WO2006014087A1 - Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same Download PDF

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Publication number
WO2006014087A1
WO2006014087A1 PCT/KR2005/002545 KR2005002545W WO2006014087A1 WO 2006014087 A1 WO2006014087 A1 WO 2006014087A1 KR 2005002545 W KR2005002545 W KR 2005002545W WO 2006014087 A1 WO2006014087 A1 WO 2006014087A1
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Prior art keywords
hydroxy
benzamidine
thiazol
phenoxy
pentoxy
Prior art date
Application number
PCT/KR2005/002545
Other languages
French (fr)
Inventor
Jin Soo Lee
Seok Hoon Ahn
Young Goo Jin
Sang Mi Jin
Whui-Jung Park
Sae Kwang Ku
Yun Ha Hwang
Pan Soo Kim
Sun Shin Yi
Jei Man Ryu
Original Assignee
Dong Wha Pharmaceutical. Ind. Co., Ltd.
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
Application filed by Dong Wha Pharmaceutical. Ind. Co., Ltd. filed Critical Dong Wha Pharmaceutical. Ind. Co., Ltd.
Priority to US11/659,556 priority Critical patent/US8178688B2/en
Priority to ES05771173.1T priority patent/ES2549263T3/en
Priority to AU2005267950A priority patent/AU2005267950B2/en
Priority to JP2007524754A priority patent/JP4990135B2/en
Priority to EP05771173.1A priority patent/EP1781629B1/en
Priority to BRPI0514111A priority patent/BRPI0514111B8/en
Priority to CA2576065A priority patent/CA2576065C/en
Publication of WO2006014087A1 publication Critical patent/WO2006014087A1/en
Priority to IL181022A priority patent/IL181022A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same.
  • Bone is the body's framework. Bone contains calcium
  • Osteoporosis is a metabolic bone disease, which results from a disturbance in the normal bone remodeling, tilting the balance between bone resorption and formation, thus 45
  • Bone is the dynamic structures, in which the osteoblast bone formation and osteoclast bone resorption are continuously- occurred.
  • bisphosphonates alendronate, etidronate etc.
  • hormones raloxifen
  • Vitamin D Vitamin D
  • Calcitonin calcium agents
  • they have some adverse side effect or defects.
  • Bisphosphontes show low pharmacokinetic profiles, are difficult to dose and may induce esophagitis.
  • Hormone agents must be administered continuously.
  • severe side effects such as breast cancer, gallstones and embolism may be induced.
  • Vitamin D agents are expensive and show little efficacy in treating estrogen-deficient osteoporetic patients.
  • Calcitonin is also very expensive and difficult to administrate. Calcium has few adverse side effects, but its effects is restricted to the prevention of osteoporosis not the treatment of it. 5 002545
  • a bone fracture is a break or crack in a bone, with complete or incomplete disruption of the continuity of a bone, epiphyseal plate or articular surface.
  • a bone fracture is caused mostly by some type of trauma to a bone. This trauma might occur as a result of a motor vehicle accident, workplace accident, physical abuse, repetitive stress such as exercise, heavy lifting, etc.
  • fracture line line along epiphyseal ends generated upon fracture
  • bone fractures are classified into fissured fractures, greenstick fractures, transverse fractures, oblique fractures, spiral fractures, segmental fractures, comminuted fractures, avulsion fractures, compression fractures, depressed fractures, etc.
  • osteocytes and bone matrix are removed by macrophages while osteoprogenitor cells of the perilsteum and endosteum around the fracture region actively proliferate to form cellular tissue around the fracture region and are then integrated with the fracture region.
  • osteoprogenitor cells of the perilsteum and endosteum around the fracture region actively proliferate to form cellular tissue around the fracture region and are then integrated with the fracture region.
  • a bone tissue arises by endochondral ossification from a small cartilage fragment or an immature bone is formed by intramembranous ossification. Accordingly, intramembranous ossification from mesenchymal tissue and endochondral ossification are observed concurrently in the connective tissue of a fracture region.
  • the trabecula of the immature bone irregularly formed in this way temporarily connects ends of the fractured bone fragments, resulting in the formation of a bony callus.
  • the woven bone of the bony callus formed in the fracture region is gradually resorbed as the healing process progresses, and undergoes rearrangement resulting in the development of lamellar bone.
  • the healing process for fracture is largely divided into three phases: inflammatory phase, bone reparative phase, and remodeling phase.
  • the hematoma is removed from the fracture gap and substituted with granulation tissue while soft callus is formed.
  • two processes proceed concurrently: endochondral ossification, in which the soft callus is remodeled into hard callus, and fibrous/intramembranous ossification, in which a new bone is formed by osteogenic cells.
  • BMPs bone morphogenic proteins
  • TGFs transforming growth factors
  • mice into which the general PDE inhibitor pentoxipylline or the selective PDE4 inhibitor rolipram had been subcutaneously injected every day, were observed to have the vertebrate and femur increased in bone mineral density, and showed hyperplasia of cortical bones (Bone, vol. 27., 6th edition, pp. 811-817 (2000)).
  • attention has long been paid to osteogenesis and fracture healing, and extensive studies on fracture healing processes have been conducted from various points of view, including genetic factors, adolescent influence, hematopoietic effect, fixture effect, bone grafts, other healing promoting factors, etc. (Kawamura, M and Urist MR., Clin. Orthop., 236, 240-248, 1988).
  • Fracture healing requires a significant period of time and elderly patients with osteoporosis tend to suffer more from bone fractures. Falling short of the expectation of usefulness in fracture healing, currently available therapeutic agents for the treatment of osteoporosis, such as calcium, estrogen, calcitonin, active vitamin D, biphosphonate, etc., are found only to lower the risk of fracture by obstructing the decrease of bone density, and have no function of joining fractured bones or generating bone tissues.
  • the pathogenic mechanism of osteoporosis can be explained by a subtle bone matrix resulting from long maintenance of negative bone homeostasis due to genetic or constitutional predispositions, stagnant osteogenesis with normal bone resorption, and increased bone resorption with normal osteogenesis. Osteoporosis agents are, therefore, ineffective for the treatment of bone fractures because the healing mechanism is quite different between fractures and osteoporosis.
  • Allergic inflammatory disease is attributed to abnormality in the immune system where the nasal or bronchial mucosa or skin is hypersensitive to external allergens.
  • Basic causes of allergy include nutrition imbalance, stress, extravasated blood, etc., with the major cause being nutrition imbalance.
  • allergic inflammatory disease is represented as various symptoms including allergic rhinitis, asthma, atopic dermatitis, etc.
  • allergic conjunctivitis, allergic dermatitis, contact dermatitis, urticaria, etc. are within the scope of allergic inflammatory diseases. Since these symptoms, although very diverse, are common in the pathology based on the hypersensitivity to externally introduced matter, a suppressant of excessive immune responses can be prescribed for all of them.
  • Asthma is a chronic inflammatory disease occurring in the respiratory organ, especially, the lungs and the bronchi.
  • patients with asthma take drugs or excessive exercise or inhale contaminated and/or cold air
  • their respiratory organs, especially, upper respiratory organs increase in responsiveness.
  • This hyper-responsiveness is associated with the airflow obstruction in the airway, that is, airway obstruction or tracheal stenosis, but is readily alleviated using a bronchodilator.
  • hyper-responsiveness to indoor and/or outdoor allergens and airway contraction are known to be mediated by mast cells and eosinophil IgE (Beasley et al., Am. Rev. Respir. Dis., 129, 806-817, 1989) .
  • ⁇ sthma is accompanied by the allergic • hyper- responsiveness mainly in the bronchia and the lungs.
  • the air passage becomes clogged by the proliferation of mucous cells and the inflammation of epithelial connective tissues in the bronchia.
  • the lungs are known to show similar histological behaviors.
  • the pathology of asthma although not yet clearly revealed thus far, is reported to be featured by airway stenosis, edema, mucus secretion, inflammatory cell infiltration, etc.
  • B cells produce antigen specific antibodies IgE and IgG in cooperation with macrophages and helper T-cells.
  • antigen specific antibodies bind to receptors on the surfaces of mast cells and basophils, which are then activated upon re-exposure to the same antigen so as to release various cytokines and mediators of allergy/inflammation, including histamine, prostaglandin D 2 , slow reacting substances (leukotriene C 4 , D 4 ), etc. out of the cells. Due to these cytokines and mediators, when exposed to aeroallergen, patients with asthma exhibit an early asthma response characterized by a rapid airway constriction over a period of seconds to minutes and apparent recovery within 30 to 60 min from the constriction.
  • the mediators secreted from mast cells and the cytokines secreted from macrophages, mast cells and helper T-cells proliferate and activate inflammatory cells, including eosinophils, to exhibit a late asthmatic response in which bronchoconstriction, mucus secretion and inflammatory cell infiltration begin 3 to 4 hours and peak 4 to 18 hours after exposure to aeroallergens (Robertson et al., J. Allergy Clin. Immunol., 54, 244-257, 1974) .
  • beta 2-adreno receptor agonists which dilate airway smooth muscles and effectively inhibit the secretion of hyperresponsiveness mediators from mast cells, adrenal cortical hormones, which exhibit an immunosuppressive effect, and disodium cromoglycate and nedocromil sodium, both known to inhibit both the early and the late asthma response.
  • beta 2-adreno receptor antagonists show the treatment effect only for a short period of time and allow the ready recurrence of the disease.
  • Adrenal cortical hormones have fragmentary treatment effects
  • An object of the present invention is to provide novel
  • invention is to provide their preparation method. Further,
  • Another object of the present invention is to provide
  • the invention relates to novel benzamdine derivatives
  • Ri is C x -C 6 alkyl; C 3 -C 6 cycloalkyl; phenyl; benzyl;
  • R 2 is hydrogen; C 1 -C 6 alkyl; C 3 -C 6 cycloalkyl; phenyl;
  • R 6 and R 7 are hydrogen; Ci-C 6 alkyl; phenyl; benzyl; pyridinyl; Ci ⁇ C 6 alkyl which is substituted by
  • Ci-C 6 alkanesulfonyl Ci-C 6 alkyl which is substituted by hydroxy or
  • Ci-C 6 alkoxy acetyl which is substituted by hydroxy or Ci-C 6
  • Y is oxygen; sulfur; NR 6; or CH 2 ;
  • Xi and X 3 are oxygen; sulfur; NH;
  • N-Ci-C 6 alkyl N-C 3 -C 6 cycloalkyl; N-benzyl; N-phenyl;
  • X 2 is C 3 -C 7 alkylene; C x -C 3 alkylene-alkenylene-Ci-C 3 -
  • phenylene-Ci-C 3 alkylene C x -C 3 alkylene-pyridylene-Ci-C 3 alkylene; Ci-C 3 alkylene-naphtylene-Ci-C3 alkylene; C 3 -C 7 alkylene which is substituted by Ci-C 3 alkyl and hydroxy; C 3 - C 7 alkylenecarbonyl; C 3 -C 7 alkylene which is interrupted by piperazine .
  • the invention especially relates to compounds of the formula 1 in which:
  • Ri is Ci-C 6 alkyl; C 3 -C 6 cycloalkyl; phenyl; pyridinyl;
  • R 2 is hydrogen; C x -C 6 alkyl; C 3 -C 6 cycloalkyl; benzyl; C x -C 6 alkyl which is substituted by hydroxyl, methoxy,
  • R 3 and R 4 are hydrogen; halogen; hydroxy; C 3 -C 6 cycloalkylamino; C x -C 6 alkoxy; Ci-C 5 alkanoyloxy; C 3 ⁇ C 6 cycloalkyloxy which is substituted by carboxy, esterified carboxy or amidated carboxy; aminooxy; R 5 is hydrogen or hydroxy; Re and R 7 , each independently, are hydrogen; C 1 -C 6 alkyl;
  • Y is oxygen; sulfur; NR ⁇ ; CH 2 ;
  • Xi and X 3 are oxygen; sulfur; NH;
  • X 2 is C 3 -C 7 alkylene;
  • the invention further especially relates to compounds
  • R 1 is methyl; ethyl; propyl; isopropyl; butyl; t-butyl;
  • R 2 is hydrogen; methyl; ethyl; isopropyl; propyl; butyl; isobutyl; methoxymethyl; hydroxymethyl; 2- methylpropyl; pentyl; chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; cyclohexyl; benzyl; vinyl;
  • R 3 and R 4 are hydrogen; halogen; hydroxy; cyclohexylamino; methoxy; Ci-C 4 alkanoyloxy; Ci-C 7 aliphatic alkoxy which is substituted by carboxy, esterified carboxy or amidated carboxy;
  • R 5 is hydrogen or hydroxy
  • R 6 and R 7 are hydrogen; methyl; ethyl; propyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2- morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; methoxyethy1; hydroxyethyl; hydroxyacetyl; methoxyacetyl;
  • Y is oxygen; sulfur; NRg; CH 2 ;
  • Xi and X 3 are oxygen; sulfur; amine;
  • X 2 is propylene; butylene; pentylene; hexylene; heptylene; ethylene-O-ethylene; 3-hydroxy-3-methyl-pentylene; methylethylene-NH-ethylene; ethylene-NH-ethylene; propylene which is interrupted by piperazine; butylene carbonyl; 2- butenyl; methylene-phenylene-methylene; methylene-pyridylene- methylene; 1,2-ethylene-l,4-phenylene-l,2-ethylene; 1,3- propylene-1,4-phenylene-l,3-propylene; 1,2-ethylene- naphthalene-1,2-ethylene.
  • the invention furthermore especially relates to compounds of the formula 1 in which,
  • Ri is methyl; ethyl; isopropyl; cyclohexyl; phenyl; aminomethyl; aminoethyl; amino; pyridinyl; NR 6 R 7 ;
  • R 2 is hydrogen; methyl; ethyl; isopropyl; isobutyl; methoxymethyl; hydroxymethyl; chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; vinyl;
  • R 3 and R 4 are hydrogen; halogen; hydroxy; methoxy;
  • R 5 is hydrogen or hydroxy
  • R 6 and R 7 are hydrogen; methyl; ethyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; hydroxyethyl; methoxyethyl; Y is oxygen; sulfur; methylamine; Xi and X 3 , each independently, are oxygen; sulfur; amino; methylamine;
  • X 2 is propylene; butylene; pentylene; hexylene; ethylene-O-ethylene; ethylene-NH-ethylene; butylenecarbonyl; 2-butenyl; methylene-l,2-phenylene-methylene; methylene-1,3- phenylene-methylene; methylene-l f 4-phenylene-methylene; methylene-pyridinyl-methylene.
  • the benzamidine derivatives of the formula 1 may be used in the form of pharmaceutically acceptable salts known in the art.
  • Preferable are acid addition salts prepared with pharmaceutically acceptable free acids.
  • Free acids suitable for use in the present invention may be inorganic acids or organic acids. Examples of the inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc, and the organic acids may be exemplified by citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonic acid, maleic acid, maleinic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethane sulfonic acid, camphorsulfonic acid, 4-nitrobenzene sulfonic acid, hydroxy- 0-sulfonic acid, 4-tol
  • organic acid can be used.
  • Halogen means halogen group atoms including chlorine
  • Alkyl radical means saturated carbohydrogens which have
  • Alkoxy radical means said alkyl radical linked to
  • oxygen for example, methoxy, ethoxy, propoxy, iso-propoxy
  • Cycloalkyl radical means nonaromatic carbohydrogen
  • Alkenyl radical means unsaturated carbohydrogens which
  • Alkanoyloxy radical means oxygen-containing radical in
  • Alkenoyloxy radical means oxygen-containing radical in
  • Alkenyloxy radical means oxygen-containing alkenyl
  • Alkylene radical means carbohydrogen radicals which
  • covalent bond including methylene, ethylene, methylethylene,
  • Alkenylene radical means carbohydrogen radicals which
  • Carbonyl radical means carbon radicals in which 2 of 4
  • the present invention provides a
  • R 1 is C 1 -C 6 alkyl; pyridine-substituted Ci-C 6 alkyl;
  • pyridinyl pyridinyl; pyridinyl which is substituted by C 1 -C 6 alkyl; A-N(CH2)n or vJ (A is Ci-C 6 alkyl and n is integer of 2 to 6) ,
  • benzamidine derivatives of the formula 1 can be prepared with Reaction Scheme 1 below comprising the steps of :
  • step 6) reacting the compound of the formula 16 prepared in step 6) with amine compound to prepared benzamidine derivatives of the formula Ib.
  • R 2 , R3, R4, R5, R 6 , ,Xi r X2 and X3 are the same as defined in the compound of the formula 1 and n is an integer of 0 to 6, except that R 6 is hydrogen.
  • step 6) reacting the compound of the formula 16 prepared in step 6) above with a compound of the formula 17 to prepare benzonitrile derivatives with thiazole ring substituted with secondary amine of the formula 18, and
  • step 8) reacting the compound of the formula 18 prepared in step 7) with amine compound to prepare benzamidine derivatives of the formula Ic.
  • n is an
  • n is an integer
  • Reaction Scheme 1 is illustrated by using specific compounds as shown below.
  • the reaction temperature is preferably maintained in the
  • (7) is a material to introduce substituent R 2 into the compound of the formula 1 and can be selected from acid chlorides with proper alkyl radical according to the type of substituents.
  • acid chloride (6) includes acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, isovaleryl chloride, 4-methylvaleryl chloride, 3- methylvaleryl chloride, hexanoyl chloride, cyclopentyryl chloride, chlorobutyl chloride, 3-bromopropionyl chloride, 2,3-dichloropropionyl chloride, 4-chlorobutyryl chloride, 3- cyclopentylpropionyl chloride, hydrocinnamoyl chloride, cyclopentylacetyl chloride, isocaproic chloride, which are available commercially or prepared simply with public methods.
  • Inorganic acid can be aluminum chloride and the
  • reaction can be carried out in the range of -20 to 30 ° C for 2 to 24 hours.
  • the reaction solvent can be selected from dichloromethane, chloroform, etc.
  • Acids used for preparing compound (8) are organic acid such as acetic acid and inorganic acid such as bromic acid and aluminum chloride. The reaction is preferably carried out in the range of 60 to
  • step 1-3 4- (5-chloropentoxyl)benzonitrile (4) prepared in step 1-1 is reacted with phenol compound(8) prepared in step 1-2 in the presence of base, thus preparing 4-(5-phenoxypentoxyl)benzonitrile compound(9) .
  • Inorganic bases can be used in this reaction, and selected form the group of potassium carbonate, sodium hydroxide and sodium hydride. The reaction can be carried out in the range of 10
  • step 1-4 compound (9) prepared in step 1-3 is reacted with brominating agent, thus preparing ⁇ -brominated compound (10) .
  • brominating agent for the reaction can include copper (II) bromide, bromine, etc. and the reaction can be
  • step 1-5 ⁇ -brominated compound (10) prepared in step 1-4 is reacted with thioamide (11) , thus preparing compound (12) which has thiazole ring.
  • thioamide (11) is a material to introduce substituent Ri into the compound of formula 1 and can be selected according to their substituent radical. Reaction time and solvent vary according to thioamide compound (11) , but in most case, the
  • Thioamide compound (11) used for the reaction includes thioacetamide, thiopropionamide, thioisobutramide, trimethylthioacetamide, thiohexanoamide, cyclohexancarbothioicacid amide, N- (2-amino-2-thioxoethyl)-2- methylpropanamide, piperidin-4-carbothioicacid amide, thiourea, amidinothiourea, thiobenzoamide, glycine thioamide, 2,2-dimethyl thiopropionamide, " which are available commercially or prepared simply with public methods. Ethanol or ethanol/water mixture is used as a solvent.
  • step 1-6 compound (12) which has thiazole ring, prepared in step 1-5, is reacted with amine compound in the presence of bases, thus preparing compound (Ia) .
  • hydroxylamine hydrochloride is reacted in the presence of a base, and the base can be selected from organic bases such as triethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, DBU, diethylmethylamine(Et 2 NMe) , N-methylmorpholine, N- methylpiperidine, pyridine and 2,6-dimethylpyridine, and inorganic bases such as potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide, sodium ethoxide.
  • the reaction is carried out in the range of 60 to
  • methoxy imine is prepared from hydrocholide methanol solution in the range of 10 to
  • ethanol solution in the range of 45 to 60 ° C for 24 to 50 hours in high pressure reactor, finally preparing target amidines.
  • Ethanol is preferably used as a solvent.
  • Reaction Scheme 2 is illustrated by using specific compounds as shown below. Steps 2-1 to 2-4 in Reaction Scheme 2 are the same as those in Reaction Scheme 1.
  • step 2-5 ⁇ -brominated compound (10) prepared in step 2-4 is reacted with thiourea (13) , thus preparing benzonitrile compound (14) which has aminothiazole radical.
  • thiourea (13) is a material to introduce substituent Ri into the compound of the formula 1 and can be selected from thioureas with proper alkyl radical according to the type of substitutents. Reaction time and solvent vary according to the type of thiourea (13) selected which is available commercially or prepared in public methods. The reaction can be preferably carried out in the
  • Ethanol or Ethanol/water mixture can be preferably used as a solvent.
