7.88 (4H, dd), 8.40 (IH, d), 8.88 (2H, brs), 9.25 (2H, brs).
Example 93.
4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]- benzoic acid ethyl ester
Intermediates (a) - (c) are the same as in Example 49.
d) 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)- phenoxy] -benzoic acid ethyl ester
Using 2.0 g (4.4 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester and 4-fluoro-benzoic acid ethyl ester (1.2 g, 6.6 mmol) and following the procedure of Example 42(b) afforded 1.8 g of the required product. 1H NMR (DMSO-d6): δ 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.2 (IH, m), 3.68 (IH, m), 4.30 (2H, q), 6.75 (IH, d), 7.20 (5H, m), 7.48 (2H, d), 7.88 (2H, d), 8.00 (2H, d), 8.36 (lH, d).
e) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)- phenoxy] -benzoic acid ethyl ester Using 4-[3-(4-tert-Butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxy] -benzoic acid ethyl ester (0.6 g, 1.0 mmol) and following the procedure of Example l(d) afforded 0.55 g of the required product. Percentage purity (LCMS): 96.0 %, (M+l) = 545.4+1.
f) 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamimidoyl-phenoxy)-phenoxy]- benzoic acid
Using 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-ethoxycarbonimidoyl-phenoxy)- phenoxy] -benzoic acid (0.45 g, 0.82 mmol) and following the procedure of Example l(e) afforded 0.25g of the required product. Percentage purity (HPLC): 97.88 %, (LCMS): 95.45 %. 1H NMR (DMSO-d6): δ 1.45 (4H, m), 1.95 (4H, m), 3.0 (2H, m), 3.4 (IH, m), 4.34 (2H, m), 7.1 (IH, s), 7.18 (2H, d), 7.3 (2H, d), 7.5 (2H, d) 7.9 (4H, m), 8.0 (2H, d), 8.4 (IH, m), 9.00 (2H, brs), 9.26 (2H, brs).
Example 94.
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl- phenoxy)-benzamide
Intermediates (a) - (e) are the same as in Example 92.
f) {4-[3-(4-Carbamoyl-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclo- hexyl}-carbamic acid tert-butyl ester
0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4- cyano-phenoxy)-phenoxy] -benzoic acid was dissolved in 15 ml of THF. At -10 °C 0.18 ml (1.57 mmol) of N-methylmorpholine was added. The reaction mixture was stirred for 15 min at 0 0C. 0.14 ml (1.36 mmol) of tert-butylchloroformate was added and the reaction mixture was stirred for 1 h at RT. Further 6.0 ml of 30 % of ammonia solution was added during 10 min at 0 °C and reaction progress was monitored by TLC. Upon completion of the reaction the contents were diluted with 50 ml ethyl acetate. Organic layer was separated and washed with 3 x 50 ml saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 0.4 g of the required product. Percentage purity (LCMS): 60.0 %, (M+l) = 570.2.
g) 4- [3 -(4- Amino-cyclohexylcarbamoyl)-5 -(4-carbamoyl-phenoxy)-phenoxy] - benzimidic acid ethyl ester
Using {4- [3 -(4-carbamoyl-phenoxy)-5 -(4-cyano-phenoxy)-benzoylamino] - cyclohexyl}-carbamic acid tert-butyl ester (0.45 g, 0.79 mmol) and following the procedure of Example l(d) afforded 0.48 g of the required product. Percentage purity (LCMS): 77.0 %, (M+l) = 516.1+1.
h) N-(4- Amino-cyclohexyl)-3 -(4-carbamimidoyl-phenoxy)-5 -(4-carbamoyl- phenoxy)-benzamide
Using 4-[3-(4-Amino-cyclohexylcarbamoyl)-5-(4-carbamoyl-phenoxy)-phenoxy]- benzimidic acid ethyl ester (0.48 g, 0.93 mmol) and following the procedure of Example l(e) afforded 0.055g of the required product. Percentage purity (HPLC): 97.22 %, (LCMS): 93.33 %. 1H NMR (DMSOd6): δ 1,45 (4H, m), 1.90 (4H, m), 3.0 (IH, m), 3.7 (IH, m), 7.0 (IH, s), 7.15 (2H, d) 7.32 (3H, d), 7.45 (2H, d), 7.88 (6H, m), 8.40 (IH, d), 8.88 (2H, brs), 9.25 (2H, brs).
Example 95.
4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclohexanecarboxylic acid ethyl ester
Intermediates (a) and (b) are the same as in Example 26.
c) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexanecarboxylic acid ethyl ester Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.0 g (2.6 mmol) and 4-amino-cyclohexanecarboxylic acid ethyl ester (0.48 g, 2.6 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSOd6): δ 1.34 (5H, m), 1.41 (5H, m), 1.92 (4H, m), 2.1 (IH, t), 3.81 (IH, m), 4.12 (2H, q), 7.04 (4H, dd), 7.51 (2H, s), 7.89 (3H, d),8.41(lH,d). Percentage purity (HPLC): 89.3 %.
d) 4- { 3 ,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclo- hexanecarboxylic acid ethyl ester
0.6 g (1.17 mmol) of 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-cyclohexane- carboxylic acid ethyl ester was dissolved in 30 ml of ethanol and 0.2 ml (9.4 mmol) of 50 % aqueous solution of hydroxylamine was added at RT during 5 min. The reaction mixture stirred for 6 h at 80 °C. Reaction progress was monitored by TLC. Reaction mixture was cooled to RT and solvent was removed under reduced pressure and thus obtained crude product, yield 0.6 g, was subjected to the next step without further purification. Percentage purity (HPLC): 80 %, (LCMS): 83.3%, (M+l) = 575.23+1.
e) 4- { 3 ,5 -Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexanecarboxylic acid ethyl ester
Using 4- { 3 ,5 -bi s- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexanecarboxylic acid ethyl ester (0.6 g, 1.14 mmol) and following the procedure of Example 2(e) afforded 0.5 g of the required product. Percentage purity (LCMS): 55.3 %, (M+l) = 659.3+1.
f) 4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclohexanecarboxylic acid ethyl ester
Using 4- { 3 , 5 -bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -benzoylamino } - cyclohexanecarboxylic acid ethyl ester (0.45 g, 0.68 mmol) and following the procedure of Example 2(f) afforded 0.25g of the required product. Percentage purity (HPLC): 92.31 %, (LCMS): 91.81 %. 1H NMR (DMSO-d6): δ 1.1 (3H, t), 1.31 (4H, m), 1.90 (4H, m), 2.21 (IH, m), 3.0 (IH, m), 4.12 (2H, q), 7.21 (7H, dd) , 7.90 (4H, d), 8.52 (IH, d), 9.21 (8H, d).
Example 96. 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.1 g (0.28 mmol) and 4-amino-cyclohexanol (0.046 g, 0.42 mmol) were used to afford 0.05 g of the required product. Percentage purity (LCMS): 92.3 %, (M+l) = 453.1+1.
d) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohexyl)- benzamide
Using 3,5-bis-(4-cyano-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide (0.5 g, 1.10 mmol) and following the procedure of Example 95(d) afforded 0.45 g of the required product. Percentage purity (LCMS): 81.1 %, (M+l ) = 519.3+1.
e) 3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy- cyclohexyl)-benzamide
Using 3 ,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy-cyclohexyl)- benzamide (0.5 g, 0.96 mmol) and following the procedure of Example 2(e) afforded 0.40 g of the required product. Percentage purity (LCMS): 49.2 %, (M+l) = 603.3+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-hydroxy-cyclohexyl)-benzamide
Using 3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-hydroxy- cyclohexyl)-benzamide (0.4 g, 0.66 mmol) and following the procedure of Example 2(f) afforded 0.2 g of the required product. Percentage purity (HPLC): 97.19 %, (LCMS): 93.81 %. 1H NMR (DMSOd6): δ 1.21 (4H, m), 1.89 (4H, m), 3.11 (IH, m), 3.7 (IH, m), 7.11 (IH, t), 7.45 (4H, d), 7.51 (2H, d), 7.88 (4H, d), 8.40 (IH, d), 9.4 (8H, d).
Example 97.
N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(6-amino-pyridin-3- yloxy)-benzamide
Intermediates (a) and (e) are the same as in Example 84.
f) (4- { 3 -(6-Nitro-pyridin-3 -yloxy)-5 - [4-(tert-butoxycarbonylamino-methyl)- phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 69(b) (4-{3-[4-(tert-Butoxycarbonylamino- methyl)-phenoxy]-5-hydroxy-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
0.4 g (0.72 mmol) and 5-bromo-2-nitro-pyridine (0.17 g, 0.86 mmol) were used to afford 0.3 g of the required product. 1H NMR (DMSOd6): δ 1.31 (18H, d), 1.8 (4H, d), 3.20 (2H, m), 3.8 (2H, m), 4.1(2H,d), 7.35 (3H, d), 7.4 (3H, m), 7.9 (IH, d), 8.35 (2H, d), 8.5 (IH, s). , g) (4-{3-(6-Amino-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino-methyl)- phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 62(e) (4-{3-(6-Nitro-pyridin-3-yloxy)-5-[4- (tert-butoxycarbonylamino-methyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester 0.3 g (0.44 mmol) was used to afford 0.2 g of the required product. Percentage purity (LCMS): 68.4 %, (M+ 1) = 647.3+1.
h) N-(4-Amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-(6-amino-pyridin-3- yloxy)-benzamide Using (4-{3-(6-Amino-pyridin-3-yloxy)-5-[4-(tert-butoxycarbonylamino- methyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.2 g, 0.30 mmol) and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 95.31 %, (LCMS): 97.4%. 1H NMR (DMSOd6): δ 1.28 (4H, m), 1.91 (4H, dd), 2.91 (IH, m), 3.8 (IH, m), 4.1 (2H, d), 6.91 (2H, m), 7.21 (4H, m), 7.51 (2H, d), 7.91 (5H, m), 8.3 (3H, brs).8.45 (IH, d).
Example 98.
4- [3 - [4-(2- Amino-ethyl)-piperidine- 1 -carbonyl] -5 -(4-aminomethyl-phenoxy)- phenoxyj-benzamidine
Intermediates (a) and (b) are the same as in Example 49.
c) (2-{l-[3-(4-Cyano-phenoxy)-5-hydroxy-benzoyl]-piperidin-4-yl}-ethyl)- carbamic acid tert-butyl ester
Following the procedure of Example 9(e) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 1.6 g (6.3 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.43 g, 6.27 mmol) were used to afford 2.0 g of the required product. Percentage purity (LCMS): 79.6 %, (M+l) = 465.2+1.
d) [2-(l-{3- [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 -hydroxy-benzoyl } - piperidin-4-yl)-ethyl] -carbamic acid tert-butyl ester
Nickelchloride (0.1 g, 0.4 mmols) and Boc-anhydride (1.9 g, 0.8 mmol) were added to a stirred solution of (2-{l-[3-(4-cyano-phenoxy)-5-hydroxy-benzoyl]- piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester (2.0 g, 4.3 mmol) dissolved in methanol (50 ml) at 0 °C. Sodiumborohydride (1.1 g, 30.1 mmol) was added in portions over 30 min at 0 °C. The obtained reaction mixture was stirred at RT for 2 h. After reaction completion solvent was evaporated under vacuo. Thus obtained residue was partitioned between ethylacetate (150 ml) and saturated solution of sodiumbicarbonate (75 ml) and stirred to get a clear layer. Organic layer was separated and further washed with saturated aqueous solution of sodiumbicarbonate and dried over anhydrous sodium sulphate. Thus obtained crude product was subjected to column chromatography using silica gel as an absorbent and eluted using ethylacetate: hexane (20:80) mixture to afford 1.2 g of the required product. Percentage purity (LCMS): 68.2%, (M+l) = 569.1+1.
e) (2-{l-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)- benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester
Using 1.2 g (2.1 mmol) of [2-(l-{3-[4-(tert-Butoxycarbonylamino-methyl)- phenoxy]-5-hydroxy-benzoyl}-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.5 g, 4.2 mmol) and following the procedure of Example 42(b) afforded 0.61O g of the required product. Percentage purity (LCMS): 89.1%, (M+l) = 670.3+1.
f) [2-(l-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoyl }-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester
Using (2-{ 1 -[3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano- phenoxy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester (0.8 g, 1.19 mmol) and following the procedure of Example 95(d) afforded 0.76 g of the required product. Percentage purity (LCMS): 69.14 %, (M+l) = 703.2+1.
g) [2-(l-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetyl- hydroxycarbamimidoyl)-phenoxy]-benzoyl}-piperidin-4-yl)-ethyl]-carbamic acid tert- butyl ester
Using [2-( 1 - { 3 - [4-(tert-Butoxycarbonylamino-methyl)-phenoxy] -5- [4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoyl }-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester (0.75 g, 1.07 mmol) and following the procedure of Example 2(e) afforded 0.80 g of the required product. Percentage purity (LCMS) : 73.97 %, (M+ 1) = 745.2+1. h) (2-{ l-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl- phenoxy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester
[2-(l-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetyl hydroxycarbamimidoyl)-phenoxy] -benzoyl } -piperidin-4-yl)-ethyl] -carbamic acid tert- butyl ester 0.8 g (1.07 mmol) was reduced using the procedure of Example 2(f) to afford 0.70 g of the required product. Percentage purity (LCMS): 92.8 %, (M+l) = 687.1+1.
i) 4-[3-[4-(2-Amino-ethyl)-piperidine- 1 -carbonyl]-5-(4-aminomethyl-phenoxy)- phenoxy]-benzamidine
Using (2-{l-[3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-(4- carbamimidoyl-phenoxy)-benzoyl]-piperidin-4-yl}-ethyl)-carbamic acid tert-butyl ester (0.70 g, 1.02 mmol) and following the procedure of Example 9(d) afforded 0.20 g of the required product. Percentage purity (HPLC): 98.22 %, (LCMS): 95.01 %. 1H NMR
(DMSO-d6): δ 1.21 (6H, m), 2.82 (4H, s), 3.02 (2H, m), 3.5 (2H, m), 4.52 (IH, m), 6.81 (3H, d), 7.21 (4H, dd), 7.51 (2H, d), 7.88 (2H, d).
