US20100291533A1 - Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect - Google Patents

Indole and indazole derivatives having a cell-, tissue- and organ-preserving effect Download PDF

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US20100291533A1
US20100291533A1 US12/811,525 US81152509A US2010291533A1 US 20100291533 A1 US20100291533 A1 US 20100291533A1 US 81152509 A US81152509 A US 81152509A US 2010291533 A1 US2010291533 A1 US 2010291533A1
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indole
methyl
phenyl
amine
dihydro
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Soon Ha Kim
Hyoung Jin Kim
Chul Woong Chung
Heui Sul Park
Hyo Shin Kwak
Sung Ho Kim
Jin Gu Park
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LG Chem Ltd
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LG Life Sciences Ltd
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Assigned to LG LIFE SCIENCES LTD. reassignment LG LIFE SCIENCES LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHUNG, CHUL WOONG, KIM, HYOUNG JIN, KIM, SOON HA, KIM, SUNG HO, KWAK, HYO SHIN, PARK, HEUI SUL, PARK, JIN GU
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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
    • C07D417/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention relates to a composition for preserving cells, tissues or organs of animals comprising an indole or indazole compound of formula (1) or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient, a preservation method by using the same and a method for preparing the same.
  • the indole and indazole compounds according to the present invention are effective in protecting cells, tissues and organs of animals to be transplanted and preventing their injury caused during transportation or storage.
  • the indole and indazole compounds according to the present invention protect organs from injury of tissues or organs caused by reperfusion after transplantation.
  • low temperature storage (below 20 ⁇ , typically below 4 ⁇ ) is utilized to preserve organs, which inhibits metabolism rather than provides appropriate physiological conditions in vivo.
  • a various kind of preserving solutions for such method have been developed and used clinically.
  • Indole and indazole compounds according to the present invention have a very suitable structure to medical purpose, and a number of researches on compounds having an indole core structure have been published. For example, their activities to glucokinase (WO2006/112549), usefulness as anti-cancer drug and cardiovascular angiogenesis inhibitor (WO95/07276) and as antibiotics (WO2004/018428) are representatively known.
  • indole and indazole derivatives represented by the following formula (1) show remarkable effects as described below.
  • Indole and indazole compounds according to the present invention have been already disclosed and claimed in Korean Patent Application Nos. 10-2007-0082687, 10-2008-0080519 and 10-2008-0080537, which were filed by the present applicant.
  • the present invention provides a composition for preserving cells, tissues or organs of animals comprising an indole or indazole compound represented by formula (1) or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient, with a pharmaceutically acceptable carrier.
  • the present invention also provides a preparation method of a composition for preserving cells, tissues or organs of animals, specifically for preventing injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion, said method comprising a step of mixing a compound represented by formula (1) or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient, together with a pharmaceutically acceptable carrier.
  • the present invention also provides a method of using the composition according to the present invention comprising a compound represented by formula (1) or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient, for preserving cells, tissues or organs of animals for transplantation.
  • composition of the present invention uses an indole or indazole compound represented by the following formula (1), or a pharmaceutically acceptable salt or isomer thereof as an effective ingredient:
  • X represents C or N
  • n is 0 or 1, and n is 1 when X is C and n is 0 when X is N,
  • A represents a direct bond, C 3 -C 8 -cycloalkyl, phenyl, or 5 ⁇ 6-membered heteroaryl or heterocycle, each of which includes 1 ⁇ 3 heteroatoms selected from N, O and S atoms,
  • R1 represents hydrogen, —C(O)—B—X′—R7 or —(CR5R6) m -B—X′—R7,
  • n is an integer of 0 to 4
  • each of R5 and R6 independently represents hydrogen or C 1 -C 5 -alkyl
  • B represents a direct bond, C 3 -C 8 -cycloalkyl optionally containing oxo, or 3 ⁇ 10-membered heterocycle or heteroaryl, each of which includes 1 ⁇ 3 heteroatoms selected from O, S and N atoms,
  • X′ represents a direct bond, —C(O)—, —SO 2 —, —CO 2 — or —C(O)NR5-,
  • R7 represents hydrogen, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogen, (CR5R6) m -phenyl, (CR5R6) m -hydroxy or (CR5R6) m -heterocycle where the heterocycle optionally contains oxo and is a 3 ⁇ 10-membered ring including 1 ⁇ 3 heteroatoms selected from N, O and S atoms,
  • R2 represents —(CR5R6) m -D-X′′—R8,
  • D represents a direct bond or a 3 ⁇ 10-membered heterocycle or heteroaryl, each of which optionally contains oxo and is optionally fused, and includes 1 ⁇ 4 heteroatoms selected from N, O and S atoms,
  • X′′ represents a direct bond, —C(O)—, —C(O)O—, —NR5C(O)—, —C(O)NR5- or —O—,
  • R8 represents hydrogen, halogen, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, tri(C 1 -C 6 -alkyl)silane or hydroxy-C 1 -C 6 -alkyl,
  • R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) m -D-R9,
  • R9 represents hydrogen, halogen, C 1 -C 6 -alkyl, cyano, nitro or C 1 -C 6 -alkoxy,
  • R4 represents —(CR5R6) m —Y-D-R10,
  • Y represents a direct bond, —C(O)O— or —O—
  • R10 represents hydrogen, nitro, halogen, C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, aryl or —C(O)O—R5,
  • each of said alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitrile, amino, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, C 1 -C 6 -alkylsulfonyl, aryl-C 1 -C 6 -alkoxy and oxo.