  • step 2-6 benzonitrile compound (14) which has aminothiazole radical prepared in step 2-5, is reacted with halide compound (15) in the presence of bases, thus preparing benzonitrile compound (16) which has thiazol ring substituted with amine.
  • halide compound (15) is a material to introduce a substitutents into the amino group of the compound of the formula 1 of which the substituent Ri is primary amine.
  • Halide compound (15) can be selected according to their substituent radical. Reaction time and solvent vary according to selecting halide compound (15) . The reaction can
  • Halide compound (15) can includes methyl iodide, ethyl iodide, propyl bromide, 2-chloroethylmethyl ether, chloroethyl morpholine, 3-bromomethyl pyridine, bromoethanol, niconoylchloride, benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride, isoniconoyl chloride, bis-dibromide ethylester, acetoxyacetyl chloride, methoxyacetyl chloride, etc., which are commercially available or prepared in public methods.
  • Acetonitrile or dimethylformamide can be preferably used as a solvent.
  • step 2-7 benzonitrile compound (16) which has thiazol ring substituted with the primary amine, prepared in step 2-6, is reacted with amine compound in the same condition as that of step 1-6, thus preparing the compound of the formula 1.
  • Reaction Scheme 3 is illustrated by using specific compound as shown below.
  • Steps 3-1 to 3-6 in Reaction Scheme 3 are the same as those in Reaction Scheme 2.
  • step 3-7 compound (16) prepared in step 3-6 is reacted with halide compound (17) in the presence of base, thus preparing benzonitrile compound (18) which has thiazole ring substituted with secondary amine.
  • halide compound (17) is a material to introduce the second substituent into the amino group of the compound of the formula 1 of which the substituent Ri is the secondary amine.
  • Halide compound (17) can be selected according to its substituent radical. Reaction time and solvent vary according to selecting the halide compound (17) selected. The reaction can be preferably carried out in the range of 0 to 90 ° C for 5 to 24 hours.
  • Halide compound (17) can include methyl iodide, ethyl iodide, propyl bromide, 2-chloroethylmethyl ether, chloroethyl morpholine, 3-bromomethyl pyridine, bromoethanol, niconoylchloride, benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride, isoniconoyl chloride, etc., which are commercially available or prepared in public methods.
  • Acetonitrile or dimethylformamide can be perferably used as a solvent.
  • step 3-8 benzonitrile compound (16) which has thiazol ring substituted with the secondary amine, prepared in step 3-7, is reacted with amine compound in the same condition as that of step 1-6, thus preparing the compound of
  • Reaction Scheme 4 is illustrated by using specific compounds as shown below.
  • Steps 4-1 to 4-5 in Reaction Scheme 4 are the same as those in Reaction Scheme 2.
  • step 4-6 benzonitrile compound(14) , which has aminothiazole, prepared in step 4-5, is reacted with the compound (19) of which both terminals are substituted by halogen in the presence of base, thus preparing benzonitrile compound (20) which has thiazole ring substituted with hetero ring.
  • compound (19) is a material to
  • the reaction can be carried out in the range of 0 to 90 ° C for 4 to 24 hours.
  • halogenate compounds can include mechloethylamine, bisdibromide ethylester, 1,5-dibomopentane, etc., which are commercially available or prepared in public methods.
  • Acetonitrile or dimethylformamide can be used as a solvent.
  • step 4-7 benzonitrile compound (20) which has thiazole ring substituted with hetero ring, prepared in step 4-6, is reacted with the amine compound in the same condition ss that of step 1-6, thus preparing the compound of the formula 1.
  • the invention relates to a pharmaceutical composition for the prevention and treatment of osteoporosis, allergic inflammatory diseases and bone fracture comprising formula 1 and their pharmaceutically acceptable salts.
  • osteoporosis means the state that minerals and substrates are reduced abnormally in large amounts, so that there is no defect in their structure, however,o many pores develop in the bone, making it like sponge and more likely to fracture.
  • the benzamidine compounds of the present invention suppressed the differentiation of osteoclast, facilitated bone formation, and remarkably inhibited the bone mass reduction in osteoporosis-induced animal models.
  • bone fracture means one of various physical injuries of a bone, based on a complete or incomplete disruption of the continuity of a bone, which .-are classified according to anatomical location (epiphyseal, metaphyseal, diaphyseal, intra-articular, proximal, midshaft, distal, etc.), degree of fracture (complete, incomplete), direction of fracture (transverse, oblique, spiral, longitudinal) , presence of open wound (open, closed) , number of fractures (simple, linear, segmental, comminuted, etc.), stability of fracture (stable, unstable) , displacement of fracture, etc.
  • anatomical location epiphyseal, metaphyseal, diaphyseal, intra-articular, proximal, midshaft, distal, etc.
  • degree of fracture complete, incomplete
  • direction of fracture transverse, oblique, spiral, longitudinal
  • presence of open wound open, closed
  • number of fractures simple, linear, segmental,
  • a group treated with the benzamidine compound of the formula 1 according to the present invention was found to have bony callus which significantly decreased in volume in a dose- dependent pattern, but increased both in bone density and in bone strength, with significance, in a dose-dependent pattern.
  • allergic inflammatory diseases means non ⁇ specific inflammatory diseases caused by various allergens, exemplified by allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, etc.
  • the benzamidine compound of the formula 1 was found to have a great effect of reducing lung weight and total leukocyte numbers in asthma-induced animal models.
  • composition of the present invention may comprises medicinally effective ingredient equivalents or similar in function to the benzamidine compound of Chemical Formula 1 or its pharmaceutically acceptable salt, in addition to Chemical Formula 1 or its pharmaceutically acceptable salt.
  • composition of the present invention may comprise one or more pharmaceutically acceptable carriers.
  • a proper carrier may be selected from a group consisting of saline, sterilized water, Ringer's solution, buffered saline, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and combinations thereof, and may be, if necessary, further
  • composition of the present invention may also
  • injectable dosage forms such as aqueous
  • the formulation may be produced using
  • composition of the present invention may be any composition of the present invention.
  • composition of the present invention varies depending on
  • Formula 1 is administered once or many times at a dose of
  • the present invention can be done alone or in combination
  • Example 1-3 prepared in Example 1-3 were added to 100 ml of dimethylformamide and stirred, 3.5g(84mmol) of sodium hydride were added, and stirring was continued for 20 rain.
  • Example 1-4 were added to 300 ml of ethylacetate and stirred,
  • Example 1-5 were added to 30 ml of ethanol and stirred, 0.25g
  • Example 1-5 were added to 30 ml of ethanol and stirred, 0.58g
  • Example 2-1 were added to 50 ml of dimethylformamide and
  • Example 2-1 were added to 50 ml of dimethyformamide and
  • Example 1-6 were added to 10 ml of ethanol and stirred,
  • Example 1-6 were added to 10 ml of saturated
  • Table 1 shows the title compounds, reactants and 1 H-NMR data.
  • Table 2 shows the title compounds, reactants and 1 H-NMR data.
  • Table 3 shows the title compounds, reactants and 1 H-NMR data. [Table 3]
  • Table 4 shows the title compounds, reactants and 1 H-NMR data.
  • Table 5 shows the title compounds, reactants and 1 H-NMR data.
  • Tibia and Femora were aseptically ectomized from male ddY mice of ⁇ 8 weeks to harvest bone marrow cells by using a syringe (21G, Korea Green Cross) .
  • the bone marrow cells were suspended in 5mL ⁇ -MEM medium (Gibco BRL Co.) containing sodium bicarbonate
  • the harvested cells were centrifuged at 600 x g for 5 mins to collect the whole quantity.
  • 3mL of Tris HCl 0.3% NH 4 Cl, pH7.5 was added and well mixed. After centrifuging above cells, the numbers of bone marrow cells were counted and then, the bone marrow cells were immediately used for co-culture system with osteoblast.
  • the calvaria were aseptically ectomized from neonate ICR mice of 1 ⁇ 2 days, washed with PBS solution and incubated with a mixture of enzyme solution (0.2% collagenase and 0.1%
  • osteoblast mostly released from IQ-VI digestion groups were collected and washed with the medium (serum-free ⁇ -MEM) .
  • the washed cells were cultivated in ⁇ -MEM medium containing 10% FBS for 2 ⁇ 3 days. After subculturing, these cells were used for this experiment, and diluted to reach the concentration
  • Benzamidine derivatives of the present invention were dissolved in a sterile distilled water or ethanol to make desired concentrations following dilution. The final volume of specimen added to the medium was determined at the ratio of 1 : 1000.
  • Bone marrow cells prepared in the above and osteoblast from calvaria were co-cultured for osteoclast differentiation. Both bone marrow cells (25,000 cells/cm 2 ) and osteoblast (10,000 cells/cm 2 ) were plated on a 96 well plate in ⁇ -MEM medium containing FBS with specimen, and then cultured with test materials for 7 days. Differentiation factors, such as dexamethasone (10 "7 M) and vitamin D3 (10 "8 M) , were also continuously added to the medium from the first day of cultivation. The medium was changed with fresh media containing a mixture of specimens and differentiation factors every 2 ⁇ 3 day.
  • TRAP was used as a marker to measure osteoclast in consideration of its characteristics showing a positive reaction to TRAP staining solution.
  • TRAP staining solution was prepared in a manner that 5mg of naphtol AS-MS phosphate
  • the medium was removed from the wells, the cells were once washed with PBS solution and fixed to PBS containing 10% formalin for 2 ⁇ 5 mins. The cells were fixed again in a mixed solution of ethanol and acetone (1/1) for about 1 min, and dried off. The cells were further treated by TRAP staining solution for 15 mins and washed with PBS.
  • the experimental results were measured by counting the number of osteoclasts with 3 or more nuclei showing TRAP-positive reaction under a microscopic examination. Each of tests was confirmed over three times for gaining more reliable data.
  • the results indicate that the benzamidine derivatives were significantly inhibited the osteoclast differentiation at a low concentration.
  • the osteoblast isolated from sequential enzymatic treatment of calvariae from neonated ICR mice, was cultured in ⁇ -MEM medium containing 10% FBS for 4 ⁇ 5days. The osteoblast was also cultured for 24hr after seeding the cells on a 12 well plate (10 5 cell/well), and medium was exchanged with the osteogenic differentiation medium
  • test substances at the concentration of 0.IuM and
  • the differentiation medium containing the test substances was exchanged every 3 or 4 days for 14 to 21 days until confirming the nodule mineralization.
  • the cell was rinsed twice with distilled water, and fixed by the 10% formalin solutions for 30 minutes. Alizarin red S and Von-kossa Solution were treated on the plate for measuring deposited calcium and phosphate in cell matrix, and the activity of the test substances on the bone formation was analyzed by deterirnining stained area.
  • stained Arizarin red S was extracted by treating 1OmM sodium phosphate solution (pH 7.0), containing 10% cetylpyridinium chrolide, for 15-30 minutes in the shaking incubator, and then the amount of the deposited calcium was estimated by calculating the absorbance of the extracted Arizarin red S at 564nm.
  • IxIO 5 of calvarial cells per well from neonated ICR mice were loaded on a 12 well plate and cultured for 24h.
  • glycerophosphate and 50 ⁇ g/mi ascorbic acid was exchanged at the confluent state of the cell, and the compounds for investigating their activities on the osteoblast were added.
  • the differentiation medium containing the test substances was exchanged every 3 days, and the culturing period was prolonged approximately 15 days.
  • the medium containing the test compounds was removed from the cells at the end of culture and then, the cells were washed with sterilized distilled water once or twice and fixed to 10% formalin solution about 30 ⁇ 60 minutes. These fixed plates were again washed once or twice, and stained 4OmM Arizarin red S for 10 minutes after drying the plates. These stained plates were rinsed 3-5 times for eliminating waste Arizarin red S. For measuring the amount of the deposited Arizarin red S, 570ul of 10% (w/v) cetylpyridinium chrolide were added on plates, extracted and stained Arizarin red S for 15-30 minutes in the shaking
  • present invention have the excellent activities on the
  • ovariect ⁇ mized osteoporeti ⁇ mouse model of each test substance The therapeutic effects of each benzamidine derivates were evaluated on the ovariectomized ddY mouse. Benzamidine derivates were dosed from 4 weeks after operation for 4 weeks and the changes on the trabecular bone volume (TBV) of the femur were observed via histomorphometry. 3-1. Animals and husbandry
  • mice Female ddY mice( ⁇ -wk old upon receipt, SLC, Japan)
  • Test substances are dissolved and/or suspended in injectable
  • ovaries are removed and then closed by routine methods.
  • TBV was calculated using automated image
  • TBV was calculated as
  • test substance-dosing groups b vehicle control
  • test substance-dosing groups are dramatically increased
  • test substances have facilitating effects on the disappearance of callus volume induced by rib-fracture.
  • the 8th rib including fracture sites of each rat was separated and fixed in 10% neutral buffered formalin, and then decalcified in decalcifying solution(24.4% formic acid, and 0.5N sodium hydroxide) for 5 days (mixed decalcifying solution was exchanges once a day for 5 days) . After decalcification, the rib was embedded in paraffin, sectioned(3 ⁇ 4um) and stained with hematoxylin-eosin or Masson's trichrome for composition of callus observation.
  • Osteloid volume (OV/callus) in callus regions of prepared histological specimens were detected as % levels using automated image analysis (analysis Image Processing; SIS, Germany) under microscopy.
  • dosing groups are significantly(p ⁇ 0.01 or p ⁇ 0.05) increased
  • mice by ovalbumin 10 mice were used as a non-treated group.
  • control group was administered with equal volumes of sterilized distilled water in the same
  • ovalbumin solution was sprayed in air using a nebulizer
  • the removed lungs were weight among individual animals, the relative weight of the lungs was calculated as a percentage of body weight using the following Equation 3.
  • Relative weight of Lung (%) (Absolute lung weight/Body weight) x 100
  • peripheral blood and BALF peripheral blood and BALF
  • abdominal vena cava from which 1 ml of blood was the taken.
  • test substance was diluted in appropriate solvent
  • microplate in a dose of lOO ⁇ L per well.
  • cytotoxitic test were plated on a 96-well microplate in a
  • benzamidine derivative shows little cytotoxicity.
  • capsules are prepared by- being filled up to gelatin capsules with generally used methods.
  • Benzamidine derivatives of the formula 1 was dissolved in adequate volume of NaCl for injections BP, then pH of the solution was controlled to pH 3.5 with dilute hydrochloric acid BP. The volume of the whole solution was fixed with NaCl for injections BP, and the solution was mixed fully. The solution was filled up to type I ampoule made with glass, then the ampoule was sealed under the upper air lattice by melting glass. The sealed ampoule was autoclaved under the condition of 120 ° C for 15mins or more to prepare the sterilized injection.
  • novel benzamidine derivatives of the present invention remarkably suppress osteoclastic bone resorption, stimulate osteoblastic bone formation in very low concentrations and inhibit decreases of bone mass in osteoporosis animal models and thus are useful for the prevention and treatment of osteoporosis. Further, the compounds of the present invention activate the loss of bony callus and its ossification and thus are useful for the prevention and treatment of bone fractures. The compounds of the present invention are also useful for the prevention and treatment of allergic inflammatory diseases.

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Abstract

The present invention relates to novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same. The novel benzamidine derivatives of the present invention are useful for the prevention and treatment of osteoporosis, bone fractures and allergic inflammatory diseases .

Description

NOVEL BENZAMIDINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
Technical Field The present invention relates to novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same.
Background Art ' Bone is the body's framework. Bone contains calcium
(Ca2+) and plays an important role in maintaining the calcium level in blood. To this end, the growth of bone is a metabolic balance between the activity of osteoblasts and osteoclasts in the bone remodeling cycle. When the balance between bone absorption and bone formation is disrupted, the amount of bone tissue replaced by osteoblasts fails to match that absorbed by osteoclasts, thus leading to osteoporosis, a common condition which result in the loss of bone density or bone mass. This disease frequently occurs in middle-aged or elderly women.
Osteoporosis is a metabolic bone disease, which results from a disturbance in the normal bone remodeling, tilting the balance between bone resorption and formation, thus 45
resulting in bone loss and fractures after mineral flux. Bone is the dynamic structures, in which the osteoblast bone formation and osteoclast bone resorption are continuously- occurred. Previous studies focused on the metabolisms of bone inorganic materials like calcium and inorganic phosphorus. Such studies did not provid sufficient findings regarding the mechanisms of osteoporosis.
Although bisphosphonates (alendronate, etidronate etc.), hormones (raloxifen) , Vitamin D, Calcitonin, calcium agents, etc. have been used as anti-osteoporetic agents, they have some adverse side effect or defects. Bisphosphontes show low pharmacokinetic profiles, are difficult to dose and may induce esophagitis. Hormone agents must be administered continuously. Also, in case of long term therapy, severe side effects such as breast cancer, gallstones and embolism may be induced. Vitamin D agents are expensive and show little efficacy in treating estrogen-deficient osteoporetic patients. Calcitonin is also very expensive and difficult to administrate. Calcium has few adverse side effects, but its effects is restricted to the prevention of osteoporosis not the treatment of it. 5 002545
Osteoporosis requires long term therapy, thus it is necessary for the development of new drugs to not include the above-mentioned adverse effects.
A bone fracture is a break or crack in a bone, with complete or incomplete disruption of the continuity of a bone, epiphyseal plate or articular surface. A bone fracture is caused mostly by some type of trauma to a bone. This trauma might occur as a result of a motor vehicle accident, workplace accident, physical abuse, repetitive stress such as exercise, heavy lifting, etc. According to fracture line (line along epiphyseal ends generated upon fracture) , bone fractures are classified into fissured fractures, greenstick fractures, transverse fractures, oblique fractures, spiral fractures, segmental fractures, comminuted fractures, avulsion fractures, compression fractures, depressed fractures, etc.
It is common for bone fractures to injure blood, thus resulting in partial hemorrhage and blood clots. In addition, the bone matrix around a fracture region breaks down or ruptures, with the death of osteocytes. During a fracture healing process, hence,, the blood clots and the injured 5 002545
osteocytes and bone matrix are removed by macrophages while osteoprogenitor cells of the perilsteum and endosteum around the fracture region actively proliferate to form cellular tissue around the fracture region and are then integrated with the fracture region. In the connective tissue of the fracture region, either a bone tissue arises by endochondral ossification from a small cartilage fragment or an immature bone is formed by intramembranous ossification. Accordingly, intramembranous ossification from mesenchymal tissue and endochondral ossification are observed concurrently in the connective tissue of a fracture region. The trabecula of the immature bone irregularly formed in this way temporarily connects ends of the fractured bone fragments, resulting in the formation of a bony callus. The woven bone of the bony callus formed in the fracture region is gradually resorbed as the healing process progresses, and undergoes rearrangement resulting in the development of lamellar bone.
The healing process for fracture is largely divided into three phases: inflammatory phase, bone reparative phase, and remodeling phase.
In the inflammatory phase, inflammatory responses occur since tissues around a fracture region are injured and hematoma fills the fracture gap. T/KR2005/002545
In the bone reparative phase, the hematoma is removed from the fracture gap and substituted with granulation tissue while soft callus is formed. According to the osteogenesis mechanism, two processes proceed concurrently: endochondral ossification, in which the soft callus is remodeled into hard callus, and fibrous/intramembranous ossification, in which a new bone is formed by osteogenic cells.
In the remodeling phase, newly formed bone tissue is extended over a long period of time by the orchestrated action of osteoclastic bone resorption and osteoblastic bone formation, with the correction of bone distortions and the reinforcement of bone defects.
During the remodeling phase, patients with a bone fracture conduct their lives without great difficulty because the newly formed bone has become hard to some extent, but the nascent bone tissue in the reparative phase is not hard enough for patients to live their daily lives without difficulty. In addition, the reparative phase is long. Thus, it is clinically important for a fracture curative to have the function of shortening the reparative phase as well as
regenerating a fractured bone into a complete bone by promoting the complex fracture healing process.
There are various promoters for fracture healing. 45
Peptides having physiologically active functions, such as bone morphogenic proteins (BMPs) and transforming growth factors (TGFs) , are found to be involved in the fracture healing process (Proc. Natl. Acad. Sci., USA, vol. 87, pp. 2220-2224 (1989)). Also, it has been studied that an increase in intracellular cyclic AMP level by use of a phosphodiesterase (PDE) inhibitor can lead to an increase in bone mass. For example, it is reported that mice, into which the general PDE inhibitor pentoxipylline or the selective PDE4 inhibitor rolipram had been subcutaneously injected every day, were observed to have the vertebrate and femur increased in bone mineral density, and showed hyperplasia of cortical bones (Bone, vol. 27., 6th edition, pp. 811-817 (2000)). As mentioned above, attention has long been paid to osteogenesis and fracture healing, and extensive studies on fracture healing processes have been conducted from various points of view, including genetic factors, adolescent influence, hematopoietic effect, fixture effect, bone grafts, other healing promoting factors, etc. (Kawamura, M and Urist MR., Clin. Orthop., 236, 240-248, 1988).