Example 99. N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl- phenoxy)-benzamide
Intermediates (a) — (e) are the same as in Example 92.
f) {4-[3-(4-Cyano-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylamino]- cyclohexyl} -carbamic acid tert-butyl ester
0.7 g (1.22 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5- (4-cyano-phenoxy)-phenoxy]-benzoic acid was dissolved in 10 ml of DMF. At 0 °C 0.125 mg (1.83 mmol) of N-methylaminehydrochloride, 0.37 mg (1.96 mmol) of EDC, 0.2 mg (1.47 mmol) of HOBt and 0.49 ml (2.69 mmol) of DIPEA were added and the resulting reaction mixture was stirred overnight at RT. Reaction progress was monitored by TLC. After reaction completion, mixture was diluted with ice- water and thus obtained white solid was filtered off and washed with water and then with hexane. Thus obtained crude product was subjected to coloumn chromatography using silica-gel as an adsorbent and the product was eluted with 50-70 % of ethylacetate:hexane mixture to afford 0.45 g of the required product. Percentage purity (LCMS): 91.9 %, (M+l) = 484.1+1. lH NMR (DMSO-dό): δ 1.21(4H,d), 1.31 (9H, s), 1.92 (4H, s), 2.81 (3H, d),3.11(1H,S),3.71(1H,S), 6.81 (IH, s), 7.35 (6H, d), 7.91 (4H, s), 8.32 (2H, d)
g) {4-[3-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using {4-[3-(4-Cyano-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester (0.61 g, 1.04 mmol) and following the procedure of Example 95(d) afforded 0.56 g of the required product. Percentage purity (LCMS): 89.6 %, (M+l) = 617.1+1.
h) {4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using 4{4-[3-[4-(N-Hydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.56 g, 0.90 mmol) and following the procedure of Example 2(e) afforded 0.53 g of the required product. (LCMS): 91.7 %, (M+l) = 659.1+1.
i) {4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)-benzoyl- amino]-cyclohexyl}-carbamic acid tert-butyl ester
Using {4-[3-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-5-(4-methylcarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.53 g, 0.80 mmol) and following the procedure of Example 2(f) afforded 0.25g of the required product. (LCMS): 94.5 %. (M+l) = 601.1+1. j) N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl- phenoxy)-benzamide
Using {4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methylcarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.50 g, 0.83 mmol) and following the procedure of Example 9(d) afforded 0.40 g of the required product. Percentage purity (HPLC): 98.72 %, (LCMS): 97.22 %. 1H NMR (DMSOd6): δ 1.31 (4H, m), 1.92 (4H, d), 2.81 (3H, d), 3.02 (IH, brs), 3.62 (IH, brs), 7.22 (7H, m), 7.91 (7H, m) 8.40 (2H, d), 9.12 (4H, d).
Example 100.
N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-dimethyl- carbamoyl-phenoxy)-benzamide
Intermediates (a) - (e) are the same as in Example 92.
f) {4-[3-(4-Cyano-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester
Using 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano- phenoxy)-phenoxy] -benzoic acid (0.7 g, 1.225 mmol) and following the procedure of Example 99(f) afforded 0.51g of the required product. Percentage purity (LCMS): 93.7 %, (M+1) = 598.1+1.
g) (4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)- phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Using {4- [3 -(4-cyano-phenoxy)-5 -(4-dimethylcarbamoyl-phenoxy)-benzoylamino] - cyclohexyl}-carbamic acid tert-butyl ester (0.6 g, 1.01 mmol) and following the procedure of Example 95(d) afforded 0.57 g of the required product. Percentage purity (LCMS): 93.2 %, (M+l) = 631.1+1. h) (4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)- phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Using (4-{3-(4-Dimethylcarbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)- phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.57 g, 0.91 mmol) and following the procedure of Example 2(e) afforded 0.6 Ig of the required product. 1H NMR (DMSO-d6): δ 1.31 (9H, s), 1.35 (3H, s), 1.95 (4H, s), 2.91(1H, s) 3.02 (3H, s), 3.11 (IH, s), 3.2 (3H, s), 3.8 (IH, s), 6.81 (IH, s), 7.22 (3H, d), 7.55 (4H, s), 7.92 (2H, s), 8.20 (IH-, s).
i) {4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using (4-{3-(4-dimethylcarbamoyl-phenoxy)-5-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.61 g, 0.91 mmol) and following the procedure of Example 2(f) afforded 0.55g of the required product. Percentage purity (LCMS): 82.1%, (M+ 1) = 615.1+1.
j) N-(4-amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-dimethylcarbamoyl- phenoxy)-benzamide
Using {4-[3-(4-carbamimidoyl-phenoxy)-5-(4-dimethylcarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.55 g, 0.89 mmol) and following the procedure of Example 9(d) afforded 200 mg of the required product. Percentage purity (HPLC): 95.01 %, (LCMS): 95.82 %. 1H NMR (DMSOd6): δ 1.21 (4H, m), 1.92 (4H, d), 2.91 (7H, s), 3.51 (IH, m), 7.21 (7H, d), 7.32 (2H, d), 7.56 (4H, d), 7.88 (5H, m), 8.45 (IH, m), 9.25 (2H, s), 9.31 (2H, s).
Example 101. N-(4-Amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methoxy- carbamoyl-phenoxy)-benzamide Intermediates (a) - (e) are the same as in Example 92.
f) {4-[3-(4-Cyano-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester
Using 4- [3 -(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5 -(4-cyano- phenoxy)-phenoxy] -benzoic acid (0.9 g, 1.6 mmol) and following the procedure of Example 99(f) afforded 0.73g of the required product. 1H NMR (DMSO-d6): δ 1.25 (15H, d), 1.92 (4H, d), 3.78 (4H, s), 6.81 (IH, d), 7.21 (5H, m), 7.51 (2H, d), 7.91 (4H, dd), 8.30 (IH, d).
g) { 4- [3 - [4-(N-hydroxycarbamimidoyl)-phenoxy] -5 -(4-methoxycarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using {4-[3-(4-cyano-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester (0.85 g, 0.14 mmol) and following the procedure of Example 95(d) afforded 0.87 g of the required product. Percentage purity (LCMS): 94.4 %, (M+l) = 633.2+1.
h) ({4-[3- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -5 -(4-methoxycarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using {4-[3- [4-(N-hydroxycarbamimidoyl)-phenoxy] -5 -(4-methoxycarbamoyl- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.87 g, 1.4 mmol) and following the procedure of Example 2(e) afforded 0.89 g of the required product. Percentage purity (LCMS): 64.5 %, (M+l) = 675.1+1.
i) {4-[3-(4-Carbamimidoyl-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester
Using ( { 4- [3 - [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -5 -(4-methoxy- carbamoyl-phenoxy)-benzoylamino]-cyclohexyl}-carbarnic acid tert-butyl ester (0.89 g, 1.3 mmol) and following the procedure of Example 2(f) afforded 0.81 g of the required product. Percentage purity (LCMS): 92.5 %, (M+l) = 617.1+1.
j) N-(4-amino-cyclohexyl)-3-(4-carbamimidoyl-phenoxy)-5-(4-methoxycarbamoyl- phenoxy)-benzamide
Using {4-[3-(4-carbamimidoyl-phenoxy)-5-(4-methoxycarbamoyl-phenoxy)- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (0.8 g, 1.3 mmol) and following the procedure of Example 9(d) afforded 0.09 mg of the required product. Percentage purity (HPLC): 95.11 %, (LCMS): 96.41 %. 1H NMR (DMSOd6): δ 1.24 (4H, m), 1.92 (4H, m), 3.11 (2H, brs), 3.92 (3 H, s), 7.22 (5H, m), 7.51 (2H, d), 7.91 (7H, m), 8.22 (IH, d), 9.25 (2H, s), 9.31(2H,s), 11.91 (lH,brs).
Example 102. N-(4-amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Intermediates (a) - (f) are the same as in Example 84.
g) (4- {3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Using {4-[3-[4-(tert-butoxycarbonylamino methyl)phenoxy]-5-(4-cyano phenoxy) benzoylamino]cyclohexyl}carbamic acid tert-butyl ester (0.3 g, 0.45 mmol) and following the procedure of Example 95(d) afforded 0.35 g of the required product. Percentage purity (LCMS): 64.5 %, (M+l) = 689.3+1.
h) N-(4-amino-cyclohexyl)-3-(4-aminomethyl-phenoxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzamide
Using 0.3 g (0.43 mmol) of (4-{3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]- 5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -cyclohexyl)-carbamic acid tert-butyl ester and following the procedure of Example 9(d) afforded 0.15 g of the required product. Percentage purity (HPLC): 98.81 %, (LCMS): 95.62 %. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.8 (4H, m), 2.9 (IH, m), 3.8 (IH, m), 4.15 (2H, d), 6.7 (IH, t), 7.3 (6H, m), 7.5 (2H, d), 7.7 (2H, d), 7.9 (3H, d), 8.2 (3H, brs), 8.4 (IH, d), 10.9 (IH, brs).
Example 103.
3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoic acid 4-amino-cyclohexyl ester
Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
1.0 g (2.8 mmol) and (4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (0.69 g, 2.8 mmol) were used to afford 0.8 g of the required product. 1H NMR (DMSOd6): δ 1.21 (4H, m), 1.32 (4H, m), 3.12 (IH, m), 3.32 (IH, m), 4.51 (2H, s), 5.21 (2H, s), 7.3 (1OH, m) ,7.89 (2H, d).
d) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoic acid 4-benzyloxy- carbonylamino-cyclohexyl ester
Following the procedure of Example 2(d) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester 0.8 g (1.36 mmol) and other reagents were used to afford 0.7 g of the required product. Percentage purity (LCMS): 73.2 %, (M+l) 653.2+1.
e) 3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoic acid 4- benzyloxycarbonylamino-cyclohexyl ester Following the procedure as in Example 2(e) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)- phenoxy] -benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester 0.7 g (1.22 mmol) was used to afford 0.7 g of the required product. Percentage purity (LCMS): 63.8 %, (M+ 1) 737.2+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoic acid 4-amino-cyclohexyl ester
3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoic acid 4- benzyloxycarbonylamino-cyclohexyl ester 0.7 g (0.9 mmol) was reduced using the procedure of Example 2(f) to afford 0.45 g of the required product. Percentage purity (HPLC): 99.21 %, (LCMS): 97.9 %. 1H NMR (DMSOd6): δ 1.21 (4H, m), 1.9 (4H, m), 3.1 (IH, m), 3.2 (IH, m), 4.91 (IH, brs), 7.35 (6H, m), 8.01 (7H, m), 9.2 (8H, d).