  • alkyl means an aliphatic hydrocarbon radical.
  • Alkyl may be a “saturated alkyl” not including alkenyl or alkynyl moiety, or “unsaturated alkyl” including at least one alkenyl or alkynyl moiety.
  • Alkenyl means a group having at least one carbon-carbon double bond and “alkynyl” means a group having at least one carbon-carbon triple bond.
  • Alkyl may be a branched or straight chain when used alone or in combination with alkoxy.
  • Alkyl may have 1 ⁇ 20 carbon atoms unless defined otherwise herein.
  • Alkyl may be a medium-sized alkyl having 1 ⁇ 10 carbon atoms.
  • Alkyl may be a lower alkyl having 1 ⁇ 6 carbon atoms.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, etc.
  • C 1 -C 4 -alkyl has 1 ⁇ 4 carbon atoms in alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • alkoxy means alkyloxy having 1 ⁇ 10 carbon atoms unless defined otherwise herein.
  • cycloalkyl means saturated aliphatic 3 ⁇ 10-membered cycle unless defined otherwise herein.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Aryl includes at least one ring having shared pi electron system, for example, monocyclic or fused-polycyclic groups (i.e., rings sharing adjacent carbon pairs).
  • aryl used herein means 4 ⁇ 10-membered, preferably 6 ⁇ 10-membered aromatic monocyclic or multicyclic ring and includes, for example, phenyl and naphtyl.
  • heteroaryl means 3 ⁇ 10-membered, preferably 4 ⁇ 8-membered, more preferably 5 ⁇ 6-membered aromatic ring, which includes 1 ⁇ 3 heteroatoms selected from N, O and S atoms and may be fused with benzo or C 3 -C 8 cycloalkyl, unless defined otherwise herein.
  • Examples of monocyclic heteroaryl include, but are not limited to, thiazole, oxazole, thiophene, furan, pyrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine and analogs thereof.
  • bicyclic heteroaryl examples include, but are not limited to, indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine and analogs thereof.
  • heterocycle means 3 ⁇ 10 membered, preferably 4 ⁇ 8-membered, and more preferably 5 ⁇ 6-membered ring which includes 1 ⁇ 3 heteroatoms selected from N, O and S atoms and may be fused with benzo or C 3 -C 8 -cycloalkylalkyl, and may be saturated or contain 1 or 2 double bonds.
  • heterocycle includes, but are not limited to, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyrane, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran, etc.