Fracture healing requires a significant period of time and elderly patients with osteoporosis tend to suffer more from bone fractures. Falling short of the expectation of usefulness in fracture healing, currently available therapeutic agents for the treatment of osteoporosis, such as calcium, estrogen, calcitonin, active vitamin D, biphosphonate, etc., are found only to lower the risk of fracture by obstructing the decrease of bone density, and have no function of joining fractured bones or generating bone tissues. The pathogenic mechanism of osteoporosis can be explained by a subtle bone matrix resulting from long maintenance of negative bone homeostasis due to genetic or constitutional predispositions, stagnant osteogenesis with normal bone resorption, and increased bone resorption with normal osteogenesis. Osteoporosis agents are, therefore, ineffective for the treatment of bone fractures because the healing mechanism is quite different between fractures and osteoporosis.
Therefore, there is an urgent need for a bone fracture curative agent that has great therapeutic effect on bone fractures, regardless of association with osteoporosis
As diverse pathologies associated with environmental pollution, stress, living environments, etc., an allergic inflammatory disease has increased. Allergic inflammatory disease is attributed to abnormality in the immune system where the nasal or bronchial mucosa or skin is hypersensitive to external allergens. Basic causes of allergy include nutrition imbalance, stress, extravasated blood, etc., with the major cause being nutrition imbalance.
Depending on the site where immune responses occur against exogenous allergens, allergic inflammatory disease is represented as various symptoms including allergic rhinitis, asthma, atopic dermatitis, etc. In addition, allergic conjunctivitis, allergic dermatitis, contact dermatitis, urticaria, etc. are within the scope of allergic inflammatory diseases. Since these symptoms, although very diverse, are common in the pathology based on the hypersensitivity to externally introduced matter, a suppressant of excessive immune responses can be prescribed for all of them.
Asthma, representative of allergies, is a chronic inflammatory disease occurring in the respiratory organ, especially, the lungs and the bronchi. When patients with asthma take drugs or excessive exercise or inhale contaminated and/or cold air, their respiratory organs, especially, upper respiratory organs increase in responsiveness. This hyper-responsiveness is associated with the airflow obstruction in the airway, that is, airway obstruction or tracheal stenosis, but is readily alleviated using a bronchodilator. Included in the consensus characteristics of asthma, hyper-responsiveness to indoor and/or outdoor allergens and airway contraction are known to be mediated by mast cells and eosinophil IgE (Beasley et al., Am. Rev. Respir. Dis., 129, 806-817, 1989) .
Δsthma is accompanied by the allergic •hyper- responsiveness mainly in the bronchia and the lungs. Particularly, the air passage becomes clogged by the proliferation of mucous cells and the inflammation of epithelial connective tissues in the bronchia. Alsom the lungs are known to show similar histological behaviors. The pathology of asthma, although not yet clearly revealed thus far, is reported to be featured by airway stenosis, edema, mucus secretion, inflammatory cell infiltration, etc. In the mechanism of a typical exogenous asthma, when an antigen is introduced into the airway, B cells produce antigen specific antibodies IgE and IgG in cooperation with macrophages and helper T-cells. These antigen specific antibodies bind to receptors on the surfaces of mast cells and basophils, which are then activated upon re-exposure to the same antigen so as to release various cytokines and mediators of allergy/inflammation, including histamine, prostaglandin D2, slow reacting substances (leukotriene C4, D4), etc. out of the cells. Due to these cytokines and mediators, when exposed to aeroallergen, patients with asthma exhibit an early asthma response characterized by a rapid airway constriction over a period of seconds to minutes and apparent recovery within 30 to 60 min from the constriction. Then, the mediators secreted from mast cells and the cytokines secreted from macrophages, mast cells and helper T-cells proliferate and activate inflammatory cells, including eosinophils, to exhibit a late asthmatic response in which bronchoconstriction, mucus secretion and inflammatory cell infiltration begin 3 to 4 hours and peak 4 to 18 hours after exposure to aeroallergens (Robertson et al., J. Allergy Clin. Immunol., 54, 244-257, 1974) . Currently available therapeutic agents for the treatment of asthma include beta 2-adreno receptor agonists, which dilate airway smooth muscles and effectively inhibit the secretion of hyperresponsiveness mediators from mast cells, adrenal cortical hormones, which exhibit an immunosuppressive effect, and disodium cromoglycate and nedocromil sodium, both known to inhibit both the early and the late asthma response. However, beta 2-adreno receptor antagonists show the treatment effect only for a short period of time and allow the ready recurrence of the disease.
Adrenal cortical hormones have fragmentary treatment effects,
with the concomitance of serious side effects upon long-term
dosage.
Leading to the present invention, intensive and
thorough study on osteoporosis, bone fractures and allergic
inflammatory diseases conducted by the present inventors,
resulted in the finding that novel benzamidine derivatives
have effects on suppressing the osteoclastic bone resorption
and inhibiting the decrease of bone mass in animal models,
indication the compounds are useful in the prevention and
treatment of osteoporosis; healing bone fractures; and
treating and preventing allergic inflammatory disease.
Disclosure of the Invention
An object of the present invention is to provide novel
benzamidine derivatives. Another objective of the present
invention is to provide their preparation method. Further
another object of the present invention is to provide
pharmaceutical compositions for the prevention and treatment
of osteoporosis, allergic inflammatory diseases and bone
fractures comprising novel benzamidine derivatives. Best Mode for Carrying out the Invention
The invention relates to novel benzamdine derivatives
of the formula 1 or pharmaceutically acceptable salts
thereof:
Formula 1
Figure imgf000013_0001
wherein
Ri is Cx-C6 alkyl; C3-C6 cycloalkyl; phenyl; benzyl;
pyridinyl; guanidino; NR6R7; CH2NR5R7;
Figure imgf000013_0005
wherein A is C1~C6 alkyl and n is an integer of 2 to β; Ci-C6 alkyl
which is substituted by pyridine or
Figure imgf000013_0002
' wherein
Figure imgf000013_0003
' is
unsubstituted or substituted by hydroxy; pyridinyl or
Figure imgf000013_0004
which is substituted by C1~C6 alkyl;
R2 is hydrogen; C1-C6 alkyl; C3-C6 cycloalkyl; phenyl;
benzyl; Cx-C6 alkyl which is substituted by hydroxy, C1~C6 alkoxy, halogen or C3-C6 cycloalkyl; C2-C6 alkenyl; R3 and R4, each independently, are hydrogen; halogen; hydroxy; Ci~C6 alkyl which is unsubstituted or substituted halogen; C3~C6 cycloalkylamino; Ci-C6 alkoxy; C1-Ce alkanoyloxy; C2-C6 alkenyloxy; phenyl-Ci~Cδ alkoxy; phenoxy; C2-C6 alkenoyloxy or phenyl~Ci~Ce alkanoyloxy; C3-C5 cycloalkyloxy which is substituted by carboxy, esterified carboxy or amidated carboxy; aminooxy;
Rs is hydrogen or hydroxy;
R6 and R7, each independently, are hydrogen; Ci-C6 alkyl; phenyl; benzyl; pyridinyl; Ci~C6 alkyl which is substituted by
pyridine or
Figure imgf000014_0001
; carbonyl which is substituted by Ci-C6
alkyl , phenyl, benzyl, pyridine or
Figure imgf000014_0002
; Ci-C6 alkanesulfonyl; Ci-C6 alkyl which is substituted by hydroxy or
Ci-C6 alkoxy; acetyl which is substituted by hydroxy or Ci-C6
alkoxy;
Y is oxygen; sulfur; NR6; or CH2;
Xi and X3, . each independently, are oxygen; sulfur; NH;
N-Ci-C6 alkyl; N-C3-C6 cycloalkyl; N-benzyl; N-phenyl;
X2 is C3-C7 alkylene; Cx-C3 alkylene-alkenylene-Ci-C3-
alkylene; Ci-C3 alkylene-O~Ci-C3 alkylene; Ci-C3 alkylene-S-Ci-
C3 alkylene; Ci-C3 alkylene-NH-Ci~C3 alkylene; Ci-C3 alkylene-
phenylene-Ci-C3 alkylene; Cx-C3 alkylene-pyridylene-Ci-C3 alkylene; Ci-C3 alkylene-naphtylene-Ci-C3 alkylene; C3-C7 alkylene which is substituted by Ci-C3 alkyl and hydroxy; C3- C7 alkylenecarbonyl; C3-C7 alkylene which is interrupted by piperazine .
The invention especially relates to compounds of the formula 1 in which:
Ri is Ci-C6 alkyl; C3-C6 cycloalkyl; phenyl; pyridinyl;
guanidino; NR6R7; CH2NReR7;
Figure imgf000015_0004
; wherein A is Cx-C6
Figure imgf000015_0005
alkyl and n is an integer of 2 to 6; Cx-C6 alkyl which is
substituted by
Figure imgf000015_0001
wherein is unsubstituted or
Figure imgf000015_0003
substituted by hydroxy;
Figure imgf000015_0002
which is substituted Ci-C6 alkyl;
R2 is hydrogen; Cx-C6 alkyl; C3-C6 cycloalkyl; benzyl; Cx-C6 alkyl which is substituted by hydroxyl, methoxy,
halogen or C3-C6 cycloalkyl; C2-C6 alk'enyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; C3-C6 cycloalkylamino; Cx-C6 alkoxy; Ci-C5 alkanoyloxy; C3~C6 cycloalkyloxy which is substituted by carboxy, esterified carboxy or amidated carboxy; aminooxy; R5 is hydrogen or hydroxy; Re and R7, each independently, are hydrogen; C1-C6 alkyl;
benzyl; pyridinyl; Ci-C6 alkyl which is substituted by
pyridine or ^—' ; carbonyl which is substituted by pyridine or Ci~C6 alkyl; C1-Ce alkanesulfonyl; Ci-C6 alkyl which is
substituted by hydroxy or C1-C6 alkoxy; acetyl which is
substituted by hydroxy or Ci~C6 alkoxy;
Y is oxygen; sulfur; NRε; CH2;
Xi and X3, each independently, are oxygen; sulfur; NH;
N-C1-C6 alkyl; X2 is C3-C7 alkylene; C1-C3 alkylene-alkenylene-Ci-C3-
alkylene; C1-C3 alkylene-O-Ci-C3 alkylene; Ci-C3 alkylene-NH-
C1-C3 alkylene; C1-C3 alkylene-phenylene-Ci-C3 alkylene; Ci-C3
alkylene-pyridylene-Ci-C3 alkylene; C1-C3 alkylene-naphtylene-
C1-C3 alkylene; C3-C7 alkylene which is substituted by C1-C3
alkyl or hydroxy; C3-C7 alkylenecarbonyl; C3-C7 alkylene which
is interrupted by piperazine.
The invention further especially relates to compounds
of the formula 1 in which: R1 is methyl; ethyl; propyl; isopropyl; butyl; t-butyl;
pentyl; cyclopentyl; hexyl; cyclohexyl; phenyl; aminomethyl;
aminoethyl; amino; isobutylamide; guanidino; 1-propyl- piperidino; 2-morpholinomethyl; NRgR7; CH2NRgR7;
Figure imgf000017_0001
; wherein A is Ci~Cg alkyl and n is an integer of 2 to 6; pyridinyl; 4-hydroxypiperidinoitιethyl; cyclohexylaminomethyl;
R2 is hydrogen; methyl; ethyl; isopropyl; propyl; butyl; isobutyl; methoxymethyl; hydroxymethyl; 2- methylpropyl; pentyl; chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; cyclohexyl; benzyl; vinyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; cyclohexylamino; methoxy; Ci-C4 alkanoyloxy; Ci-C7 aliphatic alkoxy which is substituted by carboxy, esterified carboxy or amidated carboxy;
R5 is hydrogen or hydroxy;
R6 and R7, each independently, are hydrogen; methyl; ethyl; propyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2- morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; methoxyethy1; hydroxyethyl; hydroxyacetyl; methoxyacetyl;
Y is oxygen; sulfur; NRg; CH2;
Xi and X3, each independently, are oxygen; sulfur; amine;
methylamine;
X2 is propylene; butylene; pentylene; hexylene; heptylene; ethylene-O-ethylene; 3-hydroxy-3-methyl-pentylene; methylethylene-NH-ethylene; ethylene-NH-ethylene; propylene which is interrupted by piperazine; butylene carbonyl; 2- butenyl; methylene-phenylene-methylene; methylene-pyridylene- methylene; 1,2-ethylene-l,4-phenylene-l,2-ethylene; 1,3- propylene-1,4-phenylene-l,3-propylene; 1,2-ethylene- naphthalene-1,2-ethylene.
The invention furthermore especially relates to compounds of the formula 1 in which,
Ri is methyl; ethyl; isopropyl; cyclohexyl; phenyl; aminomethyl; aminoethyl; amino; pyridinyl; NR6R7;
CH2NR6R7;
Figure imgf000018_0001
or wherein A is Ci-C2 alkyl and n is an integer of 4 to 5;
R2 is hydrogen; methyl; ethyl; isopropyl; isobutyl; methoxymethyl; hydroxymethyl; chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; vinyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; methoxy;
R5 is hydrogen or hydroxy;,
R6 and R7, each independently, are hydrogen; methyl; ethyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; hydroxyethyl; methoxyethyl; Y is oxygen; sulfur; methylamine; Xi and X3, each independently, are oxygen; sulfur; amino; methylamine;
X2 is propylene; butylene; pentylene; hexylene; ethylene-O-ethylene; ethylene-NH-ethylene; butylenecarbonyl; 2-butenyl; methylene-l,2-phenylene-methylene; methylene-1,3- phenylene-methylene; methylene-lf4-phenylene-methylene; methylene-pyridinyl-methylene.
In the compounds of the formula 1 of the present invention, the -C(NH2)^=N-Rs group is in the meta or para position, and R3 and R4 are in the ortho or meta position relative to -Xi- or -X3-.
The preferred compounds of the present invention is described in following:
1) N-hydroxy~4-5-[4-(2-isopropyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
2) 4-5-[4-(2-isoρropyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 3) N-hydroxy-4-5-[4-(2-methyl-l,3-thiazol-4- y1)phenoxy]pentoxy-benzamidine,
4) N-hydroxy-4-5-[4-(2-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 5) N-hydroxy-4-5-[4-(2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
6) N-hydroxy-4-5-[4-(2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 7) N-hydroxy-4-5-[4-(2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
8) N-hydroxy-4-5-[4-(2-cyclohexyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
9) N-hydroxy-4-5-[4-(2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
10) N-hydroxy-4-5-[4-(2,5-dimethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
11) N-hydroxy-4-5-[4-(2-ethyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 12) N-hydroxy-4-5-[4-(5-methyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
13) N-hydroxy-4-5-[4-(5-methyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
14) N-hydroxy-4-5-[4-(2-cyclohexyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
15) N-hydroxy-4-5-[4-(5-methyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 16) N-hydroxy-4^5-[4-(2-t-butyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
17) N-hydroxy-4-5-[4-(5-ethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 18) N-hydroxy-4-5-[4-(2,5-diethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
19) N-hydroxy-4-5-[4-(5-ethyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
20) N-hydroxy-4-5-[4-(5-ethyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
21) N-hydroxy-4-5-[4-(5-ethyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
22) N-hydroxy-4-5-[4-(2-cyclohexy1-5-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 23) N-hydroxy-4-5-[4-(5-ethyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
24) N-hydroxy-4-5-[4-(2-ethyl-5-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
25) N-hydroxy-4-5-[4-(2,5-diisopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
26) N-hydroxy-4-5-[4-(5-isopropyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 27) N-hydroxy-4-5-[4-(5-isopropyl-2-pyridin-3~yl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
28) N-hydroxy-4-5-[4-(5-isopropyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 29) N-hydroxy-4-5-[4-(2-methyl-5-proρyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
30) N-hydroxy-4-5-[4-(5-butyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
31) N-hydroxy-4-5-[4-(5-butyl-2-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
32) N-hydroxy-4-5-[4-(5-butyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
33) N-hydroxy-4-5-[4-(5-butyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 34) N-hydroxy-4-5-[4~(5-butyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
35) N-hydroxy-4-5-[4-(5-butyl-2-cyclohexyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
36) N-hydroxy-4-5-[4-(5-butyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
37) N-hydroxy-4-5-[4-(5-butyl-2-t-butyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 38) N-hydroxy~4-5-[4-(5~benzyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
39) N-hydroxy-4-5-[4-(5-benzyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 40) N-hydroxy-4-5-[4-(5-benzyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
41) N-hydroxy-4-5-[4-(5-benzyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
42) N-hydroxy-4-5-[4-(5-(2-chloro-ethyl)-2-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
43) N-hydroxy-4-5-[4-(5-cyclopentyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
44) N-hydroxy-4-5-[4-(5-isobutyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 45) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
46) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
47) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-isopropyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
48) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-phenyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 49) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pyridin-3-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
50) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-cyclohexyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 51) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pentyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
52) 4-5-[4-(2-methyl-l/3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
53) 4-5-[4-(2-isopropyl-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
54) 4-5-[4-(2,5-dimethyl-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
55) 4-5-[4-(5-ethyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 56) 4-5-[4-(5-ethyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
57) N-hydroxy-4-5-[4-(2-amino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
58) N-hydroxy-4-5-[4-(2-amino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
59) N-hydroxy-4-5-[4-(2-guanidino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 60) N-hydroxy-4-5-[4-(2-amino-5-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
61) N-hydroxy-4-5-[4-(2-amino-5-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 62) N-hydroxy-4-5-[4-(2-guanidino~5-isoproρyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
63) N-hydroxy-4-5-[4-(2-amino-5-butyl-l,3-thiazol-4- y1)phenoxy]pentoxy-benzamidine,
64) N-hydroxy-4-5-[4-(5-butyl-2-guanidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
65) N-hydroxy-4-5-[4-(2-amino-5-benzyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
66) N-hydroxy-4-5-[4-(5-benzyl-2-guanidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 67) N-hydroxy-4-5-[4-(2-amino-5-cyclopentylmethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
68) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(1-propyl- piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
69) N-hydroxy-4-5-[4-(2-(isobutyryl)amino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine
70) N-hydroxy-4-5-[4-(5-isopropyl-2-morpholinomethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 71) N-hydroxy-4-5-[4-(2-aminomethyl-5-benzyl~l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
72) N-hydroxy-4-5-[4-(5-methyl-2-(l-propyl-piperidin-4-yl)- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 73) N-hydroxy-4-5-[4-(5-isopropyl-2-aminomethyl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
74) N-hydroxy-4-5-[4-(5-vinyl-2-rαethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
75) N-hydroxy-4-5-[4-(5-hydroxymethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
76) N-hydroxy-4-5-[4-(5-methoxymethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
77) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-amino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine, 78) N-hydroxy-.4-5-[4-(5-vinyl-2-amino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
79) N-hydroxy-4-5-[4-(5-vinyl-2-(pyridin-3-yl)-1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
80) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-(pyridin-3-yl)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
81) N-hydroxy-4-5-[4-(2-amino-5-cyclopentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 82) N-hydroxy-4-5-[4-(5-ethyl-2-aminomethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
83) N-hydroxy-4-5-[4-(5-isopropyl-2-(piperidin-3-yl)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 84) N-hydroxy-4-5-[4-(2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
85) N-hydroxy-4-5-[4-(2-ethanesulfonylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
86) N-hydroxy-4-5-[4-(5-methyl-2-methylamino-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzamidine,
87) N-hydroxy-4-5-[4-(2-ethylamino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
88) N-hydroxy-4-5-[4-(5-methyl-2-propylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 89) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(3- pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
90) N-hydroxy-4-5-[4-(2-hydroxyacetylamino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 91) N-hydroxy-4-5-[4-(5-methyl-2-(4- pyridylcarbonyl)amino- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 92) N-hydroxy-4-5-[4-(5-methyl-2-(3- pyridylcarbonyl)amino- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 93) N-hydroxy-4-5-[4-(2-ethanesulfonylamino~5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
94) N-hydroxy-4-5-[4-(2-(2-methoxyethyl)amino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 95) N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
96) N-hydroxy-4-5-[4-(5-ethyl-2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
97) N-hydroxy-4-5-[4-(5-ethyl-2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
98) N-hydroxy-4-5-[4-(5-ethyl-2-propylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
99) N-hydroxy-4-5-[4-(5-ethyl-2-methoxyacetylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 100) N-hydroxy-4-5-[4-(5-ethyl-2-(4-pyridylcarbonyl)amino- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
101) N-hydroxy-4-5-[4-(5-ethyl-2-(3-pyridylcarbonyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
102) N-hydroxy-4-5-[4-(5-ethyl-2-(2-methoxyethyl)amino-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
103) N-hydroxy-4-5-[4-(5-isopropyl-2-rtιethylamino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine, 104) N-hydroxy-4-5-[4-(2-ethylamino-5-isopropyl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
105) N-hydroxy-4-5-[4-(5~butyl~2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 106) N-hydroxy-4-5-[4-(5-butyl-2-ethylamino~l,3-thiazol-4-
yl)phenoxy]pentoxy-benzamidine,
107) N-hydroxy-4-5-[4-(5-benzyl-2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
108) N-hydroxy-4-5-[4-(5-benzyl-2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
109) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
110) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethylaraino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 111) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-propylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
112) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(4- pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 113) N-hydroxy-4-5-[4-(5-cyclopentyl-2-propylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
114) N-hydroxy-4-5-[4-(5-isopropyl-2-[ (pyridin-3-yl- methyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 115) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-methylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
116) N-hydroxy-4-5-[4-(2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 117) N-hydroxy-4-5-[4-(5-ethyl-2-[ (pyridin-3-yl-methyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
118) N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-amino)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
119) N-hydroxy-4-5-[4-(2-methyl-(2-morpholinoethyl)amino-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
120) N-hydroxy-4-5-[4-(2-(2-hydroxyethyl)-methyl-amino-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
121) N-hydroxy-4-5-[4-(2-(ethyl-(2-hydroxyethyl)-amino)-5- methy1-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 122) N-hydroxy-4-5-[4-(2-(bis-(2-methoxyethyl)-amino)-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 123) N-hydroxy-4-5-[4-(5-methyl-2-(methyl-(2- morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 124) N-hydroxy-4-5-[4-(2-(ethyl-1-(2-morpholinoethyl)-amino)- 5-methyl-l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 125) N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 126) N-hydroxy-4-5-[4-(5-methyl-2-(methyl-pyridin-3-yl- methyl-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy~benzamidine,
127) N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 128) N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)-amino)-5- methyl-l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
129) N-hydroxy-4-5-[4-(5-ethyl-2-( (2-hydroxyethyl)-methyl- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
130) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-hydroxyethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
131) N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(2-morpholinoethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
132) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-morpholinoethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 133) N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
134) N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
135) N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
136) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 137) N-hydroxy-4-5- [4- (2- (bis- (pyridin-3-yl-methyl)amino)-5- ethyl-l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
138) N-hydroxy-4-5-[4-(2-dipropylamino-5-ethyl-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzamidine, 139) N-hydroxy-4-5-[4- (2- (bis- (2-hydroxyethyl) amino)-5-ethyl- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
140) N-hydroxy-4-5-[4-(2-( (2-hydroxyethyl) -methyl-amino)-5- isopropyl-1, 3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
141) N-hydroxy-4-5-[4- (5-isopropyl-2- (methyl- (pyridin-3-yl- methyl)amino)-1,3~thiazol-4-yl)phenoxy]pentoxy-benzamidine,
142) N-hydroxy-4-5-[4- (2-(ethanesulfonyl-methyl-amino)-5- isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
143) N-hydroxy-4-5-[4- (5-butyl-2- ( (2-hydroxyethyl)-methyl- amino) -1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 144) N-hydroxy-4-5-[4- (5-butyl-2- (methyl- (2- morpholinoethyl) amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
145) N-hydroxy-4-5-[4- (5-butyl-2-(methyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 146) N-hydroxy-4-5-[4- (5-butyl-2-dipropylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 147) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl- (pyridin-3-yl-methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
148) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(2- morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
149) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2~dipropylamino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
150) N-hydroxy-4-5-[4-(5-butyl-2-diethylamino-l,3~thiazol-4- yl)phenoxy]pentoxy-benzamidine,
151) N-hydroxy-4-5-[4-(5-butyl-2-ethylmethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
152) N-hydroxy-4-5-[4-(5-butyl-2-dimethylamino-l,3~thiazol-4- yl)phenoxy]pentoxy-benzamidine, 153) N-hydroxy-4-[5-(4-5-cyclopentyl-2-[methyl-(2- morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
154) N-hydroxy-4-[5-(4-5-isobutyl-2-[methyl-(2- morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
155) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-dimethylanαino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 156) N-hydroxy-4-5-[4-(5-cyclopentyl-2-diethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
157) N-hydroxy-4-5-[4-(5-isoρropyl-2-dipropylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 158) N-hydroxy-4-5-[4-(5-ethyl-2-diethylamino-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzamidine,
159) N-hydroxy-4-[5-(4-5-isopropyl-2-[methyl-(2- morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 160) N-hydroxy-4-5-[4-(5-cyclopentylmethyl~2-diethylamino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
161) N-hydroxy-4-5-[4-(5-isopropyl-2-dimethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
162) N-hydroxy-4-5-[4-(5-isopropyl-2-diethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
163) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dimethylamino- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
164) N-hydroxy-4-5-[4-(5-methyl-2-piperidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 165) N-hydroxy-4-5-[4-(5-methyl-2-morpholino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
166) N-hydroxy-4-5-[4-(5-ethyl-2-piperidino-l,3-thiazol-4~ yl)phenoxy]pentoxy-benzamidine, 167) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-piperidino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
168) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-morpholino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 169) N-hydroxy-4-5-[4-(5~isopropyl-2-morpholino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine
170) N-hydroxy-4-5-4-[5-cyclopentylmethyl-2-(4- methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy- benzamidine, 171) N-hydroxy-4-5-[4-(5-vinyl-2- morpholin-4-yl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
172) N-hydroxy-4-5-[4-(5-cyclopentyl-2- morpholin-4-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
173) N-hydroxy-4-5-[4-(5-isobutyl-2- morpholin-4-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
174) N-hydroxy-4-5-4-[5-ethyl-2-(4-methylpiperazino)-1,3- thiazol-4-yl]phenoxy-pentoxy-benzamidine,
175) ' N-hydroxy-4-5-[4-(2-morpholin-4-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 176) N-hydroxy-4-5-4-[5-isopropyl-2-(4-methylpiperazino)-1,3- thiazol-4-yl]phenoxy-pentoxy-benzamidine,
177) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]-pentylamino-benzamidine, 178) N-hydroxy-4-2-[2-(4~(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy)-ethoxy]-ethoxy-benzamidine,
179) N-hydroxy-4-3-hydroxy-5-[4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl)-phenoxy] -3-methyl-pentoxy-benzamidine, 180) N-hydroxy-4~2-[2-(4-(5-isopropyl-2-methyl-l,3-thiazol-4-
yl) -phenoxy) -1-methyl-ethylamino]-ethoxy-benzamidine, 181) N-hydroxy-4-3-[4-(3-(4-(5-isopropyl-2-methyl-l,3-
thiazol-4-yl)-phenoxy)-propyl)-piperazin-1-yl]-propoxy- benzamidine, 182) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-
yl) -phenoxy]-pentanoyl-amino-benzamidine,
183) N-hydroxy-4-5-[4- (5-isopropyl-2-methyl-l,3-thiazol-4-
yl) -phenoxy] -pentyl-methyl-amino-benzamidine,
184) N-hydroxy-4-4-[4-(5-isopropyl-2-rαethyl-l,3-thiazol-4- yl)-phenoxy]-2-butenyloxy-benzamidine,
185) N-hydroxy-4-4-[4- (5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxymethyl]-benzyloxy-benzainidine,
186) N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy) -ethylamino]-ethoxy-benzamidine, 187) N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl) -phenoxy]-pentoxy-benzamidine,
188) 2,N-dihydroxy-4-5-[4- (5-isoρropyl-2-methyl-l,3-thiazol- 4-yl)-phenoxy]-pentoxy-benzamidine, 189) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxy]-pentoxy-3-methoxy-benzamidine,
190) N-hydroxy-2-cyclohexylamino-4-5-[4-(5-isopropyl-2- methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine, 191) N-hydroxy-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,
192) N-hydroxy-2-fluoro-4-5-[3-fluoro-4-(5-isopropyl-2- methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,
193) N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]propoxy-benzamidine,
194) N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]butoxy-benzamidine,
195) N-hydroxy-3-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)- phenoxy]-pentylamino-benzamidine, 196) N-hydroxy-4-4-[4-(2-cyclohexyl-5-ethyl-thiazol-4-yl)- phenoxy]-butoxy-benzamidine,
197) N-hydroxy-4-[5-(4-5-ethyl-2-[ (2-hydroxyethyl)-methyl- amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,
198) N-hydroxy-4-[5-(4-5-ethyl-2-[ (2-hydroxyethyl)-methyl- amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,
199) N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl- methyl)amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine, 200) N-hydroxy-4-[5- (4-5-ethyl-2-[methyl- (pyridin-3-yl- methyl)amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,
201) N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-isoproρyl- thiazol-4-yl) -phenoxymethyl]-benzyloxy-benzamidine, 202) N-hydroxy-4-4-[4-(5-butyl-2-isopropyl-thiazol-4-yl)-
phenoxymethyl]-benzyloxy-benzamidine,
203) N-hydroxy-4-4-[4- (5-cyclopentylmethyl-2-amino-thiazol-4-
yl)-phenoxymethyl]-benzyloxy-benzamidine,
204) N-hydroxy-4-4-[4- (5-cyclopentylmethyl-2-amino-thiazol-4- yl)-phenoxymethyl]-benzyloxy-2-fluoro-benzamidine,
205) N-hydroxy-4-4-[4- (2-methylamino-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
206) N-hydroxy-4-6-[4-(5-isoρropyl-2-rαethyl~thiazol-4-yl)- phenoxymethyl]-pyridin-2-yl-methoxy-benzamidine, 207) N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-thiazol- 4-yl) -phenoxy]-butoxy-benzamidine,
208) N-hydroxy-4-2- [4- (5-isopropyl-2-methyl-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
209) N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
210) N-hydroxy-4-4-[4- (5~cycloρentylmethyl-2-cyclohexyl- thiazol-4-yl) -phenoxymethyl]-benzyloxy-benzamidine, 211) N-hydroxy-4-6-[4- (5-isopropyl-2-methyl-thiazol-4- yl)phenoxy]-hexyloxy-benzamidine,
212) N-hydroxy-4-5-[2-ethyl~5-hydroxy-4- (2-methyl-thiazol-4- yl)phenoxy]-pentyloxy-benzamidine, 213) N-hydroxy-4-5-[2-ethyl-4-(2-methyl~thiazol-4-yl)-5- propoxy-phenoxy]-pentyloxy-benzarαidine.
The benzamidine derivatives of the formula 1 may be used in the form of pharmaceutically acceptable salts known in the art. Preferable are acid addition salts prepared with pharmaceutically acceptable free acids. Free acids suitable for use in the present invention may be inorganic acids or organic acids. Examples of the inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc, and the organic acids may be exemplified by citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, benzene sulfonic acid, maleic acid, maleinic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethane sulfonic acid, camphorsulfonic acid, 4-nitrobenzene sulfonic acid, hydroxy- 0-sulfonic acid, 4-toluene sulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc. Preferably, hydrochloric acid as inorganic acid and methane sulfonic acid
as organic acid can be used.
General definitions of substituted groups of the
formula 1 have the following meanings:
Halogen means halogen group atoms including chlorine,
fluorine, bromine, iodine, etc.
Alkyl radical means saturated carbohydrogens which have
1 to 6 carbon atoms and are straight or branched, for
example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-
butyl, tert-butyl, etc.
Alkoxy radical means said alkyl radical linked to
oxygen, for example, methoxy, ethoxy, propoxy, iso-propoxy,
butoxy, sec-butoxy, tert-butoxy, etc. Cycloalkyl radical means nonaromatic carbohydrogen
ring(s) which have 3 to 6 carbon atoms on the each ring, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
etc.
Alkenyl radical means unsaturated carbohydrogens which
have 2 to 6 carbon atoms with one or more double bonds.
Alkanoyloxy radical means oxygen-containing radical in
which a terminal carbon atom of alkyl radical is substituted
by carbonyl radical. Alkenoyloxy radical means oxygen-containing radical in
which a terminal carbon atom of alkenyl radical is
substituted by carbonyl radical.
Alkenyloxy radical means oxygen-containing alkenyl
groups.
Alkylene radical means carbohydrogen radicals which
have 1 to 7 carbon atoms and 2 or more junction centers for
covalent bond, including methylene, ethylene, methylethylene,
isopropylidene, etc.
Alkenylene radical means carbohydrogen radicals which
have 2 to 7 carbon atoms, 2 or more conjunction centers for
covalent bond and 1 or more double bonds, including 1,1-
vinylidene (CH2=C) , 1,2-vinylidene (-CH=CH-) , 1,4-butadieny1 (-
CH=CH-CH=CH, etc.
Carbonyl radical means carbon radicals in which 2 of 4
covalent bonds are linked to oxygen atom.
In another aspect, the present invention provides a
method of preparing benzamidine derivatives of the formula 1
below:
If R1 is C1-C6 alkyl; pyridine-substituted Ci-C6 alkyl;
C3~C6 cycloalkyl; benzyl; phenyl; amino; guanidino;
pyridinyl; pyridinyl which is substituted by C1-C6 alkyl; A-N(CH2)n or vJ (A is Ci-C6 alkyl and n is integer of 2 to 6) ,
benzamidine derivatives of the formula 1 can be prepared with Reaction Scheme 1 below comprising the steps of :
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9,
4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10,
5) reacting α-brominated compound of the formula 10 prepared in step 4) with thioamide compound of the formula 11 to prepare benzonitrile derivatives with thiazole ring of the formula 12, and β) reacting the compound of the formula 12 prepared in step 5) with amine compound to prepare benzamidine
derivatives of the formula Ia.
[Reaction Scheme l]
C))
Figure imgf000044_0001
Figure imgf000044_0002
CI)
Figure imgf000044_0004
Figure imgf000044_0003
Figure imgf000044_0005
wherein R2, R3, R4, R5, X1, X2 and X3 are the same as
defined in the compound of the formula 1. If Ri is CH2NHR6 or NHR5 (except that R6 is hydrogen) , the compound of the formula 1 can be prepared with Reaction Scheme 2 below, comprising the steps of:
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9,
4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10,
5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14, 6) reacting the compound of the formula 14 prepared in step 5) with halide compound of the formula 15 to prepare benzonitrile derivatives with thiazole ring substituted- with primary amine of the formula 16, and
7) reacting the compound of the formula 16 prepared in step 6) with amine compound to prepared benzamidine derivatives of the formula Ib.
[Reaction Scheme 2]
Figure imgf000047_0001
Figure imgf000047_0002
wherein R2, R3, R4, R5, R6, ,Xir X2 and X3 are the same as defined in the compound of the formula 1 and n is an integer of 0 to 6, except that R6 is hydrogen.
If Ri is CH2NR6R7 or NR6R7 (except that R6 or/and R7 are hydrogen) , the compound of the formula 1 can be prepared with Reaction Scheme 3 below, comprising the steps of:
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9, 4) reacting the compound of the formula 9 prepared in step 3) withi brominating agent to prepare α-brominated compound of the formula 10, 5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14, β) reacting the compound of the formula 14 prepared in step 5) with halide compound of the formula 15 to prepare benzonitrile derivatives with thiazole ring substituted with primary amine of the formula 16,
7) reacting the compound of the formula 16 prepared in step 6) above with a compound of the formula 17 to prepare benzonitrile derivatives with thiazole ring substituted with secondary amine of the formula 18, and
8) reacting the compound of the formula 18 prepared in step 7) with amine compound to prepare benzamidine derivatives of the formula Ic.
[Reaction Scheme 3]
Figure imgf000050_0001
wherein R2, R3, R4, R5, R6, R7, Xi, X2 and X3 are the same
as defined in the compound of the formula 1 and n is an
integer of 0 to 6, except that Re/R7 are hydrogen.
If Ri is f^—\' or Ci~C6 alkyl radical substituted
by ^—' , the compound of the Formula 1 can be prepared with Reaction Scheme 4 below, comprising the steps of:
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9, 4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10, 5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14, 6) reacting the compound of the formula 14 prepared in step 5) with the compound of which both terminals are halogenated of the formula 19 to prepare benzonitrile derivatives with thiazole ring substituted with hetero atom ring of the formula 20, and 7) reacting the compound of the formula 20 prepared in step 6) with amine compound to prepare benzamidine derivatives of the formula Id.
[Reaction Scheme 4]
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000053_0003
wherein R2, R3, R4, R5, Xi, X2 and X3 are the same as
defined in the compound of the formula 1 and n is an integer
of 0 to 6. Each step for preparing benzamidine compounds substituted with thiazole derivative of the present invention, is spedifically described below:
In Reaction Scheme 1 to 4, the compound 2, the the compound 5, the acid chloride 6, the compound 4, the compound 8, the thioamide 11, the thiourea 13, the halide compound (15, 17) , the compound 19 of which both terminals are substituted with halogen are commercially available or can be prepared using the method well known in the art.
Reaction Scheme 1 is illustrated by using specific compounds as shown below.
In step 1-1, 4-hydroxy-benzonitrile (2; R4=H, X3=O) is
reacted with l-bromo-5-chloropentane (3; Br-X2-Cl : X2 = pentylene) , giving 4- (5-chloro-pentoxy) -benzonitrile (4) .
The reaction temperature is preferably maintained in the
range of 10 to 9O0C, for 1 to 9 hours and the reaction solvent is acetonitrile, dimethylformamide, etc. To ensure that the above reaction occurs under a basic condition, an inorganic basic compound such as potassium carbonate, sodium hydroxide, sodium hydride, etc, may be used. In step 1-2, anisole (5; R3=H, Xi=O) is reacted with propionyl chloride (6; R2 = CH3) in the presence of inorganic acid to afford phenone compound (7) and phenone compound (7) is consequently reacted in acidic condition to afford phenol compound (8) . Acid chloride (6) used for preparing compound
(7) is a material to introduce substituent R2 into the compound of the formula 1 and can be selected from acid chlorides with proper alkyl radical according to the type of substituents. These acid chloride (6) includes acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, isovaleryl chloride, 4-methylvaleryl chloride, 3- methylvaleryl chloride, hexanoyl chloride, cyclopentyryl chloride, chlorobutyl chloride, 3-bromopropionyl chloride, 2,3-dichloropropionyl chloride, 4-chlorobutyryl chloride, 3- cyclopentylpropionyl chloride, hydrocinnamoyl chloride, cyclopentylacetyl chloride, isocaproic chloride, which are available commercially or prepared simply with public methods. Inorganic acid can be aluminum chloride and the
reaction can be carried out in the range of -20 to 30°C for 2 to 24 hours. The reaction solvent can be selected from dichloromethane, chloroform, etc. Acids used for preparing compound (8) are organic acid such as acetic acid and inorganic acid such as bromic acid and aluminum chloride. The reaction is preferably carried out in the range of 60 to
100°G for 10 to 30 hours. To increase efficiency of the reaction, excess amount of acid can be used as solvent.
In step 1-3, 4- (5-chloropentoxyl)benzonitrile (4) prepared in step 1-1 is reacted with phenol compound(8) prepared in step 1-2 in the presence of base, thus preparing 4-(5-phenoxypentoxyl)benzonitrile compound(9) . Inorganic bases can be used in this reaction, and selected form the group of potassium carbonate, sodium hydroxide and sodium hydride. The reaction can be carried out in the range of 10
to 90°C for 1 to 9 hours and acetonitrile or dimethyl formamide are preferably used as as solvent.
In step 1-4, compound (9) prepared in step 1-3 is reacted with brominating agent, thus preparing α-brominated compound (10) . brominating agent for the reaction can include copper (II) bromide, bromine, etc. and the reaction can be
carried out in the range of 20 to 80°C for 8 to 24 hours and ethyl acetate is preferably used as solvent.
In step 1-5, α-brominated compound (10) prepared in step 1-4 is reacted with thioamide (11) , thus preparing compound (12) which has thiazole ring. In the reaction, thioamide (11) is a material to introduce substituent Ri into the compound of formula 1 and can be selected according to their substituent radical. Reaction time and solvent vary according to thioamide compound (11) , but in most case, the
reaction can be carried out in the range of 60 to 90°C for 5 to 24 hours. Thioamide compound (11) used for the reaction includes thioacetamide, thiopropionamide, thioisobutramide, trimethylthioacetamide, thiohexanoamide, cyclohexancarbothioicacid amide, N- (2-amino-2-thioxoethyl)-2- methylpropanamide, piperidin-4-carbothioicacid amide, thiourea, amidinothiourea, thiobenzoamide, glycine thioamide, 2,2-dimethyl thiopropionamide, "which are available commercially or prepared simply with public methods. Ethanol or ethanol/water mixture is used as a solvent.
In step 1-6, compound (12) which has thiazole ring, prepared in step 1-5, is reacted with amine compound in the presence of bases, thus preparing compound (Ia) . In the case of N-hydroxy amidine (Rs=OH) , hydroxylamine hydrochloride is reacted in the presence of a base, and the base can be selected from organic bases such as triethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, DBU, diethylmethylamine(Et2NMe) , N-methylmorpholine, N- methylpiperidine, pyridine and 2,6-dimethylpyridine, and inorganic bases such as potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide, sodium ethoxide. The reaction is carried out in the range of 60 to
90°G for 1 to 15 hrs. Methanol, ethanol, acetonitrile, etc., or their mixture with water can be used as a solvent. In the case of amidine(Rs=H) , methoxy imine is prepared from hydrocholide methanol solution in the range of 10 to
30°C for 24 to 48 hours and then methanol is evaporated in vacuum condition. The resultant is reacted with ammonia
ethanol solution in the range of 45 to 60°C for 24 to 50 hours in high pressure reactor, finally preparing target amidines. Ethanol is preferably used as a solvent.