Example 104. 3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoic acid 4- amino-cyclohexyl ester
Intermediate (a) is the same as in Example 42.
b) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5rhydroxy-benzoic acid ethyl ester
Using 1.3 g (4.5 mmol) of 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid ethyl ester and following the procedure of Example 95 (d) afforded 1.1 g of the required product. Percentage purity (LCMS): 48.4 %, (M+ 1) 387.1+1.
c) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid ethyl ester
Using 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoic acid ethyl ester (1.1 g, 2.48 mmol) and following the procedure of Example 42(b) afforded 0.95 g of the required product. 1H NMR (DMSOd6): δ 1.21 (2H, m), 1.32 (9H, s), 3.81 (IH, s), 4.21 (2H, d), 4.35 (2H, m), 7.32 (9H, m), 7.91 (2H, d).
d) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid
0.95 g (2.06 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4- cyano-phenoxy)-benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 0.85 g of the required product. 1H NMR (DMSOd6): δ 1.2 (9H,s),4.1(3H,s), 7.21 (9H,m) 7.9 (2H, d), 13.4 (IH, brs).
e) 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester
Following the procedure of Example 9(e) 3-[4-(tert-butoxycarbonylamino-methyl)- phenoxy]-5-(4-cyano-phenoxy)-benzoic acid (0.85 g, 1.85 mmol) and (4-hydroxy- cyclohexyl)-carbamic acid benzyl ester (0.50 g, 2.03 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 67.0 %, (M+l) 691.2+1.
f) 3 - [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester
Using 3 - [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 -(4-cyano-phenoxy)- benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester (0.6 g, 0.87 mmol) and following the procedure of Example 95(d) afforded 0.6 g of the required product. Percentage purity (LCMS): 69.3 %, (M+l) = 724+1.
g) 3 - [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester
Using 3 - [4-(tert-butoxycarbonylamino-rnethyl)-phenoxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy] -benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester (0.6 g, 0.82 mmol) and following the procedure as in Example 2(e) afforded 0.55 g of the required product. Percentage purity (LCMS): 69.1. %, (M+l) = 766.2+1.
h) 3 - [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 -(4-carbamimidoyl- phenoxy)-benzoic acid 4-amino-cyclohexyl ester
3 - [4-(tert-butoxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -benzoic acid 4-benzyloxycarbonylamino-cyclohexyl ester 0.55 g (0.71 mmol) was reduced using the procedure of Example 2(f) to afford 0.5 g of the required product. Percentage purity (LCMS): 54.6 %, (M+l) = 574.2+1.
i) 3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoic acid 4- amino-cyclohexyl ester
3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5-(4-carbamimidoyl-phenoxy)- benzoic acid 4-amino-cyclohexyl ester 0.5 g (0.87 mmol) was treated using procedure of Example 9(d) to afford 0.2 g of the required product. Percentage purity (HPLC): 94.21 %, (LCMS): 96.9 %. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.91 (4H, m), 3.1 (IH, m), 4.11 (2H, brs), 4.8 (IH, m), 7.21 (7H, m), 7.9 (4H, m), 8.2 (3H, m), 9.11 (4H, d).
Example 105. [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-2-naphthylsulphonamide
Intermediates (a) and (b) are the same as in Example 26.
c) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-carbamic acid tert-butyl ester
A mixture of 3,5-bis-(4-cyano-phenoxy)-benzoic acid (2.0 g, 5.6 mmol), diphenylphosphorylazide (1.2 ml, 5.6 mmol) and DIPEA (1 ml, 5.6 mmol) were dissolved in 20 ml of tert-butanol and stirred overnight at 80 0C. Reaction mixture was cooled and diluted with 50 ml saturated solution of sodiumhydrogencarbonate and extracted with ethylacetate (3 x 50 ml). Combined organic layer was washed with 2 x 50 ml saturated solution of brineand dried over anhydrous sodium sulphate. Solvent was evaporated under vacuo and thus obtained crude product was subjected to column chromatography using silica gel as an absorbent and eluted with 10-20 % mixture of ethylacetate and hexane to afford 1.0 g of the required product. Percentage purity (LCMS): 89.6 %, (M+ 1) = 427.1+1.
d) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine
Following the procedure of Example 9(d) [3,5-bis-(4-cyano-phenoxy)-phenyl]- carbamic acid tert-butyl ester 1.0 g (2.34 mmol) and other reagents were used to afford 0.7 g of the required product. Percentage purity (LCMS): 95.0 %, (M+ 1) = 327.1+1.
e) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-2-naphthylsulphonamide
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine (0.35 g, 1.07 mmol) and 2-naphthyl- sulphonyl chloride (0.29 g, 1.28 mmol) were dissolved in 10 ml of dichloromethane and cooled to 0 °C. Further 0.18 ml (2.14 mmol) of pyridine and 15 mg (0.107 mmol) of DMAP was added to the reaction mixture and allowed to stirred overnight at RT. After completion, reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml IN HCl solution and then with brine. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude product was subjected to column chromatography and eluted with ethylacetate and hexane mixture to afford 0.4 g of the required product. Percentage purity (LCMS): 90.4 % M+l=517.1+l.
f) [3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthyl- sulphonamide
Following the procedure of Example 95(d) [3,5-bis-(4-cyano-phenoxy)-phenyl]-2- naphthylsulphonamide 0.45 g (0.83 mmol) was afforded 0.41 g of the required product. Percentage purity (LCMS): 94.3 %, (M-I) =583.2-1. g) [3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthyl- sulphonamide
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthylsulphonamide 0.41 g (0.71 mmol) was acetylated using the procedure of Example 2(e) to afford 0.43 g of the required product. Percentage purity (LCMS): 88.3 %, (M+l) = 667.2+1.
h) [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-2-naphthylsulphonamide
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-2-naphthyl- sulphonamide 0.43 g (0.644 mmol) was reduced using the procedure of Example 2(f) to afford 0.23 g of the required product. Percentage purity (HPLC): 96.1 %, (LCMS): 97.01 %. 1H NMR (DMSOd6): δ 6.7 (IH, s), 6.8 (2H, s), 7.15 (4H, d), 8.1 (3H, t), 8.45 (IH, s), 9.2 (6H, brs), 10.8 (IH, brs).
Example 106. [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide
Intermediates (a) to (d) are the same as in Example 105.
e) [3,5-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide
Following the procedure of Example 105(e) [3,5-bis-(4-cyano-phenoxy)-phenyl]- amine (0.08 g, 0.24 mmols) and 4-fluoro-benzenesulfonyl chloride (0.05 g, 0.27 mmol) were used to afford 0.05 g of the required product. 1H NMR (DMSOd6): δ 6.56 (3H, d), 7.22 (4H, d), 7.51 (2H, d), 7.95 (6H, d).
f) [3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-benzene- sulphonamide
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-4-fluoro-benzenesulphonamide 0.4 g (0.82 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.4 g of the required product. 1H NMR (DMS0-d6): δ 6.56(3H,d), 7.22 (4H, d), 7.51 (2H, d), 7.95 (6H, d), 9.12(lH,brs).
g) [3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro- benzenesulphonamide
[3,5-Bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-benzene- sulphonamide 0.4 g (0.72 mmol) was acetylated using the procedure of Example 2(e) to afford 0.42 g of the required product. Percentage purity (LCMS): 57.3 %, (M+l) = 635.2+1.
h) [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-4-Fluoro-benzenesulphonamide
[3,5-Bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-phenyl]-4-fluoro-benzene- sulphonamide 0.42 g (0.66 mmol) was reduced using the procedure of Example 2(f) to afford 0.15 g of the required product. Percentage purity (HPLC): 95.71 %, (LCMS): 94.7 %. 1H NMR (DMSO-d6): δ 6.71 (3H, d), 7.15 (4H, d), 7.51 (2H, t), 7.91 (6H, d), 9.2 (8H, d), 10.9 (IH, s).
Example 107.
4-Amino-cyclohexanecarboxylic acid [3 ,5-bis-(4-carbamimidoyl-phenoxy)- phenyl] -amide
Intermediates (a) to (d) are the same as in Example 105.
e) {4- [3 , 5 -Bis-(4-cyano-phenoxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester
N-methylmorpholine (0.75 ml, 6.57 mmol) and 2-(lH-7-azabenzotriazol-l-yl)-- 1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (2.35 g, 6.16 mmol) were added to the stirred solution of racemic mixture of 4-tert-butoxycarbonylamino- cyclohexanecarboxylic acid (0.67 g, 2.05 mmol), dissolved in 5.0 ml of DMF. Further 0.50 g (2.05 mmol) of {4-[3,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester, dissolved in 5 ml of DMF, was added to the reaction mixture at RT and rsulting mixture was allowed to stirred overnight at RT. After reaction completion, mixture was poured into ice- water to afford white solid compound which was filtered off and dissolved in ethylacetate and organic layer was washed with 2 x 50 ml of saturated sodiumhydrogencarbonate and then with water. Organic layer was dried over anhydrous sodium sulphate and concentarted under vacuo to afford the crude product which was subjected to column chromatography using silica gel as an absorbent and eluted with 40-60 % ethylacetate :hexane mixture to afford 0.65 g of the required product. 1H NMR (DMSOd6): δ 1.25 (9H, s), 1.32 (4H, m), 2.31 (4H, m), 3.21 (IH, m), 3.52 (IH, m), 6.12 (IH, s), 7.21 (6H, d), 7.91 (4H, d), 10.01 (IH, s).
f) (4-{3,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester
{4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert- butyl ester 0.8 g (1.44 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.86 g of the required product. Percentage purity (LCMS): 93.4 %, (M+ 1) = 618.2+1.
g) (4- { 3 ,5-Bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester
(4- { 3 ,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester 0.86 g (1.39 mmol) was acetylated using the procedure of Example 2(e) to afford 0.89 g of the required product. Percentage purity (LCMS): 88.8 %, (M+l) = 702.2+1.
h) { 4- [3 , 5 -Bis-(4-carbarnimidoyl-phenoxy)-phenylcarbamoyl] -cyclohexyl } - carbamic acid tert-butyl ester (4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester 0.89 g (1.26 mmol) was reduced using the procedure of Example 2(f) to afford 0.7 g of the required product. (LCMS): 93.3 %, (M+l) = 586.2+1.
i) 4-Amino-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl-phenoxy)- phenyl] -amide
{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.7 g ( 1.19 mmol) was reduced using the procedure of Example 9(d) to afford 0.4 g of the required product. Percentage purity (HPLC): 97.81 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.31 (4H, m), 1.9 (4H, m), 2.2 (IH, m), 3.2 (IH, m), 6.7 (IH, s), 7.21 (6H, dd), 7.91 (7H, d), 9.31 (8H, s), 10.1 (IH, s).
Example 108.
7><ms-4-amino-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Intermediates (a) to (d) are the same as in Example 105.
e) { Trans-4- [3,5 -bis-(4-cyano-phenoxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester
Following the procedure of Example 107(e) trørø-4-tert-butoxycarbonylamino- cyclohexanecarboxylic acid 10.4 g (42.79 mmol) and [3,5-bis-(4-cyano-phenoxy)- phenyl] -amine (14.0 g, 42.79 mmol) were used to afford 12 g of the required product. 1H NMR (DMSOd6): δ 1.2(4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (IH, t), 3.1 (IH, m), 6.81 (IH, d), 7.04 (IH, s), 7.2(6H,m) 7.91 (4H, dd), 10.0 (IH, s).
f) (rrøm^-^S-bis-^-fN-hydroxycarbamimidoy^-phenoxyJ-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester { Trans-4- [3,5 -bis-(4-cyano-phenoxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester 5.O g (9.05 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 5.2 g of the required product. Percentage purity (LCMS): 88.9 %, (M+l) = 618.2+1.
g) (7>α«5'-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl- carbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
(7>α«5-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester 5.2 g (8.40 mmol) was acetylated using the procedure of Example 2(e) to afford 5.50 g of the required product. Percentage purity (LCMS): 91.6 %, (M+l) = 702.1+1.
h) {7Vα«5-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester
(7>α«5-4-{3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl- carbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 5.5 g (7.831 mmol) was reduced using the procedure of Example 2(f) to afford 4.2 g of the required product. Percentage purity (LCMS): 98.3 %, (M+l) = 586.1+1.
i) 7ra«.y-4-amino-cycloh.exanecarboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
{rrα«5-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester 3.8 g (6.47 mmol) was reduced using the procedure of Example 9(d) to afford 2.5 g of the required product. Percentage purity (HPLC): 99.1 %, (LCMS): 99.9 %. 1H NMR (DMSOd6): δ 1.22 (4H, m), 1.9 (4H, m), 2.1 (IH, d), 3.1 (IH, m), 6.7 (IH, s), 7.35 (5H, m), 7.91 (7H, d), 9.25 (8H, d), 10.3 (IH, brs).