  • X represents C or N
  • n is 0 or 1, and n is 1 when X is C and n is 0 when X is N,
  • A represents a direct bond, phenyl, or 5 ⁇ 6-membered heteroaryl or heterocycle, each of which includes 1 ⁇ 3 heteroatoms selected from N, O and S atoms,
  • R1 represents hydrogen, —C(O)—B—X′—R7 or —(CR5R6) m -B—X′—R7,
  • n is an integer of 0 to 2
  • each of R5 and R6 independently represents hydrogen or C 1 -C 5 -alkyl
  • B represents a direct bond, C 4 -C 7 -cycloalkyl optionally containing oxo and optionally substituted with halogen, or 4 ⁇ 8-membered heterocycle or heteroaryl, each of which includes 1 ⁇ 3 heteroatoms selected from O, S and N atoms,
  • X′ represents a direct bond, —C(O)—, —SO 2 —, —CO 2 — or —C(O)NH—,
  • R7 represents hydrogen, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, halogen, (CR5R6) m -phenyl, (CR5R6) m -hydroxy or (CR5R6) m -heterocycle where the heterocycle optionally contains oxo and is a 4 ⁇ 8-membered ring including 1 ⁇ 3 heteroatoms selected from N, O and S atoms,
  • R2 represents —(CR5R6) m -D-X′′—R8,
  • D represents a direct bond or a 4 ⁇ 8-membered heterocycle or heteroaryl, each of which optionally contains oxo and is optionally fused, and includes 1 ⁇ 4 heteroatoms selected from N, O and S atoms,
  • X′′ represents —C(O)—, —C(O)O—, —NR5C(O)—, —C(O)NR5- or —O—,
  • R8 represents hydrogen, halogen, C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl, tri(C 1 -C 6 -alkyl)silane or hydroxy-C 1 -C 6 -alkyl,
  • R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) m -D-R9,
  • R9 represents hydrogen, halogen, C 1 -C 6 -alkyl, cyano, nitro or C 1 -C 6 -alkoxy,
  • R4 represents —(CR5R6) m —Y-D-R10,
  • Y represents a direct bond, —C(O)O— or —O—
  • R10 represents hydrogen, nitro, halogen, C 1 -C 6 -alkyl, carboxy-C 1 -C 6 -alkyl, aryl or —C(O)O—R5.
  • X is C or N and the compound structure for each case may be represented by the following formula (1a) or (1b), respectively.
  • the substituent A is more preferably selected from the group consisting of phenyl, pyridine, 1,4-pyrazine, 4,5-dihydro-thiazole, thiazole, 4,5-dihydrooxazole, [1,2,4]oxadiazole and [1,3,4]oxadiazole.
  • the substituent R1 represents —C(O)—B—X′—R7 or —(CHR5) m -B—X′—R7 where m is an integer of 0 to 2;
  • R5 represents C 1 -C 3 -alkyl;
  • B represents a direct bond, C 5 -C 6 -cycloalkyl optionally containing oxo, or 5 ⁇ 6-membered heterocycle or heteroaryl, each of which includes 1 ⁇ 3 heteroatoms selected from O, S and N atoms;
  • X′ represents a direct bond, —C(O)—, —SO 2 —, —CO 2 — or —C(O)NH—;
  • R7 represents hydrogen, C 1 -C 3 -alkyl, halogeno-C 1 -C 3 -alkyl, halogen, (CH 2 ) m -phenyl, (CH 2 ) m -hydroxy or (CH 2 ) m -hetero
  • B is most preferably selected from the group consisting of cyclopentyl, cyclohexyl, piperidine, tetrahydropyran, oxocyclohexyl, pyrrolidine, difluorocyclohexyl and tetrahydrofuran; and R7 is most preferably selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, benzyl, hydroxymethyl, (morpholine-4-yl)-ethyl, tetrahydrofuran, 2,2,2-trifluoroethyl, hydroxyethyl, 1,1-dioxothiomorpholine, tetrahydropyran, (tetrahydropyran-4-yl)-methyl and trifluoromethyl.
  • D represents a direct bond, or is selected from the group consisting of piperazine, pyrrolidine, morpholine, 1,1-dioxothiomorpholine and oxopiperazine; and R8 is more preferably selected from the group consisting of hydrogen, ethyl, hydroxymethyl, methyl and fluorine.
  • the substituent R3 represents hydrogen; halogen; phenyl optionally substituted with alkoxy; or 6-membered heterocyclylmethyl including 1 ⁇ 3 heteroatoms selected from N, S and O atoms as ring members and optionally containing oxo.
  • R3 is most preferably selected from the group consisting of hydrogen, bromine, phenyl, methoxy-phenyl, morpholine-4-yl-methyl, oxopiperazine-4-yl-methyl and 1,1-dioxo-thiomorpholine-4-yl-methyl.