Reaction Scheme 2 is illustrated by using specific compounds as shown below. Steps 2-1 to 2-4 in Reaction Scheme 2 are the same as those in Reaction Scheme 1.
In step 2-5, α-brominated compound (10) prepared in step 2-4 is reacted with thiourea (13) , thus preparing benzonitrile compound (14) which has aminothiazole radical. In the reaction, thiourea (13) is a material to introduce substituent Ri into the compound of the formula 1 and can be selected from thioureas with proper alkyl radical according to the type of substitutents. Reaction time and solvent vary according to the type of thiourea (13) selected which is available commercially or prepared in public methods. The reaction can be preferably carried out in the
range of 60 to 90°C for 5 to 24 hours preferentially. Ethanol or Ethanol/water mixture can be preferably used as a solvent.
In step 2-6, benzonitrile compound (14) which has aminothiazole radical prepared in step 2-5, is reacted with halide compound (15) in the presence of bases, thus preparing benzonitrile compound (16) which has thiazol ring substituted with amine. In the reaction, halide compound (15) is a material to introduce a substitutents into the amino group of the compound of the formula 1 of which the substituent Ri is primary amine. Halide compound (15) can be selected according to their substituent radical. Reaction time and solvent vary according to selecting halide compound (15) . The reaction can
be preferably carried out in the range of 0 to 90"C for 5 to 24 hours. Halide compound (15) can includes methyl iodide, ethyl iodide, propyl bromide, 2-chloroethylmethyl ether, chloroethyl morpholine, 3-bromomethyl pyridine, bromoethanol, niconoylchloride, benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride, isoniconoyl chloride, bis-dibromide ethylester, acetoxyacetyl chloride, methoxyacetyl chloride, etc., which are commercially available or prepared in public methods. Acetonitrile or dimethylformamide can be preferably used as a solvent.
In step 2-7, benzonitrile compound (16) which has thiazol ring substituted with the primary amine, prepared in step 2-6, is reacted with amine compound in the same condition as that of step 1-6, thus preparing the compound of the formula 1.
Reaction Scheme 3 is illustrated by using specific compound as shown below.
Steps 3-1 to 3-6 in Reaction Scheme 3 are the same as those in Reaction Scheme 2.
In step 3-7, compound (16) prepared in step 3-6 is reacted with halide compound (17) in the presence of base, thus preparing benzonitrile compound (18) which has thiazole ring substituted with secondary amine. In the reaction, halide compound (17) is a material to introduce the second substituent into the amino group of the compound of the formula 1 of which the substituent Ri is the secondary amine. Halide compound (17) can be selected according to its substituent radical. Reaction time and solvent vary according to selecting the halide compound (17) selected. The reaction can be preferably carried out in the range of 0 to 90°C for 5 to 24 hours. Halide compound (17) can include methyl iodide, ethyl iodide, propyl bromide, 2-chloroethylmethyl ether, chloroethyl morpholine, 3-bromomethyl pyridine, bromoethanol, niconoylchloride, benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride, isoniconoyl chloride, etc., which are commercially available or prepared in public methods. Acetonitrile or dimethylformamide can be perferably used as a solvent. In step 3-8, benzonitrile compound (16) which has thiazol ring substituted with the secondary amine, prepared in step 3-7, is reacted with amine compound in the same condition as that of step 1-6, thus preparing the compound of
the formula 1.
Reaction Scheme 4 is illustrated by using specific compounds as shown below.
Steps 4-1 to 4-5 in Reaction Scheme 4 are the same as those in Reaction Scheme 2. In step 4-6, benzonitrile compound(14) , which has aminothiazole, prepared in step 4-5, is reacted with the compound (19) of which both terminals are substituted by halogen in the presence of base, thus preparing benzonitrile compound (20) which has thiazole ring substituted with hetero ring. In the reaction, compound (19) is a material to
introduce
Figure imgf000062_0001
into the substituent Ri of the compound of the formula 1 and can be selected according to its substituents.
The reaction can be carried out in the range of 0 to 90°C for 4 to 24 hours. These halogenate compounds can include mechloethylamine, bisdibromide ethylester, 1,5-dibomopentane, etc., which are commercially available or prepared in public methods. Acetonitrile or dimethylformamide can be used as a solvent.
In step 4-7, benzonitrile compound (20) which has thiazole ring substituted with hetero ring, prepared in step 4-6, is reacted with the amine compound in the same condition ss that of step 1-6, thus preparing the compound of the formula 1.
In further aspect, the invention relates to a pharmaceutical composition for the prevention and treatment of osteoporosis, allergic inflammatory diseases and bone fracture comprising formula 1 and their pharmaceutically acceptable salts.
The term "osteoporosis" as used herein means the state that minerals and substrates are reduced abnormally in large amounts, so that there is no defect in their structure, however,o many pores develop in the bone, making it like sponge and more likely to fracture. In specific examples, the benzamidine compounds of the present invention suppressed the differentiation of osteoclast, facilitated bone formation, and remarkably inhibited the bone mass reduction in osteoporosis-induced animal models.
The term "bone fracture" as used herein means one of various physical injuries of a bone, based on a complete or incomplete disruption of the continuity of a bone, which .-are classified according to anatomical location (epiphyseal, metaphyseal, diaphyseal, intra-articular, proximal, midshaft, distal, etc.), degree of fracture (complete, incomplete), direction of fracture (transverse, oblique, spiral, longitudinal) , presence of open wound (open, closed) , number of fractures (simple, linear, segmental, comminuted, etc.), stability of fracture (stable, unstable) , displacement of fracture, etc. As compared to a non-treated group, a group treated with the benzamidine compound of the formula 1 according to the present invention was found to have bony callus which significantly decreased in volume in a dose- dependent pattern, but increased both in bone density and in bone strength, with significance, in a dose-dependent pattern.
The term "allergic inflammatory diseases" means non¬ specific inflammatory diseases caused by various allergens, exemplified by allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, etc. In the specific embodiment of the present invention, the benzamidine compound of the formula 1 was found to have a great effect of reducing lung weight and total leukocyte numbers in asthma-induced animal models.
The composition of the present invention, a composition may comprises medicinally effective ingredient equivalents or similar in function to the benzamidine compound of Chemical Formula 1 or its pharmaceutically acceptable salt, in addition to Chemical Formula 1 or its pharmaceutically acceptable salt.
The composition of the present invention may comprise one or more pharmaceutically acceptable carriers. A proper carrier may be selected from a group consisting of saline, sterilized water, Ringer's solution, buffered saline, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and combinations thereof, and may be, if necessary, further
supplemented with other typical additives such as an
antioxidant, a buffer, a static agent, etc. In combination
with a diluent, a dispersant, a surfactant, a binder, and a
lubricant, the composition of the present invention may also
be formulated into injectable dosage forms, such as aqueous
solutions, suspensions, emulsions, etc., pills, capsules,
granules, and tablets. Moreover, depending on the kind of
ingredient or disease, the formulation may be produced using
methods known in the art or disclosed in Remington's
Pharmaceutical Science ( (latest version) , Mack Publishing
Company, Easton PA) .
The composition of the present invention may be
administered orally or parenterally (e.g., intravenously,
subcutaneousIy, intraabdominally, or topically) . The dosage
of the composition of the present invention varies depending
on body weight, age, gender, health state, diet,
administration time period, administration route, excretion
rate, disease severity, etc. When all of these factors are
taken into account, the benzamidine compound of Chemical
Formula 1 is administered once or many times at a dose of
approximately 10 to 1,000 mg/kg a day, and preferably at a
dose of approximately 50 to 500 mg/kg a day. For the prevention and treatment of osteoporosis,
allergic inflammatory disease and physical injury of bone
comprising fracture, the administraton of the composition of
the present invention can be done alone or in combination
with surgery, hormone therapy, chemical therapy, and/or a
biological response controller.
A better understanding of the present invention may be
obtained through the following examples which are set forth
to illustrate, but are not to be construed as the limit of
the present invention.
Preparative Example 1 : Preparation of compound (12) in
Reaction Scheme 1
1-1 : 4- (5-chloropentoxyl) -benzonitrile (4)
While 3. Og(25.2mmol) of 4-hydroxybenzonitrile were
added to 80 ml of acetonitrile and stirred, 3.67g(27mmol) of
potassium carbonate and 4.67g(25.2mmol) of l-bromo-5-
chloropentane were added. Subsequently, the temperature was
gradually increased and stirring under reflux was continued
for 7 hr, and then stirring was further continued to 80~82°C. The temperature was decreased to room temperature, and Ethyl
acetate was added, and organic layer washed with distilled water. Thereafter, the organic layer was dried over anhydrous
magnesium sulfate, and then concentrated under reduced
pressure. The concentrated compound was recrystallized in
methanol, then filtered, and washed with -10°C methanol, thus obtaining 5.09 g (yield: 90.3%) of a title compound (4) .
m.p. 47-490C;
1H-NMR(CDCl3) (ppm) 1.64 (m, 2H), 1.82 (m, 4H), 3.57 (t,
2H), 4.01(t, 2H), 6.93(d, 2H), 7.57 (d, 2H)
1-2 : 1-(4-methoxyphenyl) -1-propanone (7)
While 49.3g (370mmol) of aluminium chloride were added
to 200ml of dichloromethane and stirred, 40g (370mmol) of
anisole were slowly added in droplets at 5°C. Subsequently, 32ml (370mmol) of propionyl chloride were slowly added in
droplets for 30 min, and stirring was further continued at
room temperature for 2 hr. After the reaction was completed,
the resultant reaction mixture was diluted with
dichloromethane, and then washed with a saturated aqueous
solution of sodium bicarbonate and water at 5°C. The organic layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. Organic residue was
purified with column-chromatography in which the mixture of ethyl acetate and n-hexane (1:10) were used as a eluent, thus obtaining 59.5 g (yield: 98%) of a title compoundn (7) .
1H-NMR(DMSOd6) (ppm) 1.05 (t, 3H), 2.94 (q, 2H), 3.81 (s, 3H), 7.02 (d, 2H),7.93 (d, 2H)
1-3 : 1-(4-hydroxyphenyl)propan-l-one (8)
While 2Og (0.121rranol) of 1- (4-methoxyphenyl) -1- propanone (7) prepared in Example 1-2 were added to 139 ml(2.4mol) of acetic acid and stirred, 270ml (2.4mmol) of 48% bromic acid were added. Subsequently, the temperature was
gradually increased to 100°C and stirring under reflux was continued for 18 hr. The temperature was decreased to room temperature, and ethyl acetate was added, and organic layer was washed with water. Thereafter, the organic layer was washed with a saturated aqueous solution of potassium carbonate, then concentrated under reduced pressure, after which the precipitated solid was recrystallized with ethyl acetate/n-hexane system, and filtered, thus obtaining 12.7g
(yield: 70%) of a title compound (8) as a solid.
m. p . : 143 ~ 150°C
1H-NMR (DMSOd6) (ppm) 1 . 03 (t, 3H) , 2. 91 (q, 2H) , 6. 83 (d,
2H) , 7 . 82 (d, 2H) , 10 .28 (s , IH) . 1-4 : 4-[5-(4-propionylphenoxγ)pentoxyl]-benzonitrile (9)
While 12g (80mmol) of 1-(4-hydroxyphenyl)propan-l-one
(8) prepared in Example 1-3 were added to 100 ml of dimethylformamide and stirred, 3.5g(84mmol) of sodium hydride were added, and stirring was continued for 20 rain.
Thereafter, 17.9g(80mmol) of 4- (5-chloro-ρentoxy)- benzonitrile (4) prepared in Example 1-1 were dissolved in
20ml of dimethylformamide. The reaction temperature was
gradually increased and stirring was continued at 4O0C for 4 hr. After the reaction was completed, the temperature was decreased to room temperature, and the resultant reaction mixture was added with ethylacetate, and then washed with distilled water. Subsequently, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with column- chromatography in which the mixture of ethylacetate and n- hexane(l:5) were used as a eluent, thus obtaining 21.6g (yield: 80%) of a title compound (9) .
m.p. : 107 ~ Hl0C 1H-NMR(DMSO-d6) (ppm) 1.04 (t, 3H), 1.56(m, 2H), 1.78 (brm, 4H), 2.95(q, 2H), 4.07(4H), 7.00(d, 2H), 7.08(d, 2H), 7.74(d, 2H) , 7.90 (d, 2H) . 1-5 : 4-5-[4-(2-bromopropionyl)phenoxy]ρentoxy-benzonitrile
(10)
While 2Og (59mmol) of 4-[5-(4-
propionylphenoxy)pentoxy] -benzonitrile (9) prepared in
Example 1-4 were added to 300 ml of ethylacetate and stirred,
26g (119mmol) of copper (II) bromide were added, and the
reaction temperature was gradually increased and stirring was
continued at 70°C for 8 hr. After the reaction was completed, the resultant reaction mixture was cooled to room
temperature and the salts were removed by filtration. The
ethylacetate layer was washed with sodium bicarbonate and
sodium chloride. Subsequently, the organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure, thus obtaining 23 g (yield: 95.0%) of a
title compound (10) .
m.p. : 79 ~ 81°C
1H-NMR (DMSO-d6) (ppm) 1.57 (m, 2H), 1.74 (d, 2H),
1.79 (brm, 4H), 4.08 (m, 4H), 5.77 (q, IH), 7.07 (m, 4H), 7.74 (d,
2H), 7.99(d, 2H) .
1-6 : 4-5- [4- (5-methyl-2-isopropyl-l,3-thiazol-4-
y 1 ) phenoxy ] pentoxyl -benzonitrile ( 12 ) While Ig (2 .4mmol) of 4-5- [4- (2- bromopropionγl)phenoxy]pentoxyl-benzonitrile (10) prepared in
Example 1-5 were added to 30 ml of ethanol and stirred, 0.25g
(2.4mmol) of isobutrathioamide were added. Subsequently, the
temperature was gradually increased to 80°C and stirring under reflux was continued for 5 hr. After the reaction was
completed, the resultant reaction mixture was concentrated
under reduced pressure, and diluted with dichloromethane, and
then washed with a saturated aqueous solution of sodium
bicarbonate and brine. The organic layer was dried over
anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified with column-
chromatography in which the mixture of ethylacetate and n-
hexane(l:6) were used as a eluent, thus obtaining 0.9g
(yield: 89%) of a title compound(12) .
m.p. : 70 ~ 73°C
1H-NMR(DMSO-de) (ppm) 1.32 (d, 6H), 1.59 (m, 2H), 1.79 (m,
4H), 2.47(s, 3H), 3.21 (m, IH), 4.02(t, 2H), 4.09(t, 2H),
6.98 (d, 2H), 7.09(d, 2H), 7.55(d, 2H), 7.74(d, 2H) .
Preparative Example 2 : Preparation of compound (16) in
Reaction Scheme 2 2-1 : 4-5-[4-(5-methyl-2-amino-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzonitrile (14)
While 3g (7.2πrmol) of 4-5-[4- (2-
bromopropionyl)phenoxy]pentoxyl-benzonitrile (10) prepared in
Example 1-5 were added to 30 ml of ethanol and stirred, 0.58g
(7.6 mmol) of thiourea were added. Subsequently, the
temperature was gradually increased to 80°C and stirring under reflux was continued for 5 hr. After the reaction was
completed, the resultant reaction mixture was concentrated
under reduced pressure, and diluted with dichloromethane, and
then washed with a saturated aqueous solution of sodium
bicarbonate and brine. The organic layer was dried over
anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified with column-
chromatography in which the mixture of ethylacetate and n-
hexane(l:2) were used as a eluent, thus obtaining 2.5g
(yield: 89%) of a title compound (14) .
1H-NMR(DMSO-d6) (ppm) 1.57 (m, 2H), 1.78 (m, 4H), 2.27 (s,
3H), 3.98(t, 2H), 4.07(t, 2H), 6.69(s, 2H), 6.91(d, 2H),
7.09(d, 2H), 7.45(d, 2H), 7.74(d, 2H) .
2-2 : 4-5-[4-(5-methyl-2-ethylamino-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzonitrile (16) While O.βOg (1.52mmol) of 4-5- [4- (5-methyl-2-amino-l,3-
thiazol-4-yl)phenoxy]pentoxy-benzonitrile(14) prepared in
Example 2-1 were added to 50 ml of dimethylformamide and
stirred, 0.07g (1.83mmol) of sodium hydride were added.
After stirring for 20 min, 0.13ml (l.βmmol) of ethyl iodide
were added, and the temperature was gradually increased to
400C and stirring was continued for 4 hr. After the reaction was completed, the resultant reaction mixture was partitioned
between distilled water and ethylacetate. The organic layer
was dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified
with column-chromatography in which the mixture of
ethylacetate and n-hexane (1:2) were used as a eluent, thus
obtaining 0.32g (yield: 50%) of a title compound (16) .
1H-NMR(DMSOd6) (ppm) 1.13 (t, 3H), 1.56 (m, 2H), 1.78 (m,
4H), 2.28(S, 3H), 3.19 (m, 2H), 3.99(t, 2H), 4.07(t, 2H),
6.92(d, 2H), 7.09(d, 2H), 7.26(t, IH), 7.47(d, 2H), 7.74(d,
2H) .
Preparative Example 3 : Preparation of compound (18) in
Reaction Scheme 3
4-5-[4-(5-methyl-2-[ethyl-(2-morpholinoethyl)amino] -1,3-
thiazol-4-yl)phenoxy]pentoxy-benzonitrile (18) While 0.4Og (0.94mmol) of 4-5- [4- (5-methyl-2-
ethylamino-1, 3-thiazol-4-yl)phenoxy]pentoxy-benzonitrile(16)
prepared in Example 2-2 were added to 50 ml of
dimethylsulfoxide and stirred, O.lOg (2.37mmol) of sodium
hydride were added. After stirring for 20 min, 0.18g
(0.99mmol) of N- (2-chloroethyl)morpholine hydrochloride were
added, and the temperature was gradually increased to 4O0C and stirring was continued for 4 hr. After the reaction was
completed, the resultant reaction mixture was partitioned
between distilled water and ethylacetate. The organic layer
was dried over anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified
with column-chromatography in which the mixture of
ethylacetate and n-hexane (1:2) were used as a eluent, thus
obtaining 0.35g (yield: 70%) of a title compound(lδ) .
1H-NMR(DMSO-d6) (ppn) 1.15 (t, 3H), 1.55 (m, 2H),
1.77 (brm, 4H), 2.31 (s, 3H), 2.42 (brm, 4H), 2.51 (m, 2H),
3.39(t, 2H), 4.07(t, 2H), 6.93 (d, 2H), 7.09 (d, 2H), 7.48(d,
2H) , 7.74 (d, 2H) .
Preparative Example 4 : Preparation of compound (20) in
Reaction Scheme 4 4-5-[4-(5-methyl-2-piperidino-l,3-thiazol-4-
yl)phenoxy]pentoxy-benzonitrile (20)
While 0.5Og (1.27rnmol) of 4-5- [4- (5-methyl-2-amino-l, 3-
thiazol-4-yl)phenoxy]pentoxy-benzonitrile (14) prepared in
Example 2-1 were added to 50 ml of dimethyformamide and
stirred, 0.Hg (2.79mmol) of sodium hydride were added.
After stirring for 20 min, 0.19ml (1.4mmol) of 1,5-
dibroruopentane was added, and the temperature was gradually
increased to 4O0C and stirring was continued for 4 hr. After the reaction was completed, the resultant reaction mixture
was partitioned between distilled water and ethylacetate.
The organic layer was dried over anhydrous magnesium sulfate,
and then concentrated under reduced pressure. The residue was
purified with column-chromatography in which the mixture of
ethylacetate and n-hexane (1:2) were used as a eluent, thus
obtaining 0.57g (yield: 98%) of a title compound (20) .
1H-NMR(DMSOd6) (ppm) 1.57 (m, 2H), 1.63(brm, 6H),
1.77 (brm, 4H), 2.20 (s, 3H), 3.60 (brm, 4H), 4.04 (m, 4H),
7.04(d, 4H), 7.40(d, 2H), 7.68(d, 2H) .
Example 1 : Preparation of N-hydroxy-4-5-[4-(5-methyl-2-
isopropyl-1,3—thiazol-4-yl)phenoxy]pentoxyl-benzamidine While 0.3g (0.7lrtimol) of 4-5-[4- (5-methyl-2-isopropyl-
1, 3-thiazol-4-yl)phenoxy]pentoxyl-benzonitrile (12) prepared
in Example 1-6 were added to 10 ml of ethanol and stirred,
0.1Ig (2.9mmol) of sodium hydroxide and 0.2Og (2.9mmol) of
hydroxylamine hydrochloride, dissolved in
ethanol (5ml) /water (ImI) co-solvent, were added. The
temperature was gradually increased to 80°C and stirring was continued for 15 hr. The resultant reaction mixture was
concentrated under reduced pressure, and diluted with
dichloromethane, and then washed with a distilled water. The
organic layer was dried over anhydrous magnesium sulfate and
then the resultant reaction mixture was concentrated under
reduced pressure, then purified with column-chromatography in
which the mixture of ethylacetate, n-hexane and methanol
(5:10:1) were used as a eluent, thus obtaining 0.19g (yield:
52%) of a title compound.