Example 109. 1 -(2-Amino-ethyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Intermediates (a) to (d) are the same as in Example 105.
e) 4- [3 , 5 -Bis-(4-cyano-phenoxy)-phenylcarbamoyl] -piperidine- 1 -carboxylic acid tert-butyl ester
Following the procedure of Example 9(e) piperidine- 1,4-dicarboxylic acid mono- tert-butyl ester 0.7 g (3.05 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (1.0 g, 3.05 mmol) were used to afford 0.85 g of the required product. 1H NMR (DMSOd6): δ 1.2 (4H, m), 1.31 (9H, s), 1.8 (4H, d), 2.21 (IH, t), 3.1 (IH, m), 6.81 (IH, d), 7.04 (IH, s), 7.2 (6H, m), 7.91 (4H, dd), 10.0 (IH, brs).
f) 4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidine
Following the procedure of Example 9(d) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl- carbamoyl] -piperidine- 1 -carboxylic acid tert-butyl ester (0.85 g, 1.579 mmol) was used to afford 0.54 g of the required product. Percentage purity (LCMS): 90.6 %, (M+l) = 438.1+1.
g) (2- { 4- [3 ,5 -Bis-(4-cyano-phenoxy)-phenylcarbamoyl] -piperidin- 1 -yl } -ethyl)- carbamic acid tert-butyl ester
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl- carbamoyl] -piperidine (0.8 g, 1.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.19 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSOd6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (IH, m), 3.7 (IH, m), 6.76 (IH, s), 7.26 (6H, m,), 7.86 (4H, d).
h) [2-(4- { 3 ,5-Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl } - piperidin- l-yl)-ethyl]-carbamic acid tert-butyl ester (2- {4-[3,5-Bis-(4-cyano-phenoxy)-phenylcarbamoyl]-piperidin- 1 -yl } -ethyl)- carbamic acid tert-butyl ester 0.4 g (0.687 mmol) was subjected to form N- hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.4 g of the required product. Percentage purity (LCMS): 91.1 %, (M+l) = 647.2+1.
i) [2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl- carbamoyl}-piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester 0.4 g (0.618 mmol) was acetylated using the procedure of Example 2(e) to afford 0.45 g of the required product. Percentage purity (LCMS): 61.9 %, (M+l) = 731.2+1.
j) (2- {4-[3 ,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin- 1 -yl } - ethyl)-carbamic acid tert-butyl ester
[2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester 0.5 g (0.68 mmol) was reduced using the procedure of Example 2(f) to afford 0.4 g of the required product. Percentage purity (LCMS): 100 %, (M+l) = 615.2+1.
k) l-(2-Amino-ethyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
(2- {4- [3 ,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl] -piperidin- 1 -yl } - ethyl)-carbamic acid tert-butyl ester 0.4 g (0.65 mmol) was reduced using the procedure of Example 9(d) to afford 0.25 g of the required product. Percentage purity (HPLC): 98.91 %, (LCMS): 99.6 %. 1U NMR (DMSOd6): δ 1.22 (4H, m), 2.1 (4H, m), 2.8 (2H, t), 3.2 (2H, m), 3.5 (IH, m), 6.1 (IH, s), 7.2 (5H, d), 7.9 (4H, d), 8.22 (2H, brs), 9.2 (8H, d), 9.6 (IH, brs), 10.5 (IH, s).
Example 110. 1 -(3-Amino-propionyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Intermediates (a) to (f) are the same as in Example 109.
g) (3 - { 4- [3 , 5 -Bis-(4-cyano-phenoxy)-phenylcarbamoyl] -piperidin- 1 -yl } -3 -oxo- propyl)-carbamic acid tert-butyl ester
Following the procedure of Example 9(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl- carbamoyl] -piperidine 1.0 g (2.28 mmol) and 3-tert-butoxycarbonylamino-propionic acid (0.431 g, 2.28 mmol) were used to afford 0.95 g of the required product. IH NMR (DMSO-d6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (IH, m), 3.7 (IH, m), 6.76 (IH, s), 7.26 (6H, m), 7.86 (4H, d), 10.01 (IH, s).
h) [2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester
(3 - { 4- [3 , 5 -Bis-(4-cyano-phenoxy)-phenylcarbamoyl] -piperidin- 1 -yl } -3 -oxo- propyl)-carbamic acid tert-butyl ester 1.0 g (1.64 mmol) was subjected to form N- hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 1.0 g of the required product. Percentage purity (LCMS): 98.5 %, (M+l) = 675.2+1.
i) [2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenyl- carbamoyl} -piperidin- l-yl)-ethyl]-carbamic acid tert-butyl ester
[2-(4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester 1.0 g (1.48 mmol) was acetylated using the procedure of Example 2(e) to afford 0.1 g of the required product. Percentage purity (LCMS): 99.9 %, (M+l) = 759.2+1.
j) (3-{4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-piperidin-l-yl}-3- oxo-propyl)-carbamic acid tert-butyl ester [2-(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- piperidin-l-yl)-ethyl]-carbamic acid tert-butyl ester 1.1 g (1.45 mmol) was reduced using the procedure of Example 2(f) to afford 0.93 g of the required product. Percentage purity (LCMS): 99.9 %, (M+l) = 643.2+2.
k) l-(3-Amino-propionyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
(3 - { 4- [3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl] -piperidin- 1 -yl } -3 - oxo-propyl)-carbamic acid tert-butyl ester 0.93 g (1.44 mmol) was reduced using the procedure of Example 9(d) to afford 0.3 g of the required product. Percentage purity (HPLC): 97.9 %, (LCMS): 94.9%. 1H NMR (DMSOd6): δ 1.25 (4H, m), 1.92 (4H, m), 2.5 (2H, m), 3.05 (3H, m), 4.1 (IH, d), 6.7 (IH, s), 7.35 (6H, m), 7.6 (2H, brs), 7.9 (4H, d), 9.2 (7H, d), 10.4 (IH, s).
Example 111.
1 -(2-Hydroxy-ethyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Intermediates (a) to (f) are the same as in Example 109.
g) l-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid [3,5-bis-(4-cyano- phenoxy)-phenyl] -amide
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl- carbamoyl]-piperidine 1.5 g (3.42 mmol) and 2-bromoethanol (0.647 g, 4.79 mmol) were used to afford 1.1 g of the required product. 1H NMR (DMSOd6): δ 2.11 (4H, m), 2.52 (2H, m), 3.15 (4H, m), 3.21 (IH, m), 3.31 (IH, m), 4.21 (IH, t), 6.76 (IH, s), 7.31 (6H, d), 7.92 (4H, d). h) l-(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl } -amide
1 -(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid [3,5-bis-(4-cyano-phenoxy)- phenyl] -amide 1.1 g (2.28 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 1.3 g of the required product. Percentage purity (LCMS): 96.7 %, (M+ 1) = 548.2+1.
i) l-(2-Hydroxy-ethyl)-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
1 -(3-Hydroxy-propionyl)-piperidine-4-carboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl} -amide 1.3 g (2.37 mmol) was reduced using the procedure of Example 2(f) to afford 0.55 g of the required product. Percentage purity (HPLC): 97.18 %, (LCMS): 98.8 %. 1H NMR (DMSOd6): δ 1.91 (4H, m), 3.2 (6H, m), 3.5 (5H, m), 6.7 (IH, s), 7.35 (6H, d), 7.91 (4H, d), 9.25 (8H, d), 10.5 (IH, s).
Example 112.
C/5-4-amino-cyclohexanecarboxylic acid [3 ,5-bis-(4-carbamimidoyl-phenoxy)- phenyl] -amide
Intermediates (a) to (d) are the same as in Example 106.
e) { Cis-A- [3 ,5-bis-(4-cyano-phenoxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester
Following the procedure of Example 9(e) c/,s-4-tert-butoxycarbonylamino-cyclo- hexanecarboxylic acid 1.0 g (4.15 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]- amine (1.34 g, 4.15 mmol) were used to afford 1.5 g of the required product. 1H NMR (DMSOd6): δ 1.4 (9H, s), 2.3 (4H, m), 2.81 (IH, m), 3.15 (4H, m), 3.5 (IH, m), 6.71 (IH, s), 6.81 (IH, brs), 7.21 (6H, m), 7.92 (4H, d), 10.0 (IH, brs). f) (c/5-4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester
{ Cis-A- [3 ,5 -bis-(4-cyano-phenoxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester 1.56 g (2.82 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 1.5 g of the required product. Percentage purity (LCMS): 99.9 %, (M+l) = 618.2+1.
g) {Cis-A- { 3 ,5-bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -phenyl - carbamoyl }-cyclohexyl)-carbamic acid tert-butyl ester
(Cis-A- { 3 ,5 -bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester 1.5 g (0.82 mmol) was acetylated using the procedure of Example 2(e) to afford 1.4 g of the required product. Percentage purity (LCMS): 68.0 %, (M+l) - 702.2+1.
h) {C/s-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester
(Cis-A- { 3 ,5 -bis- [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester 1.4 g (2.1 mmol) was reduced using the procedure of Example 2(f) to afford 1.2 g of the required product. Percentage purity (LCMS): 100 %, (M+l) = 586.2+1.
i) C/.s-4-amino-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl-phenoxy)- phenyl] -amide
{C/s-4-[3,5-bis-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester 1.2 g ( 2.1 mmol) was reduced using the procedure of Example 9(d) to afford 1.0 g of the required product. Percentage purity (HPLC): 98.7 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.82 (4H, m), 1.9 (4H, m), 3.11 (IH, m), 3.8 (IH, m), 6.7 (IH, s), 7.21 (6H, d), 7.91 (7H, d), 9.21 (8H, d), 10.1(1 H, s). Example 113.
[3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-amine
Intermediates (a) to (d) are the same as in Example 105.
e) { 3 ,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy] -phenyl } -amine
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine 0.3 g (0.917 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.34 g of the required product. Percentage purity (LCMS): 100.0 %, (M+l) = 393.1+1.
f) [3,5-Bis-(4-carbamimidoyl-phenoxy)-phenyl]-amine
{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-phenyl}-amine 0.34 g (0.864 mmol) was reduced using the procedure of Example 2(f) to afford 0.15 g of the required product. Percentage purity (HPLC): 96.6 %, (LCMS): 99.5 %. 1H NMR (DMSOd6): δ 5.9 (IH, t), 6.2 (2H, d), 7.35 (4H, d), 7.9 (4H, d), 9.11 (4H, brs), 9.25 (4H, brs).
Example 114.
1 -(2-Amino-ethyl)-piperidine-4-carboxylic acid [3 ,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Intermediates (a) to (f) are the same as in Example 109.
g) l-Cyclopropylmethyl-piperidine-4-carboxylic acid [3,5-bis-(4-cyano-phenoxy)- phenyl] -amide
Following the procedure of Example 1 l(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl- carbamoyl] -piperidine 1.5 g (3.42 mmol) and bromomethylcyclopropane (0.647 g, 4.79 mmol) were used to afford 1.0 g of the required product. Percentage purity (LCMS): 73.1 %, (M+l) = 492.1+1. h) l-Cyclopropylmethyl-piperidine-4-carboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl } -amide
l-Cyclopropylmethyl-piperidine-4-carboxylic acid [3,5-bis-(4-cyano-phenoxy)- phenyl] -amide 1.0 g (2.03 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95 (d) to afford 1.1 g of the required product. Percentage purity (LCMS): 100.0 %, (M+l) = 558.2+1.
i) l-Cyclopropylmethyl-piperidine-4-carboxylic acid {3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -phenyl } -amide
1 -Cyclopropylmethyl-piperidine-4-carboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl} -amide 1.1 g (1.97 mmol) was acetylated using the procedure of Example 2(e) to afford 1.6 g of the required product. Percentage purity (LCMS): 57.70 %, (M+l) = 642.2+1.
j) l-Cyclopropylmethyl-piperidine-4-carboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
1 -Cyclopropylmethyl-piperidine-4-carboxylic acid {3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -phenyl} -amide 1.6 g (2.49 mmol) was reduced using the procedure of Example 2(f) to afford 0.8 g of the required product. Percentage purity (HPLC): 99.01 %, (LCMS): 98.9 %. 1H NMR (DMSOd6): δ 0.3 (2H, d), 0.6 (2H, d), 1.1 (IH, m), 1.82 (4H, m), 3.05 (4H, m), 3.1 (2H, d), 6.7 (IH, s), 7.2 (5H, d), 7.98 (4H, d), 9.11 (8H, brs), 9.55 (IH, brs), 10.5 (IH, s).
Example 115.
N-(4-Amino-cyclohexyl)-3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]- benzamide
Intermediates (a) to (c) are the same as in Example 27. d) (4-{3,5-Bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-benzoylamino}- cyclohexyl)-carbamic acid tert-butyl ester
Triethylamine (2.5 ml, 1.81 mmol) was added to the suspension of {4-[3,5-bis-(4- cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 1.81 mmol) in 15 ml of ethanol at 55 0C. O-methyl-hydroxylamine hydrochloride solution (0.91 g in 3 ml of water (30% w/w)) and mercaptoacetic acid (0.51 ml, 7.24 mmol) were added to the reaction mixture at 55 °C under inert nitrogen atmosphere. Reaction mixture was stirred under nitrogen atmosphere at 90 °C for 40 h. After reaction completion, solvent was removed under vacuo and the residue was poured into ice- water to obtain white solid product which was filtered off and washed with water and hexane to afford 0.7 g of the required product. Percentage purity (LCMS): 69.3 %, (M+l) = 646+1.
e) N-(4-Amino-cyclohexyl)-3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]- benzamide
Using (4-{3,5-bis-[4-(N-methoxy-carbamimidoyl)-phenoxy]-benzoylamino}- cyclohexyl)-carbamic acid tert-butyl ester (0.8 g, 1.23 mmol) and following the procedure of Example 9(d) afforded 0.51 g of the required product. Percentage purity (HPLC): 98.3 %, (LCMS) 98.9 %. 1H NMR (DMSOd6): δ 1.24 (4H, m), 1.82 (4H, m), 3.05 (IH, m), 3.51 (IH, m), 3.9 (6H, s), 6.9 (IH, t), 7.25 (4H, d), 7.45 (2H, d), 7.88 (4H, d), 7.9 (3H, brs), 8.45 (IH, d).