  • the substituent R4 represents —(CH 2 ) m —Y-D-R10 where m is an integer of 0 to 2; Y represents a direct bond, —C(O)O— or —O—; D represents pyridine or 5 ⁇ 6-membered heterocycle including 1 ⁇ 3 heteroatoms selected from N, S and O atoms and optionally containing oxo; and R10 represents hydrogen, halogen, C 1 -C 3 -alkyl, —(CH 2 )—CO 2 H, aryl or —C(O)O—R5 where R5 represents hydrogen or C 1 -C 3 -alkyl.
  • D is most preferably selected from the group consisting of 1,1-dioxo-thio-morpholine, oxopiperazine, pyridine, morpholine and 4,5-dihydro-thiazole; and R10 is most preferably selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl and —(CH 2 )—CO 2 H.
  • the representative compounds of formula (1) according to the present invention include the following compounds:
  • the compound of formula (1) according to the present invention may also form pharmaceutically acceptable salts.
  • Such pharmaceutically acceptable salts include acid-addition salts formed by acid to form a non-toxic acid addition salt having pharmaceutically acceptable anion including, for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; organic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • carboxylic acid salts include alkali metal salts or alkali earth metal salts formed by lithium, sodium, potassium, calcium, magnesium and the like; amino acid salts of lysine, arginine, guanidine and the like; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine and the like.
  • the compound of formula (1) according to the present invention may be converted to its salt by conventional methods.
  • the compound according to the present invention can have asymmetric carbon center(s), and so can be present as R or S isomeric forms, racemates, diastereomeric mixtures, and individual diastereomers.
  • the present invention encompasses all of these isomeric forms and mixtures.
  • the present invention also provides a process for preparing the compound of formula (1).
  • the processes for the preparation of the compound of formula (1) are explained based on exemplary reaction schemes.
  • a person skilled in the art could prepare the compound of formula (1) according to various methods based on the structure of formula (1), and such methods are included in the scope of the present invention.
  • the compound of formula (1) can be prepared by optionally combining various methods described in the present specification and/or disclosed in prior arts, which are included in the range of the present invention, and so the processes for the preparation of compound of formula (1) are not limited to those explained below.
  • the compound of formula (1) may be prepared according to the following Reaction Scheme (1) by reducing nitro group of compound (2) to obtain amine compound (3) and then introducing a substituent to the formed amine group.
  • the compound of formula (1) may be prepared according to the following Reaction Schemes (2) to (8) by modifying the substituents R3, R5, R6, R7 of compound (4).
  • a is Fe, Zn, or H 2 (Pd/C);
  • b is an acylation agent in the form of R7-B—CO—W, wherein R7 and B are the same as defined in formula (1), W is OH or a leaving group such as chloride, bromide, iodide, mixed anhydride and the like;
  • c is ketone in the form of R7-B ⁇ O or aldehyde compound in the form of R7-B—CHO, sodium triacetoxyborohydride (NaBH(OAc) 3 ) or sodium cyanoborohydride (NaBH 3 CN);
  • R3 is the same as defined in Formula (1);
  • R11 represents A-R2 or CO 2 R12, wherein A and R2 are the same as defined in formula (1), R12 represents C 1 -C 6 -alkyl;
  • R4 is the same as defined in formula (1).
  • R1 is the same as defined in formula (1).
  • Compound (2) may be prepared by the methods described in the following Reaction Schemes (2) to (8).
  • Compound (3) may be prepared by reducing Compound (2).
  • the reduction reaction may be carried out by using an acid catalyst and metal, or a metal catalyst in the presence of hydrogen gas.
  • the acid that can be used is, for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organo-carbonic acid such as acetic acid, trifluoroacetic acid and the like; or amine acid salt such as ammonium chloride, and preferably hydrochloric acid, acetic acid or ammonium chloride.
  • the use amount of acid is conventionally 0.01-10 equivalents, preferably 0.1-5 equivalents to 1 equivalent of Compound (2).
  • the metal that can be used is, for example, iron, zinc, lithium, sodium, tin (conventionally, tin chloride) and the like, and preferably iron, zinc or tin chloride.
  • the use amount of metal is conventionally 1-20 equivalents, preferably 1-10 equivalents to 1 equivalent of Compound (2).