1H-NMR(DMSOd6) (ppm) 1.31 (d, 6H), 1.58 (m, 2H), 1.79 (m,
4H), 2.47(s, 3H), 3.21(m, IH), 4.00 (m, 4H), 5.71(S, 2H),
6.91(d, 2H), 6.99(d, 2H), 7.56 (m, 4H), 9.44(s, IH) .
Example 2: Preparation of 4-5-[4- (5-methyl-2-isopropyl-l,3-
thiazol-4-yl)phenoxy]pentoxyl-benzamidine While 0.22g (0.52mmol) of 4-5-[4- (5-methyl-2~isopropyl-
1,3-thiazol-4-yl)phenoxy]pentoxyl-benzonitrile(12) prepared
in Example 1-6 were added to 10 ml of saturated
hydrochloride/methanol solution and stirred for 24 hr, and
the resultant reaction mixture was concentrated under reduced
pressure. The organic residue was dissolved with 2ml of
ethanol, and put it in sealed tube. 10ml of ammonia ethanol
solution was added to the tube, and the temperature was
gradually increased to 5O0C and stirring was continued for 40 hr. After the reaction was completed, the resultant reaction
mixture was concentrated under reduced pressure, and was
purified with column-chromatography in which the mixture of
chloroform, methanol (8:1) were used as chromatography
solvent, thus obtaining O.lOg (yield: 48%) of a title
compound.
1H-NMR(DMSO-d6) (ppm) 1.33 (d, 6H), 1.61 (m, 2H),
1.82 (brm, 4H), 2.49 (s, 3H), 3.22 (m, IH), 4.04 (t, 2H), 4.14 (t,
2H), 7.01 (d, 2H), 7.17 (d, 2H), 7.57(d, 2H), 7.85(d, 2H) .
Examples 3 to 83
1. N-hydroxγ benzamidine (R5=OH) (Examples 3 to 51, 57 to 83)
Compound (12) prepared according to the same method as
that in the Preparative Example 1-6 was reacted in the same manner as Example 1, obtaining the title compounds shown I Table 1.
Table 1 shows the title compounds, reactants and 1H-NMR data.
[Table l]
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
2. Benzamidine (Rs=H) (Examples 52 to 56)
Compound (12) prepared according to the same method as that in the Preparative Example 1-6 was reacted in the same manner as Example 2, obtaining the title compounds shown I Table 2. •
Table 2 shows the title compounds, reactants and 1H-NMR data.
[Table 2]
Figure imgf000089_0001
Examples 84 to 117
Compound (16) prepared according to the same method as that in the Preparative Example 2-2 was reacted in the same manner as Example 1, obtaining the title compounds shown I Table 3.
Table 3 shows the title compounds, reactants and 1H-NMR data. [Table 3]
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Examples 118 to 163
Compound (18) prepared according to the same method as that in the Preparative Example 3 was reacted in the same manner as Example 1, obtaining the title compounds shown I Table 4.
Table 4 shows the title compounds, reactants and 1H-NMR data.
[Table 4]
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Examples 164 to 176
Compound (20) prepared according to the same method as that in the Preparative Example 4 was reacted in the same manner as Example 1, obtaining the title compounds shown I Table 5.
Table 5 shows the title compounds, reactants and 1H-NMR data.
[Table 5]
Figure imgf000101_0001
Figure imgf000102_0001
Exaπtples 177 to 213
Compound (12) prepared according to the same method as
that in the Preparative Example 1-6 was reacted in the same
manner as Example 1, obtaining the title compounds shown I
Table 6.
Table 6 shows the title compounds, reactants and 1H-NMR
data.
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Experimental Example 1: Inhibitory effects on osteoclast
differentiation
The effect of benzamidine derivatives of the present
invention on osteoclast proliferation and differentiation
process was evaluated via co-culture with osteoblast.
1-1. Preparation of cells a) Preparation of bone marrow cells
Tibia and Femora were aseptically ectomized from male ddY mice of β~8 weeks to harvest bone marrow cells by using a syringe (21G, Korea Green Cross) . The bone marrow cells were suspended in 5mL α-MEM medium (Gibco BRL Co.) containing sodium bicarbonate
(2.0g/L), streptomycin (100mg/L) and penicillin (100,000 unit/rαL) . The harvested cells were centrifuged at 600 x g for 5 mins to collect the whole quantity. To remove the red blood cells within bone marrow cells, 3mL of Tris HCl (0.83% NH4Cl, pH7.5) was added and well mixed. After centrifuging above cells, the numbers of bone marrow cells were counted and then, the bone marrow cells were immediately used for co-culture system with osteoblast.
b) Preparation of osteoblast
The calvaria were aseptically ectomized from neonate ICR mice of 1~2 days, washed with PBS solution and incubated with a mixture of enzyme solution (0.2% collagenase and 0.1%
dispase) at 37°C gentle shaker. This procedure was sequentially repeated (10, 10, 10, 20, 20 and 20 mins), and then the calvaria cells having the characteristics of
osteoblast mostly released from IQ-VI digestion groups were collected and washed with the medium (serum-free α-MEM) . The washed cells were cultivated in α-MEM medium containing 10% FBS for 2~3 days. After subculturing, these cells were used for this experiment, and diluted to reach the concentration
of lxl06cell/mL for storage at -70°C.
1-2. Measurement of osteoclast differentiation a) Preparation of specimen
Benzamidine derivatives of the present invention were dissolved in a sterile distilled water or ethanol to make desired concentrations following dilution. The final volume of specimen added to the medium was determined at the ratio of 1 : 1000.
b) Reaction with specimens via co-culture system
Bone marrow cells prepared in the above and osteoblast from calvaria were co-cultured for osteoclast differentiation. Both bone marrow cells (25,000 cells/cm2) and osteoblast (10,000 cells/cm2) were plated on a 96 well plate in α-MEM medium containing FBS with specimen, and then cultured with test materials for 7 days. Differentiation factors, such as dexamethasone (10"7M) and vitamin D3 (10"8M) , were also continuously added to the medium from the first day of cultivation. The medium was changed with fresh media containing a mixture of specimens and differentiation factors every 2~3 day.
c) Evaluation of osteoclast differentiation
1) Preparation of tartarate resistance acid phosphatase (TRAP) staining solution
TRAP was used as a marker to measure osteoclast in consideration of its characteristics showing a positive reaction to TRAP staining solution. TRAP staining solution was prepared in a manner that 5mg of naphtol AS-MS phosphate
(sigma N-4875) , a substrate and 25mg of coloring agent (Fast
Red Violet LB salt) were dissolved in N,N-dimethylformamide
(about 0.5mL), 0.1N NaHCO3 buffer solution (5OmL) containing 5OmM tartaric acid was added, and the reaction mixture was stored at refrigerator prior to use.
2) Staining method
After culturing the cells for 7 days, the medium was removed from the wells, the cells were once washed with PBS solution and fixed to PBS containing 10% formalin for 2~5 mins. The cells were fixed again in a mixed solution of ethanol and acetone (1/1) for about 1 min, and dried off. The cells were further treated by TRAP staining solution for 15 mins and washed with PBS. The experimental results were measured by counting the number of osteoclasts with 3 or more nuclei showing TRAP-positive reaction under a microscopic examination. Each of tests was confirmed over three times for gaining more reliable data.
As shown in the following table 7, the inhibitory effect of each experimental group on the differentiation of osteoclast versus controls was expressed by inhibitory percentage value.
[Table 7]
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
As shown in the table 7, the results indicate that the benzamidine derivatives were significantly inhibited the osteoclast differentiation at a low concentration.
Experimental Example 2: Effect on bone formation
The osteoblast, treated in this experiment, was prepared from the osteoblast as prepared in the above.
2-1: Experinment 1 The osteoblast, isolated from sequential enzymatic treatment of calvariae from neonated ICR mice, was cultured in α-MEM medium containing 10% FBS for 4~5days. The osteoblast was also cultured for 24hr after seeding the cells on a 12 well plate (105 cell/well), and medium was exchanged with the osteogenic differentiation medium
containing 1OmM β-glycerophosphate and 50/Zg/ni-P, ascorbic acid.
The test substances at the concentration of 0.IuM and
0.InM were added to the above medium for evaluating the effect promoting bone formation. The differentiation medium containing the test substances was exchanged every 3 or 4 days for 14 to 21 days until confirming the nodule mineralization. The cell was rinsed twice with distilled water, and fixed by the 10% formalin solutions for 30 minutes. Alizarin red S and Von-kossa Solution were treated on the plate for measuring deposited calcium and phosphate in cell matrix, and the activity of the test substances on the bone formation was analyzed by deterirnining stained area.
Additionally, for the purpose of estimating quantitative Arizarin red S in cell matrix, stained Arizarin red S was extracted by treating 1OmM sodium phosphate solution (pH 7.0), containing 10% cetylpyridinium chrolide, for 15-30 minutes in the shaking incubator, and then the amount of the deposited calcium was estimated by calculating the absorbance of the extracted Arizarin red S at 564nm.
2-2: Experiment 2
IxIO5 of calvarial cells per well from neonated ICR mice were loaded on a 12 well plate and cultured for 24h. The osteogenic differentiation medium containing 1OmM β-
glycerophosphate and 50 μg/mi ascorbic acid was exchanged at the confluent state of the cell, and the compounds for investigating their activities on the osteoblast were added. The differentiation medium containing the test substances was exchanged every 3 days, and the culturing period was prolonged approximately 15 days.
The medium containing the test compounds was removed from the cells at the end of culture and then, the cells were washed with sterilized distilled water once or twice and fixed to 10% formalin solution about 30~60 minutes. These fixed plates were again washed once or twice, and stained 4OmM Arizarin red S for 10 minutes after drying the plates. These stained plates were rinsed 3-5 times for eliminating waste Arizarin red S. For measuring the amount of the deposited Arizarin red S, 570ul of 10% (w/v) cetylpyridinium chrolide were added on plates, extracted and stained Arizarin red S for 15-30 minutes in the shaking
incubator at 37°C. Finally, the amount of calcium was estimated by calculating the absorbance of the extracted Arizarin red S at 564nm.
The results are listed in in Table 8.
[Table 8]
Figure imgf000118_0001
As shown in Table 8, benzamidine derivatives of the
present invention have the excellent activities on the
osteblast, and thus these compounds are effective on the bone
formation process.
Experimental Example 3 : Therapeutic effect in the
ovariectαmized osteoporetiσ mouse model of each test substance The therapeutic effects of each benzamidine derivates were evaluated on the ovariectomized ddY mouse. Benzamidine derivates were dosed from 4 weeks after operation for 4 weeks and the changes on the trabecular bone volume (TBV) of the femur were observed via histomorphometry. 3-1. Animals and husbandry
Female ddY mice(β-wk old upon receipt, SLC, Japan)
were used after acclimatization for 7 days. Animals were
allocated 5 per polycarbonate cage in a temperature (20-25°C)
and humidity(30-35%) controlled room. Light : dark cycle was
12hr : 12hr and feed(Samyang, Korea) and water were supplied
free to access.
3-2. Preparations and administration of drugs
Salts of benzamidine derivates (Methansulfonic acid or
HCl) were used for the test substances of this invention.
Test substances are dissolved and/or suspended in injectable
distilled water and administered at a dosage volume of
10ml/kg by oral gavage. All test substances are dosed from 4
weeks after operation for 4 weeks at 50mg/kg/day.
3-3. Ovariectomy
To induce estrogen-deficient osteoporosis, bilateral
ovaries are removed and then closed by routine methods.
Operation was conduct under Ketamine hydrochloride and
xylazine hydrochloride anesthesia.
3-4. Histology The left femur of each mouse were separated at
sacrifice, and fixed in 10% neutral buffered formalin (NBF) ,
then decalcified in decalcifying solution(24.4% formic acid,
and 0.5N sodium hydroxide) for 5 days (mixed decalcifying
solution was exchanges once a day for 5 days) . After the
dexalcification, the femur was embedded in paraffin,
sectioned(3~4um) and stained with hematoxylin-eosin stain.
3-5. Histomorphometry
TBV was calculated using automated image
analysis (analysis Image Processing; SIS, Germany) under
magnification of χ200 in the uniform area of trochlea
epiphyseal regions (growth plate regions were excluded) of
prepared histological specimens. TBV was calculated as
percentage (%) levels.
3-6. Changes vs vehicle control
The changes of TBV compared to that of vehicle control
are calculated as following Equation 1 to help the
understanding of the efficacy of test substances.
Equation 1 Percentage changes = [((TBV of a - TBV of b) /TBV of b) x 100]
a: test substance-dosing groups b: vehicle control
Results are listed in Table 9.
[Table 9]
Figure imgf000121_0001
As shown in the table 9, the experimental results
indicate that the test substances have inhibitory effects on
the decrease of bone volumes induced by ovariectomy. TBV of
test substance-dosing groups are dramatically increased
compared to that of vehicle control.
Therefore, it is considered that the test substances
prove to be effective for the treatment of osteoporosis.
Experimental Example 4 : Effect of Promoting Fracture
Healing in Rib Fracture-Induced Rat Model
The benzamidine compounds were assayed for therapeutic
effect on bone fracture in rat models subjected to rib
fracture. Benzamidine derivates are dosed from 2 days after
operation for 2 weeks, and the changes on the volume and
histology of callus were observed.
4-1. Experimental animals and Breeding management
A total of 54 SD rats (8 weeks old upon receipt, Jung
Ang Lab. Animal Co., Korea) were used. While being housed at
a density of three to a plastic cage, the experimental
animals were kept in a breeding room under controlled
temperature (20-25 0C) and humidity(30-35%) . Under light- dark cycles of 12 hours, the rats were allowed to have free
access to feedstuff and tap water.
4-2. Preparations and administration of sample
200mg of benzamidine compounds (Methansulfonic acid or
Hydrochloride) were completely dissolved in 5ml of
sterilized distilled water. The benzamidine derivatives in
the solutions was orally administered at doses of 200mg per
kg of body weight once a day for 2 weeks from day 2 of the
surgery.
4-3. Induction of Rib-fracture
8th and 9th rib of each animal was exposed by general
operation under ketamine HCl and xylazine HCl anesthesia,
and the exposed ribs were crossly dissected using surgical
scissors. After rib-fracture, surgical wounds were closed
with general skin suture.
4-4. volume of bony callus
8th and 9th ribs of each animal were separated at
sacrifice and then the long axis and short axis of callus
were calculated as mm units. The volume of callus was
calculated as following Equation 2. Equation 2
Callus volume (mm3) = (a x b2) /2
a: long diameter of bony callus
b: short diameter of bony callus
Results are listed in Table 10.
[Table 10]
Figure imgf000124_0001
*: p < 0.01 compared to that of vehicle control
**: p < 0.05 compared to that of vehicle control
As shown in the table 10, the experimental results
indicate that the callus volume of test substance-dosing
groups are significantly(p<0.01 or p<0.05) decreased
compared to that of vehicle control. Therefore, it is considered that the test substances have facilitating effects on the disappearance of callus volume induced by rib-fracture.
4-5. Histopathological observation
The 8th rib including fracture sites of each rat was separated and fixed in 10% neutral buffered formalin, and then decalcified in decalcifying solution(24.4% formic acid, and 0.5N sodium hydroxide) for 5 days (mixed decalcifying solution was exchanges once a day for 5 days) . After decalcification, the rib was embedded in paraffin, sectioned(3~4um) and stained with hematoxylin-eosin or Masson's trichrome for composition of callus observation.
Osteloid volume (OV/callus) in callus regions of prepared histological specimens were detected as % levels using automated image analysis (analysis Image Processing; SIS, Germany) under microscopy.
Results are, listed in Table 11.
[Table ll]
Figure imgf000125_0001
Figure imgf000126_0001
*: p < 0.01 compared to that of vehicle control
**: p < 0.05 compared to that of vehicle control
As shown in the table 11, the experimental results
indicate that the callus osteoid volume of test substance-
dosing groups are significantly(p<0.01 or p<0.05) increased
compared to that of vehicle control.
Therefore, it is considered that the test substances
have favorable effects on the facilitating the ossification
in the callus induced by rib-fracture.
Experimental Example 5 : Therapeutic Effect in Mouse Model
of Asthma Induced with Ovalbumin
The benzamidine compounds were assated for therapeutic
effect on allergic inflammation in mouse models of
ovalbumin-induced asthma. Starting on the day of
immunization the benzamidine compounds were dosed for 17
consecutive days. The experimental animals were re-exposed
to ovalbumin 14 days after the sensitization and then
sacrificed 3 days after the re-exposure. Changes in lung weight, cellular components of peripheral blood and
bronchoalveolar lavage fluid, and lung histopathology were
observed.
5-1. Experimental animals and Breeding management
A total of 110 female C57BL/6 mice (7-week-old, SLC,
Japan) were adapted to a laboratory envirionment for 6 days
before being used in earnest experiments. While being housed
at a densirt of five in a plastic cage, the experimental
animals were breed in a breeding room with controlled
temperature (20-25"Q: and humidity (30-35%) . Under light-dark
cycles of 12 hours, mice were allowed to have free access to
feedstuff and tap water. While asthma was induced in 100
mice by ovalbumin, 10 mice were used as a non-treated group.
5-2. Preparations and administration of sample
200mg of benzamidine compounds (Methansulfonic acid or
Hydrochloride) were completely dissolved in 5ml of
sterilized distilled water. The benzamidine compound in the
solutions was orally administered at doses of 200mg per kg
of body weight once a day from the day of the sensitization
with ovalbumin. The control group was administered with equal volumes of sterilized distilled water in the same
manner.
5-3. Asthma induction by immunization with and exposure to
ovalbumine
A solution of 200 μg of ovalbumin (Grade VI; Sigma,
st. Louis, MO, USA) and 180 mg of aluminium
hydroxide (Al (OH)3, dried powder gel; Aldrich, Milwaukee, USA)
in 4ml of physiological saline was allowed to stand at 4°C
overnight and was administered to the experimental animals
(200 μl, abdominal injection) for sensitization. As for the
non-treated group, a solution of only aluminium hydroxide in
saline was injected. 15 days after sensitization, a 1.5%
ovalbumin solution was sprayed in air using a nebulizer,
followed by exposing the experimental animals to the spray
for 10 min to induce asthma therein. The non-treated group
was exposed only to saline in the same manner. All the
experimental animals were sacrificed 3 days after the
exposure.
5-4. Measurement of lung weight
On the final day of experiment, the lungs were
separated form adjacent organs. The removed lungs were weight among individual animals, the relative weight of the lungs was calculated as a percentage of body weight using the following Equation 3.
Equation 3
Relative weight of Lung (%) = (Absolute lung weight/Body weight) x 100
Results are listed in Table 12.
[Table 12]
Figure imgf000130_0001
*: p < 0.01 compared to that of sham
**: p < 0.05 compared to that of sham
#: p < 0.01 compared to that of vehicle control
##: p < 0.05 compared to that of vehicle control
As shown in the table 12, significantly(p<0.01 or
p<0.05) increase of absolute and relative lung weights are
detected in vehicle control compared to those of sham.
However, they were significantly(p<0.01 or p<0.05) or
dramatically decreased in test substance-dosing groups
compared to that of vehicle control.
Therefore, it is considered that the test substances
inhibit the increase of lung weight induced by asthmatic
changes. 5-5. Changes on the total count of leukocytes in the
peripheral blood and BALF
a) Total count of leukocytes in peripheral blood
On the final day of experiment, all the experimental
animals were etherized and underwent laparotomy to expose the
abdominal vena cava, from which 1 ml of blood was the taken.
Using a hemocytometer, a blood sample was measured for total
leukocyte counts in a x 103/lmm3 units.
b) Total count of leukocytes in BALF
On the final day of experiment, secretions present in
bronchi and alveola were examined for cyrological
constitution. After veing etherized, the experimental animals
were operated to open the cervical region and the thorax. The
jugular vein was allowed to bleed, followed by endotracheal
intubation. 3 ml of phosphate buffered saline was injected
twice through the tube and the thorax was massaged for 30 sec
to obtain cell suspension from the lungs. Using a
hemocytometer, a blood sample was measured for total
leukocyte counts in a * 105/lml units.
Results are listed in Table 13.
[Table 13]
Figure imgf000132_0001
*: p < 0.01 compared to that of sham
**: p < 0.05 compared to that of sham
#: p < 0.01 compared to that of vehicle control
■ ##: p < 0.05 compared to that of vehicle control
As shown in the table 13, significant (p<0.01) increase
of total leukocytes in peripheral blood and BALF are
detected in vehicle control compared to those of sham,
respectively. However, they were significantly(p<0.01 or
p<0.05) or dramatically decreased in the test substance-
dosing groups compared to that of vehicle control,
respectively.
Therefore, it is considered that the test substances
have favorable effects on the inhibition of the inflammatory
responses induced by asthmatic changes. Experimental Example 6: Cytotoxicity Test
Cytotoxic effect of benzamidine derivatives was
evaluated by the experiment described below.
The test substance was diluted in appropriate solvent
at 10"2M concentration. This substance was diluted in culture
medium at ICT5 concentration, and loaded into a 96-well
microplate in a dose of lOOμL per well. Cells to be used in
cytotoxitic test were plated on a 96-well microplate in a
dose of 1 x 104 cell/lOOμL per well and cultured for 72 hrs.