Example 116.
4-Amino-cyclohexanecarboxylic acid [3-(4-aminomethyl-phenoxy)-5-(4- carbamimidoyl-phenoxy)-phenyl]-amide
Intermediate (a) to (c) are same as in Example 104.
d) 3-(4-Aminomethyl-phenoxy)-5-(4-cyano-phenoxy)-benzoic acid ethyl ester Using 10.0 g (20.48 mmol) of 3-[4-(tert-butoxycarbonylamino-methyl)-phenoxy]-5- (4-cyano-phenoxy)-benzoic acid ethyl ester and following the procedure of Example 9(d) afforded 7.4 g of the required product. Percentage purity (LCMS): 82.0 %, (M+l) = 388.4+1.
e) 3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid ethyl ester
Mixture of 7.4 g (15.1 mmol) of 3-(4-aminomethyl-phenoxy)-5-(4-cyano- phenoxy)-benzoic acid ethyl ester, benzyl chloro formate (3.8 g, 22.6 mmol) and triethylamine (4.6 g, 45.4 mmol) were stirred overnight at RT. After reaction completion solvent was removed under reduced pressure and thus obtained rsidue was dissolved in ice- water and extrated with 500 ml x 2 of ethylacetate. Organic layer was dried over anhydrous sodium sulphate, solvent was removed and thus obtained crude product was purified by column chromatography using silica-gel as an adsorbent and eluted with ethylacetate : hexane (10:90) to afford 8.O g of the required product. Percentage purity (LCMS): 87.2 %, (M+l) = 522.5+1.
f) 3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid
8.0 g (15.32 mmol) of 3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5-(4- cyano-phenoxy)-benzoic acid ethyl ester was hydrolysed using the procedure of Example 5(b) to afford 7.0 g of the required product. Percentage purity (LCMS): 91.6 %, (M+l) = 494.5+1.
g) [3 - [4-(Benzyloxycarbonylamino-methyl)-phenoxy] -5 -(4-cyano-phenoxy)- phenylj-carbamic acid tert-butyl ester Using 7.0 g (14.1 mmol) of 3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5-(4- cyano-phenoxy)-benzoic acid and following the procedure of Example 105(c) afforded 3.5 g of the required product. Percentage purity (LCMS): 65.0 %, (M+l) = 565.6+1.
h) {4-[3-Amino-5-(4-cyano-phenoxy)-phenoxy]-benzyl}-carbamic acid benzyl ester
Using 1.0 g (1.76 mmol) of [3-[4-(benzyloxycarbonylamino-methyl)-phenoxy]-5- (4-cyano-phenoxy)-phenyl]-carbamic acid tert-butyl ester and following the procedure of Example 9(d) afforded 0.90 g of the required product. Percentage purity (LCMS): 89.2 %, (M+l) = 465.5 + 1.
i) { 4- [3 - [4-(Benzyloxycarbonylamino-methyl)-phenoxy] -5 -(4-cyano-phenoxy)- phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
Using 0.9 g (1.93 mmol) of {4-[3-amino-5-(4-cyano-phenoxy)-phenoxy]-benzyl}τ carbamic acid benzyl ester and 0.47 g (1.93 mmol) of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester, and following the procedure of Example 9(e) afforded 1.0 g of the required product. Percentage purity (LCMS): 91.0 %, (M+l) = 690.7 + 1.
j) (4-{3- [4-(Benzyloxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-hydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
{4-[3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-(4-cyano-phenoxy)- phenylcarbamoyl]-cyclohexyl} -carbamic acid tert-butyl ester 0.9 g (1.30 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95 (d) to afford 1.0 g of the required product. Percentage purity (LCMS): 74.4 %, (M+l) = 723.8+1.
k) (4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester (4-{3-[4-(Benzyloxycarbonylamino-methyl)-phenoxy]-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
1.0 g (1.38 mmol) was acetylated using the procedure of Example 2(e) to afford 1.10 g of the required product. Percentage purity (LCMS): 78.2 %, (M+ 1) = 765.8+1.
1) { 4- [3 -(4- Aminomethyl-phenoxy)-5 -(4-carbamimidoyl-phenoxy)- phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
(4- { 3 - [4-(Benzyloxycarbonylamino-methyl)-phenoxy] -5 - [4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
1.1 g (1.43 mmol) was reduced using the procedure of Example 2(f) to afford 0.8 g of the required product. Percentage purity (LCMS): 54.2 %, (M+l) = 573.2+1.
1) 4-Amino-cyclohexanecarboxylic acid [3-(4-aminomethyl-phenoxy)-5-(4- carbamimidoyl-phenoxy)-phenyl] -amide
{4-[3-(4-Aminomethyl-phenoxy)-5-(4-carbamimidoyl-phenoxy)-phenylcarbamoyl]- cyclohexyl}-carbamic acid tert-butyl ester 0.80 g (1.39 mmol) was treated using the procedure of Example 9(d) to afford 0.50 g of the required product. Percentage purity (HPLC): 98.3 %, (LCMS): 100.0 %. 1H NMR (DMSOd6): δ 1.44 (4H, m), 1.82 (4H, m), 3.05 (2H, m), 6.51(lH,s),7.15 (6H, m), 7.50 (2H, d), 8.02 (5H, d), 8.45 (2H, m), 9.11 (4H, brs), 10.11 (lH, brs).
Example 117. 4-Amino-cyclohexanecarboxylic acid [3-(2-amino-lH-benzoimidazol-5-yloxy)-
5 -(4-carbamimidoyl-phenoxy)-phenyl] -amide
Intermediates (a) and (b) are the same as in Example 49.
c) [3-(4-Cyano-phenoxy)-5-hydroxy-phenyl]-carbamic acid tert-butyl ester Using 3-(4-cyano-phenoxy)-5-hydroxy-benzoic acid (1.4 g, 5.4 mmol) and following the procedure of Example 105(c) afforded 1.0 g of the required product. Percentage purity (LCMS): 86.7 %, (M+l) = 326.3+1.
d) [3-(4-Cyano-phenoxy)-5-hydroxy-phenyl]-amine
Using [3-(4-cyano-phenoxy)-5-hydroxy-phenyl]-carbamic acid tert-butyl ester (1.0 g, 3.06 mmol) and following the procedure of Example 9(d) afforded 0.67 g of the required product. Percentage purity (LCMS): 92.5 %, (M+l) = 226.2+1.
e) { Trans A- [3 -(4-cyano-phenoxy)-5 -hydroxy-phenylcarbamoyl] -cyclohexyl } - carbamic acid tert-butyl ester
Following the procedure of Example 9(e) 7rø«s-4-tert-butoxycarbonylamino- cyclohexanecarboxylic acid 0.72 g (2.96 mmol) and [3-(4-cyano-phenoxy)-5-hydroxy- phenyl]-amine (0.67 g, 2.96 mmol) were used to afford 1.0 g of the required product. Percentage purity (LCMS): 73.5 %, (M+l) = 451.5+1.
f) {7>α«5-4-[3-(3-amino-4-nitro-phenoxy)-5-(4-cyano-phenoxy)-phenyl- carbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester
Using { trans-4- [3 -(4-cyano-phenoxy)-5 -hydroxy-phenylcarbamoyl] -cyclohexyl } - carbamic acid tert-butyl ester (1.5 g, 5.29 mmol) and 5-fluoro-2-nitro-phenylamine (0.91 g, 5.82 mmol) following the procedure of Example 42(b) afforded 1.6 g of the required product 1H NMR (DMSOd6): δ 1.45 (9H, s), 1.8 (4H, m), 2.5 (4H, m), 3.2 (IH, m), 6.48 (2H, m), 6.75 (IH, d), 7.24 (2H, m), 7.51 (4H, m), 7.78 (2H, d), 8.05 (IH, d), 8.38 (IH, d).
g). { Trans-4- [3 -(4-cyano-phenoxy)-5 -(3 ,4-diamino-phenoxy)-phenylcarbamoyl] - cyclohexyl} -carbamic acid tert-butyl ester { Trans-4- [3 -(3 -amino-4-nitro-phenoxy)-5 -(4-cyano-phenoxy)-phenyl- carbamoyl]-cyclohexyl}-caτbamic acid tert-butyl ester (1.0 g, 1.7 mmol), zinc (1.11 g, 17.02 mmol) and ammoniumchloride (0.91 g, 17.02 mmol) were dissolved in 20 ml of methanol and stirred for 2 h at 60 °C. After reaction completion contents were filtered through celite and filetrate was concentrated to afford 0.8 g of the required product. 1H NMR (DMSOd6): δ 1.45 (9H, s), 1.78 (4H, m), 2.45 (4H, m), 3.2 (IH, m), 4.42 (2H, s), 6.45 (2H, m), 6. 5 (IH, d), 6.71 (2H, m), 7.15 (2H, d), 7.3 (2H, s), 7.8 (2H, d), 8.28 (IH, d).
h) {rrαrø-4-[3-(2-amino-lH-benzoimidazol-5-yloxy)-5-(4-cyano-phenoxy)- phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
{ Trans-4- [3 -(4-cyano-phenoxy)-5 -(3 ,4-diamino-phenoxy)-phenylcarbamoyl] - cyclohexyl}-carbamic acid tert-butyl ester (0.9 g, 1.61 mmol) and canogenbromide (0.25 g, 2.42 mmol) were dissolved in 10 ml of ethanol and stirred at 80 °C for 4 h. After reaction completion mixture was cooled to RT and concentrated under vacuo to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.8 (4H, m), 2. 5 (4H, m), 3.1 (IH, m), 3.8 (IH, m), 6.46 (IH, brs), 6. 7 (IH, d), 6.95 (3H, m), 7.17 (5H, m), 7.4 (4H, m), 7.78 (2H, d), 8.4 (IH, d), 8.51 (2H, s), 12.4 (2H, brs).
i) (rra«^-4-{3-(2-amino-lH-benzoimidazol-5-yloxy)-5-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
{ Trans-4- [3 -(2-amino- 1 H-benzoimidazol-5 -yloxy)-5 -(4-cyano-phenoxy)- phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.9 g (1.54 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.85 g of the required product. Percentage purity (LCMS): 100.0 %, (M+l) = 615.3+1.
j) {Trans-4-[3-(2 -Amino- 1 H-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl- phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester ( Trans-4- { 3 -(2 -amino- 1 H-benzoimidazol-5 -yloxy)-5 - [4-(iV-hydroxy- carbamimidoyl)-phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 0.85 g (1.38 mmol) was reduced using the procedure of Example 2(f) to afford 0.7 g of the required product. Percentage purity (LCMS): 99.8 %, (M+l) = 599.2+1.
k) 4-Amino-cyclohexanecarboxylic acid [3-(2-amino-lΗ-benzoimidazol-5-yloxy)- 5 -(4-carbamimidoyl-phenoxy)-phenyl] -amide
{4-[3-(2-Amino-lH-benzoimidazol-5-yloxy)-5-(4-carbamimidoyl-phenoxy)- phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.7 g (0.45 mmol) was treated using the procedure of Example 9(d) to afford 0.23 g of the required product. Percentage purity (HPLC): 96.9 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.40 (4H, m), 1.82 (4H, m), 3.0 (IH, m), 3.67 (IH, m), 6.92 (2H, m), 7.12 (IH, s), 7.22 (2H, d), 7.38 (3H, m), 7.78 (5H, m), 8.40 (IH, d),8.62 (2H, s), 9.25 (4H, brs).
Example 118.
4-Amino-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl-benzyloxy)- phenyl] -amide
Intermediates (a) and (b) are the same as in Example 75.
c) [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl ester
Using 3,5-bis-(4-cyano-benzyloxy)-benzoic acid (1.6 g, 4.2 mmol) and following the procedure of Example 105(c) afforded 0.65 g of the required product. 1H NMR
(DMSOd6): δ 1.3 (9H, s), 5.2 (4H, s), 6.48 (IH, s), 6.9 (2H, d), 7.72 (2H, m), 7.81 (2H, d), 7.91 (4H, m) 9.52 (IH, s).
d) [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-amine
Using [3,5-Bis-(4-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl ester (0.6 g, 1.32 mmol) and following the procedure of Example 9(d) afforded 0.37 g of the required product. 1H NMR (DMSOd6): δ 5.2 (4H, s), 6.48 (IH, s), 6.9 (2H, d), 7.72 (2H, m), 7.81 (2H, d), 7.91 (4H, m).
e) {4-[3,5-Bis-(4-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester
Following the procedure of Example 107(e) trα«s-4-tert-butoxycarbonylamino- cyclohexanecarboxylic acid 0.255 g (1.04 mmol) and [3,5-Bis-(4-cyano-benzyloxy)- phenyl]-amine (0.37 g, 1.04 mmol) were used to afford 0.39 g of the required product. Percentage purity (LCMS): 94.8 %, (M-I) = 580.0-1.
f) (4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester
{4-[3,5-Bis-(4-cyano-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert- butyl ester 0.39 g (0.672 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.4 g of the required product. Percentage purity (LCMS): 100.0 %, (M+ 1) = 646.2+1.
g) { 4- [3 ,5 -Bis-(4-carbamimidoyl-benzyloxy)-phenylcarbamoyl] -cyclohexyl } - carbamic acid tert-butyl ester
Acetic anhydride (0.36 ml, 3.72 mmol) was added to the solution of (4-{3,5-bis-[4- (N-hydroxycarbamimidoyl)-benzyloxy] -phenylcarbamoyl } -cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, 0.62 mmol) in 10 ml of acetic acid and reaction mixture was stirred for 3 h. After completion of reaction, at RT zinc dust (0.4 g, 6.2 mmol) was added and resulting mixture was stirred over night. Recation mixture was filtered through celite and fϊlterate was concentrated to dryness. Product was washed with cold diethyl ether and dried to afford 0.52 g of the required product. Percentage purity (LCMS): 100.0 %, (M-I) = 615.2-1. h) 4-Amino-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl-benzyloxy)- phenyl] -amide
{4-[3,5-Bis-(4-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.52 g (0.846 mmol) was treated using the procedure of Example 9(d) to afford 0.3 g of the required product. Percentage purity (HPLC): 94.49 %, (LCMS): 99.4%. 1H NMR (DMSOd6): δ 1.24 (4H, m), 1.41 (4H, m), 2.1(lH,m), 2.31(lH,m), 5.2 (4H, s), 6.71 (IH, s), 7.01 (3H, s), 7.90 (8H, dd), 9.11 (IH, s), 9.25 (8H, brs).
Example 119.
4-Amino-cyclohexanecarboxylic acid [3,5-bis-(3-carbamimidoyl-benzyloxy)- phenyl] -amide
Intermediates (a) and (b) are the same as in Example 77.
c) [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl ester
Using 3,5-bis-(3-cyano-benzyloxy)-benzoic acid (2.2 g, 5.7 mmol) and following the procedure of Example 105(c) afforded 0.85 g of the required product.
d) [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-amine
Using [3,5-Bis-(3-cyano-benzyloxy)-phenyl]-carbamic acid tert-butyl ester (0.8 g, 1.76 mmol) and following the procedure of Example 9(d) afforded 0.6 g of the required product. Percentage purity (LCMS): 100.0 %, (M+l) = 355.0+1.
e) { 4- [3 , 5 -Bis-(3 -cyano-benzyloxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert-butyl ester
Following the procedure of Example 107(e) trøra^-tert-butoxycarbonylamino- cyclohexanecarboxylic acid 0.41 g (1.68 mmol) and [3,5-Bis-(3-cyano-benzyloxy)- phenyl] -amine (0.6 g, 1.68 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 79.8 %, (M-I) = 580.0-1.
f) (4- { 3 , 5 -Bis- [3 -(N-hydroxycarbamimidoyl)-benzyloxy] -phenylcarbamoyl } - cyclohexyl)-carbamic acid tert-butyl ester
{4- [3 ,5 -Bis-(3 -cyano-benzyloxy)-phenylcarbamoyl] -cyclohexyl } -carbamic acid tert- butyl ester 0.6 g (1.03 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.615 g of the required product. Percentage purity (LCMS): 100 %, (M+ 1) = 646.2+1.
g) {4-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester
Using (4-{3,5-bis-[3-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}- cyclohexyl)-carbamic acid tert-butyl ester 0.61 g (0.94 mmol) and following the procedure of Example 118(g) afforded 0.6 g of the required product. Percentage purity (LCMS): 100 %, (M-I) = 614.-1.
h) 4-Amino-cyclohexanecarboxylic acid [3,5-bis-(3-carbamimidoyl-benzyloxy)- phenyl] -amide
{4-[3,5-Bis-(3-carbamimidoyl-benzyloxy)-phenylcarbamoyl]-cyclohexyl}- carbamic acid tert-butyl ester 0.6 g (0.97 mmol) was treated using the procedure of Example 9(d) to afford 0.3 g of the required product. Percentage purity (HPLC): 85.98 %, (LCMS): 98.14 %. 1H NMR (DMSOd6): δ 1.44 (4H, m), 1.82 (4H, m), 3.05 (IH, m), 3.31 (IH, m), 5.2 (4H, s), 6.71 (IH, s), 7.15 (2H, s), 7.88 (2H, m), 7.9 (8H, m), 9.11 (4H, brs), 9.25 (6H, brs), 10.01 (IH, s).
Example 120. rrα«5-4-methyl-cyclohexanecarboxylic acid [3 ,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
Figure imgf000203_0001
Intermediates (a) to (d) are the same as in Example 105.
e) 7>α«5-4-methyl-cyclohexanecarboxylic acid [3,5-bis-(4-cyano-phenoxy)- phenyl] -amide
Following the procedure of Example 107(e) trαns-4-methyl-cyclohexanecarboxylic acid 0.21 g (1.52 mmol) and [3,5-bisr(4-cyano-phenoxy)-phenyl]-amine (0.50 g, 1.52 mmol) were used to afford 0.65 g of the required product. Percentage purity (LCMS): 85.4 %, (M+1) = 451.1+1.
f) 7rø«s-4-methyl-cyclohexanecarboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl } -amide
7>α«5f-4-methyl-cyclohexanecarboxylic acid [3,5-bis-(4-cyano-phenoxy)-phenyl]- amide 0.65 g (1.44 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.80 g of the required product. Percentage purity (LCMS): 82.7 %, (M+ 1) = 517.2+1.
g) rrα«5'-4-methyl-cyclohexanecarboxylic acid {3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -phenyl } -amide
Trans-4-methyl-cyclohexanecarboxylic acid {3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy] -phenyl} -amide 0.80 g (1.54 mmol) was acetylated using the procedure of Example 2(e) to afford 1.00 g of the required product. Percentage purity (LCMS): 82.7 %, (M+l) = 601.2+1.
h) Trans-4-methyl-cyclohexanecarboxylic acid [3,5-bis-(4-carbamimidoyl- phenoxy)-phenyl] -amide
rrα«5i-4-methyl-cyclohexanecarboxylic acid {3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-phenyl}-amide 1.00 g (1.66 mmol) was reduced using the procedure of Example 2(f) to afford 0.40 g of the required product. Percentage purity (HPLC): 98.4 %, (LCMS): 98.2 %. 1H NMR (DMSOd6): δ 0.9 (5H, m), 1.32 (3H, m), 1.7 (4H, m), 2.2 (IH, m), 3.05 (2H, m), 7.31 (6H, m), 7.92 (4H, d), 9.1 (4H, brs), 9.3 (4H, brs), 10.1 (IH, s).
Example 121. 4-[3-[(4-Amino-cyclohexanecarbonyl)-amino]-5-(4-carbamimidoyl-phenoxy)- phenoxy] -benzamide
Intermediates (a) - (e) are the same as in Example 117.
f) { Trans-A- [3 -(4-cyano-phenoxy)-5 -(4-formyl-phenoxy)-phenylcarbamoyl] - cyclohexyl}-carbamic acid tert-butyl ester
Following the procedure of Example 42(b) {trα«s-4-[3-(4-cyano-phenoxy)-5- hydroxy-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 2.21 mmol) and 4-fluorobenzaldehyde (0.475 ml, 4.43 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.11 (4H, m), 1.29 (9H, s), 1.8 (4H, m), 2.11 (IH, m), 3.15 (IH, m), 6.82 (IH, d), 7.34 (6H, m), 7.86 (2H, d), 7.92 (2H, d), 10.11 (IH, s).
g) 4-[3-[(rrα«i'-4-tert-butoxycarbonylamino-cyclohexanecarbonyl)-amino]-5-(4- cyano-phenoxy)-phenoxy] -benzoic acid Following the procedure of Example 92(e) {trø«s-4-[3-(4-cyano-phenoxy)-5-(4- formyl-phenoxy)-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (0.4 g, 0.72 mmol) was used to afford 0.15 g of the required product. 1H NMR (DMSOd6): δ 1.21 (9H, s), 1.32 (4H, m), 1.8 (4H, m), 2.11 (IH, m), 2.62 (IH, m), 6.62 (IH, s), 6.81 (IH, m), 7.26 (5H, m), 7.92 (3H, dd), 10.1 (IH, s).
h) { Trans-4- [3 -(4-carbamoyl-phenoxy)-5 -(4-cyano-phenoxy)-phenylcarbamoyl] - cyclohexylj-carbamic acid tert-butyl ester
Following the procedure of Example 94(f) 4-[3-[(/rømf-4-tert-butoxycarbonyl- amino-cyclohexanecarbonyl)-amino] -5 -(4-cyano-phenoxy)-phenoxy] -benzoic acid (0.15 g, 0.26 mmol) was used to afford 0.12 g of the required product. Percentage purity (LCMS): 86.7 %, (M+l) = 570.2+1.
i) (rrα«5-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-hydroxycarbamimidoyl)-phenoxy]- phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
{ Trans-4- [3 -(4-carbamoyl-phenoxy)-5 -(4-cyano-phenoxy)-phenylcarbamoyl] - cyclohexyl}-carbamic acid tert-butyl ester 0.12 g (0.21 mmol) was subjected to form N- hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.12 g of the required product. Percentage purity (LCMS): 55.5 %, (M+l) = 603.2+1.
j) (7>α«5'-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)- phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester
(Trans-4- { 3 -(4-carbamoyl-phenoxy)-5- [4-(iV-hydroxycarbamimidoyl)-phenoxy] - phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 0.12 g (0.198 mmol) was acetylated using the procedure of Example 2(e) to afford 0.13 g of the required product. Percentage purity (LCMS): 50.0 %, (M+l) = 645+1.
k) {7>ύi«5-4-[3-(4-carbamimidoyl-phenoxy)-5-(4-carbamoyl-phenoxy)-phenyl- carbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (rrα«5'-4-{3-(4-carbamoyl-phenoxy)-5-[4-(N-acetylhydroxycarbamimidoyl)- phenoxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester 0.13 g (0.2 mmol) was reduced using the procedure of Example 2(f) to afford 0.1 g of the required product. Percentage purity (LCMS): 73.6 %, (M+l) = 587+1.
1) 4-[3-[(rrøraf-4-amino-cyclohexanecarbonyl)-amino]-5-(4-carbamimidoyl- phenoxy)-phenoxy] -benzamide
{ Trans-4- [3 -(4-carbamimidoyl-phenoxy)-5 -(4-carbamoyl-phenoxy)-phenyl- carbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester 0.1 g (0.17 mmol) was treated using the procedure of Example 9(d) to afford 0.03 g of the required product. Percentage purity (HPLC): 97.1 %, (LCMS): 100.0 % (M+l). 1H NMR (DMSOd6): δ 1.44 (4H, m), 1.82 (4H, m), 2.2 (IH, t), 3.05 (IH, m), 6.71 (IH, s), 7.11 (2H, s), 7.30 (3H, m), 7.88 (7H, m), 9.1 (2H, brs), 9.25 (2H, brs), 10.1(1 H, s).
Example 122.
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(l-cyclopropylmethyl-piperidin-4-yl)- benzamide
Intermediates (a) - (d) are the same as in Example 32.
e) 3,5-Bis-(4-cyano-phenoxy)-N-(l-cyclopropylmethyl-piperidin-4-yl)-benzamide
Following procedure of Example 1 l(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4- yl-benzamide 0.5 g (1.14 mmol) and bromomethyl-cyclopropane (0.231 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 45.0 %, (M+l) = 492.2+1
f) N-(l-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-hydroxycarbamimidoyl)- phenoxy] -benzamide 3,5-Bis-(4-cyano-phenoxy)-N-(l-cyclopropylmethyl-piperidin-4-yl)-benzamide 0.4 g (0.812 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.4 g of the required product. Percentage purity (LCMS): 100 %, (M+1) = 558+1.
g) N-(l-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy] -benzamide
N-(l-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-hydroxycarbamimidoyl)- phenoxy] -benzamide 0.4 g (0.716 mmol) was acetylated using the procedure of
Example 2(e) to afford 0.45 g of the required product. Percentage purity (LCMS): 29.1 %, (M+1) = 642.2+1.
h) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(l-cyclopropylmethyl-piperidin-4-yl)- benzamide
N-(l-Cyclopropylmethyl-piperidin-4-yl)-3,5-bis-[4-(N-acetylhydroxy- carbamimidoyl)-phenoxy]-benzamide 0.45 g (0.7 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of the required product. Percentage purity (HPLC): 97.24 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 0.3 (2H, m), 0.6 (2H, d), 1.1 (IH, m), 1.82 (2H, m), 2.13 (3H, m), 3.05 (4H, m), 3.6 (2H, d), 7.15 (IH, m), 7.22 (2H, m), 7.40 (4H, d), 7.5 (2H, d), 7.9 (4H, d), 8.6 (IH, d), 9.21 (8H, brs), 9.6 (IH, brs).