25 μL of MTT [3- (4,5-dimetyl-2-thiazolyl)-2,5-diphenyl-2H-
tetrazolium bromide] dissolved in PBS at 2mg/mL were added
before 4 hrs of the end of culture. After reaction, the
plates were centrifuged, medium was decanted and 100 μL of
DMSO was added to dissolve formazan. Lastly, the absorbance
of developed plates was measured at 540nm. Survival rates of
the cells were showed by % concentration compared with the
control group.
Results were displayed in table 14.
[Table 14]
Figure imgf000134_0001
As shown in table 14, benzamidine derivative shows little cytotoxicity.
Examples of preparation of this invention are following.
Formulation Example 1. Preparation of powders
Benzamidine derivatives 2g
lactose Ig
2g of benzamidine derivatives of the formula (1) was
mixed with Ig of lactose, thus preparing powder from the
mixture with filling to a air tight bag.
2. Preparation of tablets
Benzamidine derivatives 100 tng
corn starch 100 mg
lactose 100 mg
magnesium stearate 2 mg
After mixing all components, tablets are prepared by
being tableted with generally used methods.
3. Preparation of capsules
Benzamidine derivatives 100 mg
corn starch 100 mg
lactose 100 mg
magnesium stearate 2 mg After mixing all components, capsules are prepared by- being filled up to gelatin capsules with generally used methods.
4. Preparation of injections
Benzamidine derivatives 10 /ιg/m& dilute hydrochloric acid BP to pH 3.5
NaCl for injections BP Max. ImI
Benzamidine derivatives of the formula 1 was dissolved in adequate volume of NaCl for injections BP, then pH of the solution was controlled to pH 3.5 with dilute hydrochloric acid BP. The volume of the whole solution was fixed with NaCl for injections BP, and the solution was mixed fully. The solution was filled up to type I ampoule made with glass, then the ampoule was sealed under the upper air lattice by melting glass. The sealed ampoule was autoclaved under the condition of 120°C for 15mins or more to prepare the sterilized injection.
Industrial Applicability
The novel benzamidine derivatives of the present invention remarkably suppress osteoclastic bone resorption, stimulate osteoblastic bone formation in very low concentrations and inhibit decreases of bone mass in osteoporosis animal models and thus are useful for the prevention and treatment of osteoporosis. Further, the compounds of the present invention activate the loss of bony callus and its ossification and thus are useful for the prevention and treatment of bone fractures. The compounds of the present invention are also useful for the prevention and treatment of allergic inflammatory diseases.

Claims

Claims
1. Benzamidine derivate of the formula 1 or pharmaceutically
acceptable salts thereof.
Formula 1
Figure imgf000138_0001
wherein
Ri is Ci-Cg alkyl ; C3-C6 cycloalkyl ; phenyl; benzyl ;
pyridinyl ; guanidino; NR6R7; CH2NR6R7;
Figure imgf000138_0002
wherein A is Ci-C6 alkyl and n is an integer of 2 to 6; C1-C6 alkyl
which is substituted by pyridine or
Figure imgf000138_0003
is
unsubstituted or substituted by hydroxy; pyridinyl or
Figure imgf000138_0004
which is substituted by Ci-C6 alkyl;
R2 is hydrogen; Ci-C6 alkyl; C3-C6 cycloalkyl; phenyl;
benzyl; Ci-C6 alkyl which is substituted by hydroxy, Ci-C6
alkoxy, halogen or C3-C6 cycloalkyl; C2-C6 alkenyl;
R3 and R4, each independently, are hydrogen; halogen;
hydroxy; Ci-C6 alkyl which is unsubstituted or substituted halogen; C3-C6 cycloalkylamino; Ci-C6 alkoxy; Ci-C6 alkanoyloxy; C2-Ce alkenyloxy; phenyl-Ci~C6 alkoxy; phenoxy; C2-C6 alkenoyloxy or phenyl-Ci~C6 alkanoyloxy; C3~C6 cycloalkyloxy which is substituted by carboxy, esterified
carboxy or amidated carboxy; aminooxy;
R5 is hydrogen or hydroxy;
R6 and R7, each independently, are hydrogen; Ci-C6 alkyl; phenyl; benzyl; pyridinyl; Ci-C6 alkyl which is substituted by
N Y pyridine or N—' ; carbonyl which is substituted by Ci-C6
alkyl, phenyl, benzyl, pyridine or
Figure imgf000139_0001
; Ci~C6 alkanesulfonyl; Cχ~C6 alkyl which is substituted by hydroxy or
Ci-C6 alkoxy; acetyl which is substituted by hydroxy or Cx-C6 alkoxy;
Y is oxygen; sulfur; NR6. or CH2; Xi and X3, each independently, are oxygen; sulfur; NH;
N-Ci-C6 alkyl; N-C3-C6 cycloalkyl; N-benzyl; N-phenyl;
X2 is C3-C7 alkylene; Cx-C3 alkylene-alkenylene-Ci-C3-
alkylene; Ci-C3 alkylene-O-Ci~C3 alkylene; C1-C3 alkylene-S-Ci-
C3 alkylene; Ci-C3 alkylene-NH-Ci-C3 alkylene; C1-C3 alkylene-
phenylene-Ci-C3 alkylene; C1-C3 alkyl ene-pyridylene-Ci-C3
alkylene; C1-C3 alkylene-naphtylene-Ci-C3 alkylene; C3-C7
alkylene which is substituted by Ci-C3 alkyl and hydroxy; C3- C7 alkylenecarbonyl; C3-C7 alkylene which is interrupted by piperazine; with the proviso that if Xi and X3 are oxygen, X2 is pentyl and R3 and R4 are hydrogen, the compound of the formula 1 wherein Ri is methyl and R2 is isopropyl is excluded.
2. The compound according to claim 1, wherein
Ri is Cx-C6 alkyl; C3-C6 cycloalkyl; phenyl; pyridinyl;
guanidino; NR6R7; CH2NR6R7;
Figure imgf000140_0002
;
Figure imgf000140_0003
wherein A is Cx-C6 alkyl and n is an integer of 2 to 6; Ci~C6 alkyl which is
substituted by
Figure imgf000140_0001
wherein
Figure imgf000140_0004
is unsubstituted or
substituted by hydroxy;
Figure imgf000140_0005
which is substituted Ci-C6 alkyl; R2 is hydrogen; Cx-C6 alkyl; C3-C6 cycloalkyl; benzyl;
Ci-Cg alkyl which is substituted by hydroxyl, methoxy, halogen or C3-C6 cycloalkyl; C2-C6 alkenyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; C3-C6 cycloalkylamino; Ci-C6 alkoxy; Cx-C5 alkanoyloxy; C3-C5 cycloalkyloxy which is substituted by carboxy, esterified carboxy or amidated carboxy; aminooxy; R5 is hydrogen or hydroxy;
Rβ and R7, each independently, are hydrogen; Ci~C6 alkyl;
benzyl; pyridinyl; Ci~C6 alkyl which is substituted by
pyridine or ^—' ; carbonyl which is substituted by pyridine or QL~C6 alkyl; Ci~Cg alkanesulfonyl; Ci~C6 alkyl which is
substituted by hydroxy or Ci~C6 alkoxy; acetyl which is
substituted by hydroxy or Ci-Cβ alkoxy;
Y is oxygen; sulfur; NRε; CH2;
Xi and X3, each independently, are oxygen; sulfur; NH;
N-C1-C6 alkyl;
X2 is C3-C7 alkylene; C1-C3 alkylene-alkenylene-Ci-C3-
alkylene; C1-C3 alkylene-0-Ci-C3 alkylene; C1-C3 alkylene-NH-
C1-C3 alkylene; C1-C3 alkylene-phenylene-Ci-C3 alkylene; C1-C3
alkylene-pyridylene-Ci-C3 alkylene; C1-C3 alkylene-naphtylene-
C1-C3 alkylene; C3-C7 alkylene which is substituted by C1-C3
alkyl or hydroxy; C3-C7 alkylenecarbonyl; C3-C7 alkylene which
is interrupted by piperazine; or pharmaceutically acceptable
salts thereof.
3. The compound according to claim 2, wherein
R1 is methyl; ethyl; propyl; isopropyl; butyl; t-butyl;
pentyl; cyclopentyl; hexyl; cyclohexyl; phenyl; aminomethyl;
aminoethyl; amino; isobutylamide; guanidine; 1-propyl- piperidino; 2-morpholinomethyl; NR6R7; CH2NReR7;
Figure imgf000142_0001
wherein A is Ci~C6 alkyl and n is an integer of 2 to 6; pyridinyl; 4-hydroxypiperidinomethyl; cyclohexylaminomethyl;
R2 is hydrogen; methyl; ethyl; isopropyl; propyl; butyl; isobutyl; methoxymethyl; hydroxymethyl; 2- methylpropyl; pentyl; chloromethyl; chloroethyl; cyclopentyl;
cyclopentylmethyl; cyclohexyl; benzyl; vinyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; cyclohexylamino; methoxy; C1-C4 alkanoyloxy; Ci-C7 aliphatic alkoxy which is substituted by carboxy, esterified carboxy or amidated carboxy;
R5 is hydrogen or hydroxy;
Re and R7, each independently, are hydrogen; methyl; ethyl; propyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2- morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; methoxyethyl; hydroxyethyl; hydroxyacetyl; methoxyacetyl;
Y is oxygen; sulfur; NR6; CH2;
Xi and X3, each independently, are oxygen; sulfur; amine; methylamine;
X2 is propylene; butylene; pentylene; hexylene; heptylene; ethylene-O-ethylene; 3-hydroxy-3-methyl-pentylene; methylethylene-NH-ethylene; ethylene-NH-ethylene; propylene which is interrupted by piperazine; butylene carbonyl; 2- butenyl; methylene-phenylene-methylene; methylene-pyridylene- methylene; 1,2-ethylene-l,4-phenylene-l,2-ethylene; 1,3- propylene-lf 4-phenylene-l,3-propylene; 1,2-ethylene- naphthalene-1,2-ethylene/ or pharmaceutically acceptabel salts thereof.
4. The compound according to claim 3, wherein
Ri is methyl; ethyl; isopropyl; cyclohexyl; phenyl; aminomethyl; aminoethyl; amino; pyridinyl; NReR7;
CH2NR6R7;
Figure imgf000143_0001
or wherein A is Ci~C2 alkyl and n is an integer of 4 to 5;
R2 is hydrogen; methyl; ethyl; isopropyl; isobutyl; methoxymethyl; hydroxymethyl; chloromethyl; chloroethyl; cyclopentyl; cyclopentylmethyl; vinyl;
R3 and R4, each independently, are hydrogen; halogen; hydroxy; methoxy;
R5 is hydrogen or hydroxy; ,
Re and R7, each independently, are hydrogen; methyl; ethyl; benzyl; pyridin-3-yl; pyridin-4-yl; 2-morpholinoethyl; 4-pyridinylcarbonyl; 3-pyridinylcarbonyl; isobutylcarbonyl; ethanesulfonyl; hydroxyethyl; methoxyethyl; Y is oxygen; sulfur; methylamine; Xi and X3, each independently, are oxygen; sulfur; amino; methylamine;
X2 is propylene; butylene; pentylene; hexylene; ethylene-O-ethylene; ethylene-NH-ethylene; butylenecarbonyl; 2-butenyl; methylene-l,2-phenylene-methylene; methylene-1,3- phenylene-methylene; methylene~l,4-phenylene-methylene; methylene-pyridinyl-methylene; pharmaceutically acceptable salts thereof.
5. The compound according to claim 1, wherein pharmaceutically acceptable salt is hydrogen chloride salt or methanesulfonic acid salt.
6. The compound according to claim 1 which is selected from the group consisiting of
1) N-hydroxy-4-5-[4-(2-isopropyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
2) 4-5-[4-(2-isopropyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 3) N-hydroxy-4-5-[4-(2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
4) N-hydroxy-4-5-[4-(2-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 5) N-hydroxy-4-5-[4-(2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, β) N-hydroxy-4-5-[4-(2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 7) N-hydroxy-4-5-[4-(2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
8) N-hydroxy-4-5-[4-(2-cyclohexyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
9) N-hydroxy-4-5-[4-(2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
10) N-hydroxy-4-5-[4-(2,5-dimethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
11) N-hydroxy-4-5-[4-(2-ethyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 12) N-hydroxy-4-5-[4-(5-methyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
13) N-hydroxy-4-5-[4-(5~methyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
14) N-hydroxy-4-5-[4-(2-cyclohexyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
15) N-hydroxy-4-5-[4-(5-methyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 16) N-hydroxy-4-5-[4-(2-t-butyl-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
17) N-hydroxy-4-5-[4-(5-ethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 18) N-hydroxy-4-5-[4-(2,5-diethyl-l,3~thiazol-4- yl)phenoxy]pentoxy-benzamidine,
19) N-hydroxy-4-5-[4-(5-ethyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
20) N-hydroxy-4-5-[4-(5-ethyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
21) N-hydroxy-4-5-[4-(5-ethyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
22) N-hydroxy-4-5-[4-(2-cyclohexyl-5-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 23) N-hydroxy-4-5-[4-(5-ethyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
24) N-hydroxy-4-5-[4-(2-ethyl-5-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
25) N-hydroxy-4-5-[4-(2,5-diisopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
26) N-hydroxy-4-5-[4-(5-isopropyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 27) N-hydroxy-4-5-[4-(5-isopropyl-2-pyridin-3-yl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
28) N-hydroxy-4-5-[4-(5-isopropyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 29) N-hydroxy-4-5-[4-(2-methyl-5-propyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
30) N-hydroxy-4-5-[4-(5-butyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
31) N-hydroxy-4-5-[4-(5-butyl-2-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
32) N-hydroxy-4-5-[4-(5-butyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
33) N-hydroxy-4-5-[4-(5-butyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 34) N-hydroxy-4-5-[4-(5-butyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
35) N-hydroxy-4-5-[4-(5-butyl-2-cyclohexyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
36) N-hydroxy-4-5-[4-(5-butyl-2-pentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
37) N-hydroxy-4-5-[4-(5-butyl-2-t-butyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 38) N-hydroxy-4-5-[4-(5-benzyl-2~methyl-l,3-thiazol~4- yl)phenoxy]pentoxy-benzamidine,
39) N-hydroxy-4-5-[4-(5-benzyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 40) N-hydroxy-4-5-[4-(5-benzyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
41) N-hydroxy-4-5-[4-(5-benzyl-2-pyridin-3-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
42) N-hydroxy-4-5-[4-(5-(2-chloro-ethyl)-2-methy1-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
43) N-hydroxy-4-5-[4-(5-cyclopentyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
44) N-hydroxy-4-5-[4-(5-isobutyl-2-methyl-lf3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 45) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
46) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
47) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-isopropyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
48) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-phenyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 49) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pyridin-3-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
50) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-cyclohexyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 51) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-pentyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
52) 4-5-[4-(2-methyl-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
53) 4-5-[4-(2-isopropyl-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
54) 4-5-[4-(2,5-dimethyl-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
55) 4-5-[4-(5-ethyl-2-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 56) 4-5-[4-(5-ethyl-2-phenyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
57) N-hydroxy-4-5-[4-(2-amino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
58) N-hydroxy-4-5-[4-(2-amino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
59) N-hydroxy-4-5-[4-(2-guanidino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 60) N-hydroxy-4-5-[4-(2-amino-5-ethyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
61) N-hydroxy-4-5-[4-(2-amino-5-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 62) N-hydroxy-4-5-[4-(2-guanidino-5-isopropyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
63) N-hydroxy-4-5-[4-(2-amino-5-butyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
64) N-hydroxy-4-5-[4-(5-butyl-2-guanidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
65) N-hydroxy-4-5-[4-(2-amino-5-benzyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
66) N-hydroxy-4-5-[4-(5-benzyl-2-guanidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 67) N-hydroxy-4-5-[4-(2-amino-5-cyclopentylmethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
68) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(1-propyl- piperidin-4-yl)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
69) N-hydroxy-4-5-[4-(2-(isobutyryl)amino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine
70) N-hydroxy-4-5-[4-(5-isopropyl-2-morpholinomethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 71) N-hydroxy-4-5-[4-(2~aminomethyl-5-benzyl-lf3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
72) N-hydroxy-4-5-[4-(5-methyl-2-(l-propyl-piperidin-4-yl)- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 73) N-hydroxy-4-5-[4-(5-isopropyl-2-aminomethyl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
74) N-hydroxy-4-5-[4-(5-vinyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
75) N-hydroxy-4-5-[4-(5-hydroxymethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
76) N-hydroxy-4-5-[4-(5-methoxymethyl-2-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
77) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-amino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine, 78) N-hydroxy-4-5-[4-(5-vinyl-2~amino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
79) N-hydroxy-4-5-[4-(5-vinyl-2-(pyridin-3-yl)-1,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
80) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-(pyridin-3-yl)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
81) N-hydroxy-4-5-[4-(2-amino-5-cyclopentyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 82) N-hydroxy-4-5-[4-(5-ethyl-2-aminomethyl-l,3-thiazol~4- yl)phenoxy]pentoxy-benzamidine,
83) N-hydroxy-4-5-[4-(5~isopropyl-2-(piperidin-3-yl)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 84) N-hydroxy-4-5-[4-(2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
85) N-hydroxy-4-5-[4-(2-ethanesulfonylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
86) N-hydroxy-4-5-[4-(5~methyl-2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
87) N-hydroxy-4-5-[4-(2-ethylamino-5-methyl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
88) N-hydroxy-4-5-[4-(5-methyl-2-propylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 89) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(3- pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
90) N-hydroxy-4-5-[4-(2-hydroxyacetylamino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 91) N-hydroxy-4-5-[4-(5-methyl-2-(4- pyridylcarbonyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 92) N-hydroxy-4-5-[4-(5-methyl-2-(3- pyridylcarbonyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 93) N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-methyl~l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
94) N-hydroxy-4-5-[4-(2-(2-methoxyethyl)amino-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 95) N-hydroxy-4-5-[4-(2-ethanesulfonylamino-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
96) N-hydroxy-4-5-[4-(5-ethyl-2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
97) N-hydroxy-4-5-[4-(5-ethyl-2-ethylamino-l,3-thiazol-4~ yl)phenoxy]pentoxy-benzamidine,
98) N-hydroxy-4-5-[4-(5-ethyl-2-propylamino-l,3-thiazol-4~ yl)phenoxy]pentoxy-benzamidine,
99) N-hydroxy-4-5-[4-(5-ethyl-2-methoxyacetylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 100) N-hydroxy-4-5-[4-(5-ethyl-2-(4-ρyridylcarbonyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
101) N-hydroxy-4-5-[4-(5-ethyl-2-(3-ρyridylcarbonyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
102) N-hydroxy-4-5-[4-(5-ethyl-2-(2-methoxyethyl)amino-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
103) N-hydroxy-4-5-[4-(5-isopropyl-2-methylamino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine, 104) N-hydroxy-4-5-[4-(2-ethylamino-5-isopropyl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
105) N-hydroxy-4-5-[4-(5-butyl-2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 106) N-hydroxy-4-5-[4-(5-butyl-2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
107) N-hydroxy-4-5-[4-(5-benzyl-2~methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
108) N-hydroxy-4-5-[4-(5-benzyl-2-ethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
109) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-methylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
110) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-ethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 111) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-propylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
112) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(4- pyridylcarbonyl)amino-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 113) N-hydroxy-4-5-[4-(5-cyclopentyl-2-propylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
114) N-hydroxy-4-5-[4-(5-isopropyl-2-[ (pyridin-3-yl- methyl)amino]-I13-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 115) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-methylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
116) N-hydroxy-4-5-[4-(2-methylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 117) N-hydroxy-4-5-[4-(5-ethyl-2-[ (pyridin-3-yl-methyl)amino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
118) N-hydroxy-4-5-[4-(2-(ethanesulfonyl-methyl-arαino)-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
119) N-hydroxy-4-5-[4-(2-methyl-(2-morpholinoethyl)amino-1,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
120) N-hydroxy-4-5-[4-(2-(2-hydroxyethyl)-methyl-amino-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
121) N-hydroxy-4-5-[4-(2-(ethyl-(2-hydroxyethyl)-amino)-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 122) N-hydroxy-4-5-[4-(2-(bis-(2-methoxyethyl)-amino)-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 123) N-hydroxy-4-5-[4-(5-methyl-2-(methyl-(2- morpholinoethyl)-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 124) N-hydroxy-4-5-[4-(2-(ethyl-1-(2-morpholinoethyl)-amino)- 5-methyl-l,3-thiazol~4-yl)phenoxy]pentoxy-benzamidine, 125) N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 5 002545