Example 123. 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-[l-(2-hydroxy-ethyl)-piperidin-4-yl]- benzamide
Intermediates (a) - (d) are the same as in Example 32.
e) 3,5-Bis-(4-cyano-phenoxy)-N-[l-(2-hydroxy-ethyl)-piperidin-4-yl]-benzamide Following procedure of Example 1 l(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin-4- yl-benzamide 0.5 g (1.14 mmol) and 2-bromoethanol (0.214 g, 1.71 mmol) were used to afford 0.4 g of the required product. Percentage purity (LCMS): 76.2 %, (M+ 1) = 482+1.
f) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-[l-(2-hydroxy-ethyl)- piperidin-4-yl] -benzamide
3,5-Bis-(4-cyano-phenoxy)-N-[l-(2-hydroxy-ethyl)-piperidin-4-yl]-benzamide 0.4 g (0.829 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.4 g of the required product. Percentage purity (LCMS): 100 %, (M+1) = 548.2+1.
g) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-[l-(2-hydroxy-ethyl)-piperidin-4-yl]- benzamide
To a stirred solution of 3,5-bis-(4-carbamimidoyl-phenoxy)-N-[l-(2-hydroxy- ethyl)-piperidin-4-yl]-benzamide 0.35 g (0.638 mmol) in 15 ml of methanol, ammonium formate (201 mg, 3.192 mmol) followed by acetic acid (0.36 ml) were added. After 10 min stirring, under inert atmosphere of nitrogen Pd/C (102 mg, 0.957 mmol) was added and resulting mixture was further stirred for 5 h at 60 °C. Reaction progress was monitored by TLC. Reaction mixture was cooled to RT and filtered through celite and washed with methanol (20 ml). Thus obtained filterate was concentrated under vacuo to afford 0.15 g of the required product. Percentage purity (HPLC): 95.4 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.82 (2H, m), 2.01 (2H, m), 3.2 (4H, m), 3.61 (4H, m), 4.01 (IH, m), 7.21 (IH, s), 7.35 (4H, d), 7.50 (2H, d), 7.91 (4H, d), 8.6 (IH, d), 9.2 (8H, brs), 9.4 (IH, brs).
Example 124. 4-[3,5-Bis-(4-carbamimidoyl-phenoxy)-benzoylamino]-piperidine- 1 -carboxylic acid ethyl ester Intermediates (a) - (d) are the same as in Example 32.
e) 4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid ethyl ester
Following procedure of Example 1 l(e) 3,5-bis-(4-cyano-phenoxy)-N-piperidin- 4-yl-benzamide 0.5 g (1.14 mmol) and ethyl choroformate (0.186 g, 1.71 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSOd6): δl.21 (3H, t), 1.42 (4H, m), 1.81 (3H, d), 2.92 (2H, m), 4.12 (2H, m), 7.26 (5H, d), 7.52 (2H, d), 7.92 (4H, d), 8.41 (IH, d).
f) 4- { 3 , 5 -Bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoylamino } -piperidine- 1-carboxylic acid ethyl ester
4-[3,5-Bis-(4-cyano-phenoxy)-benzoylamino]-piperidine-l-carboxylic acid ethyl ester 0.4 g (0.784 mmol) was subjected to form N-hydroxycarbamimidoyl using the procedure of Example 95(d) to afford 0.40 g of the required product. Percentage purity (LCMS): 87.6 %, (M+l) = 576.2+1.
g) 3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-N- [ 1 -(2-hydroxy-ethyl)-piperidin-4-yl] - benzamide
4-{3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-piperidine- 1-carboxylic acid ethyl ester 0.4 g (0.52 mmol) was subjected to reduction using the procedure of Example 123(g) to afford 0.2 g of the required product. Percentage purity (HPLC): 97.4 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.22 (3H, m), 1.41 (2H, m), 1.7 (2H, d), 2.81(2H, brs), 4.1 (5H, q), 7.21 (IH, t), 7.35 (4H, d), 7.50 (2H, d), 7.9 (4H, d), 8.45 (lH, d), 9.2 (8H, brs).
Example 125.
3 , 5 -Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexyl-benzamide Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-cyclohexyl-benzamide
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.5 g (1.4 mmol) and cyclohexylamine (0.14 g, 1.4 mmol) were used to afford 0.61 g of the required product. Percentage purity (LCMS): 78.1 %, (M+l) = 437.0+1.
d) N-Cyclohexyl-3 , 5 -bis- [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzamide
Following the procedure of Example 95(d) 3,5-bis-(4-cyano-phenoxy)-N-cyclo- hexyl-benzamide 0.61 g (1.4 mmol) and other reagents were used to afford 0.65 g of the required product. Percentage purity (LCMS): 85.1.0 %, (M+l) = 503.1+1.
e) N-Cyclohexyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzamide
Following the procedure of Example 2(e) N-cyclohexyl-3,5-bis-[4-(N-hydroxy- carbamimidoyl)-phenoxy]-benzamide 0.65 g (1.29 mmol) was used to afford 0.76 g of the required product. Percentage purity (LCMS): 39.0 %, (M+l) = 587.2+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexyl-benzamide
(4-{3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclo- hexyl)-carbamic acid tert-butyl ester 0.76 g (1.29 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of the required product. Percentage purity
(HPLC): 95.01 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.22 (4H, m), 1.91 (6H, m), 3.11 (IH, t), 7.15 (IH, s), 7.2 (4H, d), 7.50 (2H, d), 7.78 (4H, d), 8.45 (IH, d), 9.21 (8H, brs).
Example 126.
3,5-Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexylmethyl-benzamide Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-cyclohexylmethyl-benzamide
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid
0.5 g (1.26 mmol) and cyclohexylmethylamine (0.143 g, 1.26 mmol) were used to afford 0.60 g of the required product. Percentage purity (LCMS): 97.6 %, (M+ 1) = 451.1+1.
d) N-Cyclohexylmethyl-3,5-bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]- benzamide
Following the procedure of Example 95(d) 3,5-bis-(4-cyano-phenoxy)-N-cyclo- hexylmethyl-benzamide 0.60 g (1.22 mmol) and other reagents were used to afford 0.65 g of the required product. Percentage purity (LCMS): 89.0 %, (M+l) = 517.2+1.
e) N-Cyclohexylmethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]- benzamide
Following the procedure of Example 2(e) N-cyclohexylmethyl-3,5-bis-[4-(N- hydroxycarbamimidoyl)-phenoxy]-benzamide 0.65 g (1.16 mmol) was used to afford 0.5 g of the required product. Percentage purity (LCMS): 72.0 %, (M+l) = 601.2+1.
f) 3 ,5 -Bis-(4-carbamimidoyl-phenoxy)-N-cyclohexylmethyl-benzamide
N-Cyclohexylmethyl-3,5-bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]- benzamide 0.5 g (0.78 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of the required product. Percentage purity (HPLC) 98.9 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 0.8 (2H, t), 1.2 (3H, m), 1.62 (6H, d), 3.1 (2H, t), 7.15 (IH, s), 7.25 (4H, d), 7.50 (2H, d), 7.91 (4H, d), 8.61 (IH, t), 9.25 (4H, brs).
Example 127. 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide Intermediates (a) and (b) are the same as in Example 26.
c) 3,5-Bis-(4-cyano-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide
Following the procedure of Example 9(e) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.5 g (1.26 mmol) and 4-methylcyclohexylamine (0.143 g, 1.26 mmol) were used to afford 0.6 g of the required product. Percentage purity (LCMS): 84.6 %, (M+l) = 451.1+1.
d) 3,5-Bis-[4-(N-hydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohexyl)- benzamide
Following the procedure of Example 95(d) 3,5-bis-(4-cyano-phenoxy)-N-(4-methyl- cyclohexyl)-benzamide 0.6 g (1.22 mmol) and other reagents were used to afford 0.65 g of the required product. Percentage purity (LCMS): 43.8 %, (M+l) = 517.2+1.
e) 3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohexyl)- benzamide
Following the procedure as in Example 2(e) 3,5-bis-[4-(N-hydroxycarbamimidoyl)- phenoxy]-N-(4-methyl-cyclohexyl)-benzamide 0.65 g (1.16 mmol) was used to afford 0.7 g of the required product. Percentage purity (LCMS): 75.2 %, (M+l) = 601.2+1.
f) 3,5-Bis-(4-carbamimidoyl-phenoxy)-N-(4-methyl-cyclohexyl)-benzamide
3,5-Bis-[4-(N-acetylhydroxycarbamimidoyl)-phenoxy]-N-(4-methyl-cyclohexyl)- benzamide 0.7 g (1.16 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of required product. Percentage purity (HPLC): 97.7 %, (LCMS): 97.1 %. 1H NMR (DMSOd6): δ 0.9 (3H, d), 1.3 (4H, m), 1.52 (4H, m), 3.05 (IH, m), 3.61 (IH, m), 7.15 (IH, m), 7.42 (4H, d), 7.50 (2H, t), 7.91 (4H, d), 9.11 (4H, brs), 9.25 (4H, brs). Example 128.
N-(4-Amino-cyclohexyl)-3-(3-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)- benzamide
Intermediates (a) and (c) are the same as in Example 49.
d) { 4- [3 -(3 -Bromo-phenoxy)-5 -(4-cyano-phenoxy)-benzoylamino] -cyclohexyl } - carbamic acid tert-butyl ester
{4-[3-(4-Cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid isopropyl ester (1.0 g, 2.2 mmol) and copper acetate (0.4 g, 2.2 mmol), dissolved in 30 ml of dichloromethane, were charged in a 100 ml capacity seal-tube. 3-bromophenyl boronic acid (0.667 g, 3.32 mmol), 4 A molecular sieves (3.0 g) and 0.438 g (5.53 mmol) of pyridine, in 20 ml of dichloromethane, was added to the reaction mixture in a sealed-tube and reaction mixture was stirred at RT for 20 h. After reaction completion 2.0 g of silica-gel was added and the mixture was filtered. Thus obtained filterate was concentrated under reduced pressure and subjected to column chromatography to afford 0.3 g of the required product. Percentage purity (LCMS): 86.0 %, (M+l) = 605.1+1.
e) (4-{3-(3 -Bromo-phenoxy)-5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] -benzoyl- amino }-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 95(d) {4-[3-(3-bromo-phenoxy)-5-(4- cyano-phenoxy)-benzoylamino] -cyclohexyl} -carbamic acid tert-butyl ester 0.3 g (0.49 mmol) and other reagents were used to afford 0.30 g of the required product. Percentage purity (LCMS): 72.0 %, (M+l) = 581.8+1 (Boc acid).
f) (4- { 3 -(3 -Bromo-phenoxy)-5 - [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 2(e) (4-{3-(3-bromo-phenoxy)-5-[4-(N- hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.30 g (4.69 mmol) was used to afford 0.31 g of the required product. Percentage purity (LCMS): 71.0 %, (M+ 1) = 580.1+1 (de-Boc).
g) {4-[3-(3-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester
{4-[3-{4-[(acetyl-hydroxy-amino)-imino-methyl]-phenoxy}-5-(3-bromo- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.31 g (4.55 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of the required product. Percentage purity (LCMS): 60.0 %, (M+l) = 623.9+1
h) {4-[3-(3-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]- cyclohexyl}-carbamic acid tert-butyl ester
{ 4- [3 -(3 -Bromo-phenoxy)-5 -(4-carbamimidoyl-phenoxy)-benzoylamino] -cyclo- hexyl}-carbamic acid tert-butyl ester 0.25 g (4.01 mmol) was treated using the procedure of Example 9(d) to afford 0.1 g of the required product. Percentage purity (HPLC): 96.2 %, (LCMS): 97.8 %. 1H NMR (DMSO-d6): δl.41(4H,d), 1.9(4H, m), 3.05 (IH, m), 7.15 (IH, m),7.21(lH,m), 7.42 (4H, d), 7.91 (5H, d),8.5(lH,d), 9.11 (2H, brs), 9.25 (2H, brs).
Example 129.