126) N-hydroxy-4-5-[4-(5-methyl-2-(methyl-pyridin-3-yl- methy1-amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
127) N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-methyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 128) N-hydroxy-4-5-[4-(2-(bis-(2-hydroxyethyl)-amino)-5- methyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
129) N-hydroxy-4-5-[4-(5-ethyl-2-( (2-hydroxyethyl)-methyl- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
130) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-hydroxyethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
131) N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(2-morpholinoethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
132) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(2-morpholinoethyl)- amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 133) N-hydroxy-4-5-[4-(2-(benzyl-methyl-amino)-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
134) N-hydroxy-4-5-[4-(5-ethyl-2-(methyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
135) N-hydroxy-4-5-[4-(2-(benzyl-ethyl-amino)-5-ethyl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
136) N-hydroxy-4-5-[4-(5-ethyl-2-(ethyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 137) N-hydroxy-4-5-[4- (2- (bis- (pyridin-3-yl-methyl)amino)-5- ethyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
138) N-hydroxy-4-5-[4- (2~dipropylamino-5-ethyl-l,3~thiazol-4- yl)phenoxy]pentoxy-benzamidine, 139) N-hydroxy-4-5-[4- (2- (bis- (2-hydroxyethyl)amino)-5-ethyl- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
140) N-hydroxy-4-5-[4- (2- ( (2-hydroxyethyl)-methyl-amino)-5- isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
141) N-hydroxy-4-5-[4- (5-isopropyl-2- (methyl-(pyridin-3-yl- methyl)amino) -1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
142) N-hydroxy-4-5- [4- (2- (ethanesulfonyl-methyl-amino)-5- isopropyl-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
143) N-hydroxy-4-5-[4- (5-butyl-2~( (2-hydroxyethyl)-methyl- amino) -1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 144) N-hydroxy-4-5-[4- (5-butyl-2- (methyl-(2- morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
145) N-hydroxy-4-5-[4-(5-butyl-2-(methyl-(pyridin-3-yl- methyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine, 146) N-hydroxy-4-5-[4-(5-butyl-2-dipropylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 147) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl- (pyridin-3-yl-methyl)amino)-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
148) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-(methyl-(2- morpholinoethyl)amino)-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
149) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dipropylamino- l,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
150) N-hydroxy-4-5-[4-(5-butyl-2-diethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
151) N-hydroxy-4-5-[4-(5-butyl-2-ethylmethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
152) N-hydroxy-4-5-[4-(5-butyl-2-dimethylamino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 153) N-hydroxy-4-[5-(4-5-cyclopentyl-2-[methyl-(2- morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
154) N-hydroxy-4-[5-(4-5-isobutyl-2-[methyl-(2- morpholinoethyl)amino]-l,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine,
155) N-hydroxy-4-5-[4-(5-(2-chloroethyl)-2-dimethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 2005/002545
156) N-hydroxy-4-5-[4-(5-cyclopentyl-2-diethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
157) N-hydroxy-4-5-[4-(5-isopropyl-2-dipropylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine, 158) N-hydroxy-4-5-[4-(5-ethyl-2-diethylamino-l,3-thiazol~4-- y1)phenoxy]pentoxy-benzamidine,
159) N-hydroxy-4-[5-(4-5-isopropyl-2-[methyl-(2- morpholinoethyl)amino]-1,3-thiazol-4-yl)phenoxy]pentoxy- benzamidine, 160) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-diethylamino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
161) N-hydroxy-4-5-[4-(5-isopropyl-2-dimethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
162) N-hydroxy-4-5-[4-(5-isopropyl-2-diethylamino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
163) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-dimethylamino- 1,3-thiazol-4-yl)phenoxy]pentoxy-benzamidine,
164) N-hydroxy-4-5-[4-(5-methyl-2-piperidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 165) N-hydroxy-4-5-[4-(5-methyl-2-morpholino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine,
166) N-hydroxy-4-5-[4-(5-ethyl-2-piperidino-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 167) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-piperidino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
168) N-hydroxy-4-5-[4-(5-cyclopentylmethyl-2-morpholino-l,3- thiazol-4-yl)phenoxy]pentoxy-benzarαidine, 169) N-hydroxy-4-5-[4-(5-isopropyl-2-morpholino-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine
170) N-hydroxy-4-5-4-[5-cyclopentylmethyl-2-(4- methylpiperazino)-1,3-thiazol-4-yl]phenoxy-pentoxy- benzamidine, 171) N-hydroxy-4-5-[4-(5-vinyl-2- morpholin-4-yl-l,3-thiazol- 4-yl)phenoxy]pentoxy-benzamidine,
172) N-hydroxy-4-5-[4-(5-cyclopentyl-2- morpholin-4-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
173) N-hydroxy-4-5-[4-(5-isobutyl-2- morpholin-4-yl-l,3- thiazol-4-yl)phenoxy]pentoxy-benzamidine,
174) N-hydroxy-4-5-4-[5-ethyl-2-(4-methylpiperazino)-1,3- thiazol-4-yl]phenoxy-pentoxy-benzamidine,
175) N-hydroxy-4-5-[4-(2-morpholin-4-yl-l,3-thiazol-4- yl)phenoxy]pentoxy-benzamidine, 176) N-hydroxy-4-5-4-[5-isopropyl-2-(4-methylpiperazino)-1,3- thiazol-4-yl]phenoxy-pentoxy-benzamidine,
177) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]-pentylamino-benzamidine, 5 002545
178) N-hydroxy-4-2-[2-(4~(5-isoρropyl-2-methyl-l,3-thiazol-4-
yl)phenoxy)-ethoxy]-ethoxy-benzamidine,
179) N-hydroxy-4-3-hydroxy-5-[4-(5-isopropyl-2-methyl~l,3- thiazol-4-yl)-phenoxy]-3-methyl~pentoxy-benzamidine, 180) N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxy)-1-methyl-ethylamino]-ethoxy-benzamidine, 181) N-hydroxy-4-3-[4-(3-(4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl)-phenoxy)-propyl)-piperazin-1-yl]-propoxy- benzamidine, 182) N-hydroxy-4-5-[4-(5-isopropyl~2~methyl-l,3-thiazol-4- yl)-phenoxy]-pentanoyl-amino-benzamidine,
183) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4-
yl)-phenoxy]-pentyl-methyl-amino-benzamidine,
184) N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxy]-2-butenyloxy-benzamidine,
185) N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxymethyl]-benzyloxy-benzamidine,
186) N-hydroxy-4-2-[2-(4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy)-ethylamino]-ethoxy-benzamidine, 187) N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,
188) 2,N-dihydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol- 4-yl)-phenoxy]-pentoxy-benzamidine, 189) N-hydroxy-4-5-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)-phenoxy]-pentoxy-3~methoxy-benzamidine,
190) N-hydroxy-2-cyclohexylamino-4-5-[4-(5-isopropyl-2- methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine, 191) N-hydroxy-4-5-[3-fluoro-4-(5-isopropyl-2-methyl-l,3- thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,
192) N-hydroxy-2-fluoro-4-5-[3-fluoro-4-(5-isopropyl-2- methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy-benzamidine,
193) N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]propoxy-benzamidine,
194) N-hydroxy-4-4-[4-(5-isopropyl-2-methyl-l,3-thiazol-4- yl)phenoxy]butoxy-benzamidine,
195) N-hydroxy-3-5-[4-(5-isopropyl-2-methyl-thiazol-4-yl)- phenoxy]-pentylamino-benzamidine, 196) N-hydroxy-4-4-[4-(2-cyclohexyl-5-ethyl-thiazol-4-yl)- phenoxy]-butoxy-benzamidine,
197) N-hydroxy-4-[5-(4-5-ethyl-2-[ (2-hydroxyethyl)-methyl- amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine,
198) N-hydroxy-4-[5-(4-5-ethyl-2-[ (2-hydroxyethyl)-methyl- amino]-thiazol-4-yl)phenoxy]butoxy-benzamidine,
199) N-hydroxy-4-[5-(4-5-ethyl-2-[methyl-(pyridin-3-yl- methyl)amino]-thiazol-4-yl)phenoxy]propoxy-benzamidine, 200) N-hydroxy-4-[5-(4-5~ethyl-2-[methyl-(pyridin-3-yl- methyl)amino]-thiazol-4-yl)phenoxγ]butoxy-benzamidine,
201) N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-isopropyl- thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine, 202) N-hydroxy-4-4-[4-(5-butyl-2~isopropyl-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
203) N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4- yl)-phenoxymethyl]-benzyloxy-benzamidine,
204) N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-amino-thiazol-4- yl)-phenoxymethyl]-benzyloxy-2-fluoro-benzamidine,
205) N-hydroxy-4-4-[4-(2-methylamino-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
206) N-hydroxy-4-6-[4-(5-isopropyl-2-methyl-thiazol-4~yl)- phenoxymethyl]-pyridin-2-yl-methoxy-benzamidine, 207) N-hydroxy-2-fluoro-4-5-[4-(5-isopropyl-2-methyl-thiazol- 4-yl)-phenoxy]-butoxy-benzamidine,
208) N-hydroxy-4-2-[4-(5-isopropyl-2-methyl-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
209) N-hydroxy-4-3-[4-(5-isopropyl-2-methyl-thiazol-4-yl)- phenoxymethyl]-benzyloxy-benzamidine,
210) N-hydroxy-4-4-[4-(5-cyclopentylmethyl-2-cyclohexyl- thiazol-4-yl)-phenoxymethyl]-benzyloxy-benzamidine, R2005/002545
211) N-hydroxy-4-β-[4-(5-isopropyl-2-methyl~thiazol-4- yl)phenoxy]-hexyloxy-benzamidine,
212) N-hydroxy-4-5-[2-ethyl-5-hydroxy-4-(2-methyl-thiazol-4-
yl)phenoxy]-pentyloxy-benzamidine, and 213) N-hydroxy-4-5-[2-ethyl-4-(2-methyl-thiazol-4-yl)-5- propoxy-phenoxy]-pentyloxy-benzamidine; or pharmaceutically acceptable salts thereof.
7. A process for producing a compound of the formula Ia or pharmaceutically acceptable salts thereof which comprises the steps of
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4, 2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8, 3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step
2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9, 4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10,
5) reacting α-brominated compound of the formula 10 prepared in step 4) with thioamide compound of the formula 11 to prepare benzonitrile derivatives with thiazole ring of the formula 12, and
6) reacting the compound of the formula 12 prepared in step 5) with amine compound to prepare benzamidine derivatives of the formula Ia.
Figure imgf000165_0001
Formula 2
Figure imgf000165_0002
Formula
Br~X2-Br(orCl) Fformula 4
Figure imgf000166_0001
Formula 5
Figure imgf000166_0002
Formula 6 o
R2.
Cl
Formula 7
Figure imgf000166_0003
Figure imgf000166_0004
Formula 9
Figure imgf000167_0001
Formula 10
Figure imgf000167_0002
Formula 11
Figure imgf000167_0003
Figure imgf000167_0004
wherein
Ri is C1~C6 alkyl; pyridine-substituted C1-C6 alkyl; C3-C6 cycloalkyl; benzyl; phenyl; amino; guanidino; pyridinyl;
C1~C6 alkyl-substituted pyridinyl; or wherein A is
Figure imgf000167_0005
C1~C6 alkyl and n is integer of 2 to 6; and R2, R3, R4, R5, X1 ,
X2 and X3 are defined in claim 1 .
8. A process for producing a compound of the formula Ib or pharmaceutically acceptable salts thereof which comprises the steps of 1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9,
4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10, 5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14, 6) reacting the compound of the formula 14 prepared in step 5) with halide compound of the formula 15 to prepare benzonitrile derivatives with thiazole ring substituted with primary amine of the formula 16, and
7) reacting the compound of the formula 16 prepared in step β) with amine compound to prepared benzamidine derivatives of the formula Ib.
Figure imgf000169_0001
Formula 3
Br-X2~Br(or Cl]
Formula 4 Cl)
Figure imgf000169_0003
Formula 5
Figure imgf000170_0001
Formula 6 o
R2. Cl
Figure imgf000170_0002
Formula 8
Figure imgf000170_0003
Figure imgf000170_0004
Formula 10
Figure imgf000171_0001
Formula 13
Figure imgf000171_0002
Formula 14
Figure imgf000171_0003
Formula 15
RgC!(or Br)
Formula 16
Figure imgf000171_0004
wherein R2, R3, R-a, R5, Re, Xi/ X2 and X3 are defined in claim 1 and n is an integer of 0 to 6, with the proviso that Rβ is not hydrogen
9. A process for producing a compound of the formula Ic or pharmaceutically acceptable salts thereof which comprises the steps of
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9, 4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10, 5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14,
6) reacting the compound of the formula 14 prepared in step 5) with halide compound of the formula 15 to prepare benzonitrile derivatives with thiazole ring substituted with primary amine of the formula 16,
7) reacting the compound of the formula 16 prepared in step 6) above with a compound of the formula 17 to prepare benzonitrile derivatives with thiazole ring substituted with secondary amine of the formula 18, and
8) reacting the compound of the formula 18 prepared in step 7) with amine compound to prepare benzamidine derivatives of the formula Ic.
Formula Ic
Figure imgf000173_0001
Formula 2
Figure imgf000174_0001
Formula 3
Br-X2-Br(OrCl)
Formula 4
Figure imgf000174_0002
Formula 5
Figure imgf000174_0003
Formula 6 o
R2.
Cl
Formula 7
Figure imgf000174_0004
Formula 8
Figure imgf000175_0001
Figure imgf000175_0002
Formula 10
Figure imgf000175_0003
Formula 13
Figure imgf000175_0004
Formula 14
Figure imgf000175_0005
Formula 15
R6CI(Or Br)
Formula 16
Figure imgf000176_0001
Formula 17
R7 Cl<or Br)
Formula 18
Figure imgf000176_0002
wherein 1*2/ R3/ Rj/ R5/ Re, R7/ Xi/ X2 and X3 are defined in claim 1 and n is integer of 0 to 6, with the proviso that RQ , R7 and both of them are not hydrogen.
10. A process for producing a compound of the formula Id or pharmaceutically acceptable salts thereof which comprises the steps of
1) reacting a compound of the formula 2 with a compound of the formula 3 in the presence of inorganic base to prepare a compound of the formula 4,
2) reacting a compound of the formula 5 with acid chloride of the formula 6 in the presence of inorganic acid to prepare phenone of the formula 7, and reacting the phenone of the formula 7 with acid to prepare a compound of the formula 8,
3) reacting the compound of the formula 4 prepared in step 1) with the compound of the formula 8 prepared in step 2) in the presence of inorganic base to prepare benzonitrile derivatives of the formula 9, 4) reacting the compound of the formula 9 prepared in step 3) with brominating agent to prepare α-brominated compound of the formula 10, 5) reacting α-brominated compound of the formula 10 prepared in step 4) with thiourea of the formula 13 to prepare benzonitrile derivatives with aminothiazole ring of the formula 14,
6) reacting the compound of the formula 14 prepared in step 5) with the compound of which both terminals are halogenated of the formula 19 to prepare benzonitrile derivatives with thiazole ring substituted with hetero atom ring of the formula 20, and
7) reacting the compound of the formula 20 prepared in step 6) with amine compound to prepare benzamidine derivatives of the Formula Id.
Figure imgf000178_0001
Formula 2
Figure imgf000178_0002
Formula 3 Br-X2-Br(OrCl)
Formula 4 Cl)
Figure imgf000179_0001
Formula 5
Figure imgf000179_0002
Formula 6
Figure imgf000179_0005
Figure imgf000179_0003
Formula
Figure imgf000179_0004
Figure imgf000180_0001
Fformula 10
Figure imgf000180_0002
Formula 13
Figure imgf000180_0004
Formula 14
Figure imgf000180_0003
Formula 19
Figure imgf000180_0005
Formula 20
Figure imgf000181_0001
wherein R2, R3, R4, R5, Xi, X2 and X3 are defined in claim 1 and n is
integer of 0 to 6.
11. The process according to claim 7 wherein the compound of
the formula 11 is selected from the group consisting of
thioacetamide, thiopropionamide, thioisobutramide,
trimethylthioacetamide, thiohexanoylamide,
cyclohexanecarbothioic acide amide, and piperidin-4-
carbothioic acid amide.
12. The process according to claim 8 or 9 wherein the halide
compound of the formula 15 and 17 is selected from the group
consisting of iodomethane, iodoethane, propyl bromide, 2-
chloroethyl methyl ether, 2-chloroethylmorpholine, 3-
bromomethylpyridine, 2-bromoethanol, niconoyl chloride,
benzyl bromide, nicotinoyl chloride, ethanesulfonyl chloride
and isoniconoyl chloride.
13. The process according to claim 10, wherein the compound of which both terminals are halogenated of the formula 19 is mechloethylamine, dibromoethylether or dibromopentane.
14. The process according to any one of claims 7 to 10, wherein, in the conversion of benzonitrile into benzamidine, where R5 is OH, hydroxylamine hydrochloride is used as amine; and the amine is reacted in the presence "of a base, wherein the base is organic bases selected from triethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, DBU, diethylmethylamine (Et2NMe) , N-methylmorpholine, N- methylpiperidine, pyridine and 2,β-dimethylpyridine, or inorganic bases selected from potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, sodium methoxide and sodium ethoxide, at a temperature of 60 to 80°Cfor 1 to 9 hours in methanol, ethanol, acetonitrile or its mixture with water.
15. The process according to any one of claims 7 to 10 wherein, in the conversion of benzonitrile into benzamidine, where R5 is H, methoxy imine prepared from hydrochoride methanol solution at a temperature of 10 to 30"Cfor 24 to 48 hours, is reacted with ammonia ethanol solution at a temperature of 45 to 60°Cfor 24 to 50 hours.
16. A pharmaceutical composition for the prevention and treatment of osteoporosis comprising the compound of the formula 1 according to claim 1 or phamceutical acceptable salts thereof.
17. A pharmaceutical composition for the prevention and treatment of bone fracture comprising the compound of the formula 1 according to claim 1 or phamceutical acceptable salts thereof.
18. A pharmaceutical composition for the prevention and treatment of allergic inflammatory diseases comprising the compound of the formula 1 according to claim 1 or pharmaceutical acceptable salts thereof.
19. The pharmaceutical composition according to claim 18 wherein allergic inflammatory disease is asthma.
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US8741960B2 (en) 2006-01-25 2014-06-03 Synta Pharmaceuticals Corp. Substituted aromatic compounds for inflammation and immune-related uses
WO2007089101A1 (en) 2006-01-31 2007-08-09 Dong Wha Pharmaceutical Ind.Co., Ltd. Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same
JP2009525321A (en) * 2006-01-31 2009-07-09 ドン ファ ファーマシューティカル インダストリー カンパニー リミテッド NOVEL BENZAMIDINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
US7943646B2 (en) 2006-01-31 2011-05-17 Dong Wha Pharmaceutical Co., Ltd. Benzamidine derivative, process for the preparation thereof and pharmaceutical composition comprising same
WO2009017346A1 (en) * 2007-07-27 2009-02-05 Dong Wha Pharmaceutical Co., Ltd. Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition for preventing or treating osteoporosis comprising the same
JP2010534648A (en) * 2007-07-27 2010-11-11 ドン ファ ファーマシューティカル カンパニー リミテッド NOVEL BENZAMIDINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATMENT OF OSTEOPOROSIS CONTAINING THE SAME
AU2008283211B2 (en) * 2007-07-27 2011-04-07 Dong Wha Pharmaceutical Co., Ltd. Novel benzamidine derivatives, process for the preparation thereof and pharmaceutical composition for preventing or treating osteoporosis comprising the same
JP5379690B2 (en) * 2007-09-28 2013-12-25 武田薬品工業株式会社 5-membered heterocyclic compounds
US8008329B2 (en) * 2008-08-01 2011-08-30 Dong Wha Pharmaceutical Co., Ltd. Method of treating or preventing osteoporosis comprising administering to a patient in need thereof an effective amount of pharmacuetical composition comprising benzamidine derivative or it's salt, and bisphosphonate
WO2010064769A1 (en) * 2008-12-05 2010-06-10 한국화학연구원 2-piperazino-4,5-double substitution-1,3-thiazole derivative and method of preparing the same, and therapeutic agent containing the same as its active ingredient for diseases related to inflammation caused by spc receptor activity

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KR20060017929A (en) 2006-02-28
CA2576065C (en) 2012-05-15
JP2011026334A (en) 2011-02-10
KR100705875B1 (en) 2007-04-10
JP4990135B2 (en) 2012-08-01
EP1781629A1 (en) 2007-05-09
CA2576065A1 (en) 2006-02-09
EP1781629A4 (en) 2009-12-30
JP2008509134A (en) 2008-03-27
US20100240890A1 (en) 2010-09-23
KR20060049301A (en) 2006-05-18
IL181022A0 (en) 2007-07-04
BRPI0514111B1 (en) 2021-02-09
IL181022A (en) 2013-01-31
EP1781629B1 (en) 2015-07-29
BRPI0514111A (en) 2008-05-27
BRPI0514111B8 (en) 2021-05-25
ZA200700397B (en) 2007-11-28
JP5351117B2 (en) 2013-11-27
AU2005267950A1 (en) 2006-02-09
CN101010308A (en) 2007-08-01
US8178688B2 (en) 2012-05-15
ES2549263T3 (en) 2015-10-26
AU2005267950B2 (en) 2009-10-01

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