N-(4-amino-cyclohexyl)-3-(4-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)- benzamide
Intermediates (a) and (c) are the same as in Example 49.
d) {4-[3-(4-Bromo-phenoxy)-5-(4-cyano-phenoxy)-benzoylamino]-cyclohexyl}- carbamic acid tert-butyl ester
Following the procedure of Example 128(c) {4-[3-(4-cyano-phenoxy)-5-hydroxy- benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 2.21 mmol) and 4- bromo phenyl boronic acid (0.67 g, 3.32 mmol) were used to afford 0.32 g of the required product. Percentage purity (LCMS): 55.7 %, (M+l) = 605.1+1 (de-Boc; -100).
e) (4- { 3 -(4-Bromo-phenoxy)-5 - [4-(N-hydroxycarbamimidoyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure of Example 95(d) 3{4-[3-(4-Bromo-phenoxy)-5-(4- cyano-phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.32 g (0.52 mmol) and other reagents were used to afford 0.30 g of the required product. Percentage purity (LCMS): 37.5 %, (M+l) = 640.1+1.
f) (4- { 3 -(4-Bromo-phenoxy)-5 - [4-(N-acetylhydroxycarbamimidoyl)-phenoxy] - benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester
Following the procedure as in Example 2(e) (4-{3-(4-bromo-phenoxy)-5-[4-(N- hydroxycarbamimidoyl)-phenoxy]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester 0.30 g (4.69 mmol) was used to afford 0.31 g of the required product. Percentage purity (LCMS): 38.6 %, (M+l) = 584+1 (de-Boc; -100).
g) { 4- [3 -(4-Bromo-phenoxy)-5 -(4-carbamimidoyl-phenoxy)-benzoylamino] - cyclohexyl}-carbamic acid tert-butyl ester
{4-[3-{4-[(Acetyl-hydroxy-amino)-imino-methyl]-phenoxy}-5-(4-bromo- phenoxy)-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester 0.31 g (4.55 mmol) was reduced using the procedure of Example 2(f) to afford 0.25 g of the required product. Percentage purity (LCMS): 22.8 %, (M+l) = 522.1+1 (de-Boc; -100).
h) N-(4-amino-cyclohexyl)-3-(4-bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)- benzamide
{4-[3-(4-Bromo-phenoxy)-5-(4-carbamimidoyl-phenoxy)-benzoylamino]-cyclo- hexyl}-carbamic acid tert-butyl ester 0.1 g (4.01 mmol) was treated using the procedure of Example 9(d) to afford 0.1 g of the required product. Percentage purity (HPLC): 93.6 %, (LCMS): 100 %. 1H NMR (DMSOd6): δ 1.41 (4H, d), 1.9 (4H, m), 3.05 (IH, m), 3.61(1H, m), 7.15 (IH, m), 7.21 (IH, m), 7.42 (IH, d), 7.6 (IH, d), 7.91 (4H, d), 8.5 (IH, d), 9.11 (2H, brs), 9.25 (2H, brs).
Abbreviations:
DMF - N,N-dimethylformamide
THF - Tetrahydrofuran TEA - Triethyl Amine
EDC - l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
HOBT - hydroxybenzotriazole
DIPEA - iV,7V-diisopropylethylamine
PyBop - Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate Na2CO3 - Sodium carbonate
RT - Room temperature

Claims

Claims
1. A compound of formula (I)
Figure imgf000217_0001
wherein
Pi and P2 are, independently a bond or Ci-3 alkyl; A is CH or N; B is CH or N;
Ri is hydrogen, amino, -NH-SO2- ZR9Ri3, -NR4-CO-ZR9Ri3, -CO-NR7R8, -CO-O-ZR9R)3, -CO-NR4-R^ZR9Ri3 or a group of formula
Figure imgf000217_0002
wherein the ring portion in formula (II) is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 further heteroatoms selected from N, O, S or combinations thereof;
R3 is -C(NRi7)NH2, or in case A is CH, R3 can also be amino Ci-7 alkyl; Ri0, R)4 and Ri5 are independently hydrogen, halogen, hydroxy, Ci-7 alkyl, halogen C]-7 alkyl or -C(NRn)NH2;
Q is hydrogen or halogen, with a proviso that Ri and Q are not simultaneously hydrogen;
R4 is hydrogen or Cj-7 alkyl; Z is a 5 -12 membered saturated, partially saturated or aromatic ring which may be monocyclic or bicyclic, and which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof; R9 and R13 are, independently, hydrogen, halogen, hydroxy, carboxy, C1-7 alkyl, carboxy C1-7 alkyl, hydroxy C1-7 alkyl, C1-7 alkoxycarbonyl, RANH2 or -COR8NH2;
RA, RB and Rx are, independently, a bond or C1-7 alkyl;
R7 and R8 are, independently, hydrogen, amino Ci-7 alkyl, carboxy Ci-7 alkyl, or in case A is CH, R7 and R8, independently, can also be C)-7 alkyl, with a proviso that R7 and R8 are not simultaneously hydrogen;
R2 is Ci-7 alkyl, amino Ci-7 alkyl, carboxy Cj-7 alkyl, Ci-7 alkoxycarbonyl Ci-7 alkyl, Cj-7 alkylamino, carboxy Ci-7 alkylamino, R0C(NRi7)NH2, or a group of formula (III)
Figure imgf000218_0001
(III)
y = 0-2; RD is a bond or C]-7 alkyl; G is CH or N;
Rn is hydrogen, halogen, amino, carboxy, amino Ci-7 alkyl, Ci-7 alkoxycarbonyl, halogen Ci-7 alkoxy, -C(NR17)NH2, -NHCOR0NH2, RJNHC00Ru or -CONRi9R20;
RG is Ci-7 alkyl; RJ is a bond or Ci-7 alkyl; Ru is hydrogen or Cj-7 alkyl; Ri2 and Rj6 are, independently, hydrogen, halogen or Ci-7 alkyl; or Ri2 and Ri6 form, together with the carbon atoms to which they are attached, a 5 or 6 membered saturated, partially saturated or aromatic ring which may contain 1-3 heteroatoms selected from N, O, S or combinations thereof, which ring can be substituted;
Rn is hydrogen, -OH, Ci-7 alkoxy, -O(CO)OR]8 or -(CO)OR)8; Ri 8 is Ci-7 alkyl; Ri 9 and R20 are, independently, hydrogen, Ci-7 alkyl or Ci-7 alkoxy; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein A is CH and B is CH.
3. A compound according to claim 1 or 2, wherein R3 is -C(NRi7)NH2 and Ri0, Ri4 and Ri5 are hydrogen.
4. A compound according to any of claims 1 to 3, wherein R2 is a group of formula (III) wherein G is CH, y is 0-1, Rn is -C(NRi7)NH2 or amino Ci-7 alkyl, and R)2 and Ri6 are hydrogen.
5. A compound according to any of claims 1 to 4, wherein Pj and P2 is a bond.
6. A compound according to any of claims 1 to 5, wherein P1 is a bond and P2 is -CH2-
7. A compound according to any of claims 1 to 6, wherein R1 is a group of formula (II).
8. A compound according to claim 7, wherein the ring portion of formula (II) is a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain one further heteroatom N.
9. A compound according to claim 8, wherein the ring portion of formula (II) is piperidinyl, piperazinyl, nonahydro-quinolinyl or 3,4-dihydro-lH-quinolinyl.
10. A compound according to claim 1, wherein R1 is -NR4-CO-ZR9Rn, -CO-O-ZR9Ri3 or -CO-NR4-R^ZR9Ri3.
11. A compound according to claim 10, wherein Z is a 6 or 10 membered saturated, partially saturated or aromatic ring, which may be monocyclic or bicyclic, and which may contain 1 or 2 N atoms.
12. A compound according to claim 11, wherein Z is cyclohexyl, piperidinyl, phenyl, naphthyl or quinolinyl.
13. A compound according to claim 12, wherein Z is cyclohexyl or piperidinyl, R4 is hydrogen, Rx is a bond, R9 is RΛNH2 and Rj3 is hydrogen.
14. A pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable carrier.
15. A method for the treatment of a matriptase dependent condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
16. A method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140077891A (en) 2011-09-29 2014-06-24 오노 야꾸힝 고교 가부시키가이샤 Phenyl derivative
KR20140117301A (en) 2013-03-26 2014-10-07 오노 야꾸힝 고교 가부시키가이샤 A medicine comprising phenyl derivatives
WO2016200827A1 (en) * 2015-06-11 2016-12-15 University Of Pittsburgh - Of The Commonwealth System Of Higher Education P62-zz chemical inhibitor
US9676719B2 (en) 2013-03-26 2017-06-13 Ono Pharmaceutical Co., Ltd. Phenyl derivative
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
EP3806836A4 (en) * 2018-06-14 2022-07-20 Georgia State University Research Foundation, Inc. Amidines and amidine analogs for the treatment of bacterial infections and potentiation antibiotics
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2432556A1 (en) * 2009-05-18 2012-03-28 Orion Corporation Protease inhibitors
CN107973727B (en) * 2017-12-11 2020-04-17 中山大学 M-disubstituted phenol compound, preparation method and anti-tubercle bacillus application thereof
CN109503464A (en) * 2018-12-17 2019-03-22 天津药明康德新药开发有限公司 A kind of synthetic method of nitrogen-(Benzyloxycarbonylpiperidin -4- base) -2- (trifluoromethyl) benzamide

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996028427A1 (en) * 1995-03-10 1996-09-19 Berlex Laboratories, Inc. Benzamidine derivatives their preparation and their use as anti-coagulants
US5691364A (en) * 1995-03-10 1997-11-25 Berlex Laboratories, Inc. Benzamidine derivatives and their use as anti-coagulants
WO2001097794A2 (en) 2000-06-21 2001-12-27 Georgetown University Inhibitors of matriptase for the treatment of cancer
WO2004058688A1 (en) 2002-12-23 2004-07-15 Dendreon Corporation Matriptase inhibitors and methods of use
WO2004101507A2 (en) 2003-05-16 2004-11-25 Curacyte Chemistry Gmbh N-sulphonylated amino acid derivatives and use thereof as matriptase inhibitors
WO2008085608A1 (en) 2007-01-10 2008-07-17 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008097676A1 (en) 2007-02-09 2008-08-14 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008097673A1 (en) 2007-02-09 2008-08-14 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008107176A1 (en) 2007-03-06 2008-09-12 The Medicines Company (Leipzig) Gmbh Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
WO2009027450A1 (en) * 2007-08-29 2009-03-05 Boehringer Ingelheim International Gmbh Novel bradykinin b1-antagonists

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2432556A1 (en) * 2009-05-18 2012-03-28 Orion Corporation Protease inhibitors

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996028427A1 (en) * 1995-03-10 1996-09-19 Berlex Laboratories, Inc. Benzamidine derivatives their preparation and their use as anti-coagulants
US5691364A (en) * 1995-03-10 1997-11-25 Berlex Laboratories, Inc. Benzamidine derivatives and their use as anti-coagulants
EP0813525A1 (en) 1995-03-10 1997-12-29 Berlex Laboratories, Inc. Benzamidine derivatives their preparation and their use as anti-coagulants
WO2001097794A2 (en) 2000-06-21 2001-12-27 Georgetown University Inhibitors of matriptase for the treatment of cancer
WO2004058688A1 (en) 2002-12-23 2004-07-15 Dendreon Corporation Matriptase inhibitors and methods of use
WO2004101507A2 (en) 2003-05-16 2004-11-25 Curacyte Chemistry Gmbh N-sulphonylated amino acid derivatives and use thereof as matriptase inhibitors
WO2008085608A1 (en) 2007-01-10 2008-07-17 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008097676A1 (en) 2007-02-09 2008-08-14 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008097673A1 (en) 2007-02-09 2008-08-14 Irm Llc Compounds and compositions as channel activating protease inhibitors
WO2008107176A1 (en) 2007-03-06 2008-09-12 The Medicines Company (Leipzig) Gmbh Meta-substituted phenyl sulfonyl amides of secondary amino acid amides, the production thereof, and use thereof as matriptase inhibitors
WO2009027450A1 (en) * 2007-08-29 2009-03-05 Boehringer Ingelheim International Gmbh Novel bradykinin b1-antagonists

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 November 1996 (1996-11-22), XP002595441, Database accession no. 183303-55-1 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 30 October 2007 (2007-10-30), XP002595443, Database accession no. 951907-50-9 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 30 October 2007 (2007-10-30), XP002595444, Database accession no. 951917-38-7 *
ENYEDY I J ET AL: "STRUCTURE-BASED APPROACH FOR THE DISCOVERY OF BIS-BENZAMIDINES AS NOVEL INHIBITORS OF MATRIPTASE", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US LNKD- DOI:10.1021/JM000395X, vol. 44, no. 9, 26 April 2001 (2001-04-26), pages 1349 - 1355, XP001104512, ISSN: 0022-2623 *
ENYEDY, I. ET AL., J. MED. CHEM., vol. 44, 2001, pages 1349 - 1355
GARY PHILLIPS ET AL.: "Design, Synthesis, and Activity of 2,6-Diphenoxypyridine-Derived Factor Xa Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, 24 April 1999 (1999-04-24), pages 1749 - 1756, XP002595442, DOI: 10.1021/jm980667k *
PHILLIPS, G. ET AL., J. MED. CHEM., vol. 41, 1998, pages 3557 - 3562
PHILLIPS, G. ET AL., J. MED. CHEM., vol. 42, 1999, pages 1749 - 1756

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WO2016200827A1 (en) * 2015-06-11 2016-12-15 University Of Pittsburgh - Of The Commonwealth System Of Higher Education P62-zz chemical inhibitor
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US11560352B2 (en) 2015-06-11 2023-01-24 University of Pittsburgh—of the Commonwealth System of Higher Education P62-ZZ small molecule modulators
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
EP3806836A4 (en) * 2018-06-14 2022-07-20 Georgia State University Research Foundation, Inc. Amidines and amidine analogs for the treatment of bacterial infections and potentiation antibiotics
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