  • the reaction of metal in the presence of acid catalyst may be carried out in an inert solvent.
  • inert solvent is, for example, alkyl alcohol such as methanol, ethanol and the like; ether such as tetrahydrofuran, diethyl ether and the like; or alkyl ester such as ethyl acetate, and preferably methanol, ethanol, tetrahydrofuran or ethyl acetate.
  • the reaction temperature is conventionally ⁇ 10 to 200 ⁇ , preferably 25 to 120 ⁇
  • the reaction time is conventionally 10 minutes—60 hours, and preferably 10 minutes—12 hours.
  • the metal catalyst that can be used is palladium, nickel, platinum, ruthenium, rhodium and the like, and preferably palladium, nickel or the like.
  • the use amount of metal catalyst is conventionally 0.001-2 equivalents, and preferably 0.01-1 equivalent to 1 equivalent of Compound (2).
  • the pressure of hydrogen gas is conventionally 1-10 atms, and preferably 1-3 atms.
  • the reaction may be carried out in an inert solvent, for example, alkyl alcohol such as methanol, ethanol and the like; ether such as tetrahydrofuran, diethyl ether and the like; or alkyl acetate such as methyl acetate, ethyl acetate and the like, and preferably methanol, ethanol or ethyl acetate.
  • alkyl alcohol such as methanol, ethanol and the like
  • ether such as tetrahydrofuran, diethyl ether and the like
  • alkyl acetate such as methyl acetate, ethyl acetate and the like, and preferably methanol, ethanol or ethyl acetate.
  • the temperature of reaction using metal catalyst is conventionally ⁇ 10 to 200 ⁇ , and preferably 25 to 50 ⁇
  • the reaction time is conventionally 10 minutes-60 hours, and preferably 10 minutes-12 hours.
  • Compound (4) may be prepared though acylation reaction or reductive alkylation reaction of Compound (3).
  • the acylation reaction to amine group of Compound (3) may be carried out by using an acylation agent in the presence of a base.
  • the base that can be used is an organic base such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like.
  • the use amount of base is conventionally 1-10 equivalents, and preferably 1-5 equivalents to 1 equivalent of Compound (3).
  • the use amount of acylation agent is conventionally 1-10 equivalents, and preferably 1-3 equivalents to 1 equivalent of Compound (3).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; or chloroalkane such as dichloromethane, chloroform and the like, and preferably dichloromethane or chloroform.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • chloroalkane such as dichloromethane, chloroform and the like, and preferably dichloromethane or chloroform.
  • the temperature of reaction is conventionally ⁇ 10 to 100 ⁇ , preferably ⁇ 10 to 50 ⁇
  • reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • the reductive alkylation to amine group of Compound (3) may be carried out thorough the reaction with aldehyde or ketone with the use of a reducing agent.
  • An acid catalyst may also be used if necessary.
  • the amount of aldehyde or ketone is conventionally 1-10 equivalents, and preferably 1-3 equivalents to 1 equivalent of Compound (3).
  • the reducing agent that can be used is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the use amount of reducing agent is conventionally 1-10 equivalents, and preferably 1-3 equivalents to 1 equivalent of Compound (3).
  • the acid catalyst that can be used is, for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organo-carbonic acid such as acetic acid, trifluoroacetic acid and the like; or amine acid salt such as ammonium chloride, and preferably hydrochloric acid or acetic acid.
  • inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organo-carbonic acid such as acetic acid, trifluoroacetic acid and the like
  • amine acid salt such as ammonium chloride
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; or chloroalkane such as dichloromethane, chloroform, dichloroethane and the like, and preferably dichloroethane or chloroform.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • chloroalkane such as dichloromethane, chloroform, dichloroethane and the like, and preferably dichloroethane or chloroform.
  • the temperature of reaction is conventionally ⁇ 10 to 100 ⁇ , preferably ⁇ 10 to 50 ⁇
  • the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (2) according to the present invention may be prepared by the methods concretely exemplified in the following Reaction Schemes (2) to (8).
  • c is PCl 5 or Tf 2 O and Ph 3 PO;
  • d is a metal catalyst (e.g., Pd/C, MnO 2 , etc.) or BrCCl 3 or the like;
  • e is a reducing agent (e.g., NaBH 4 , LiAlH 4 );
  • f is I 2 or MsCl
  • R2 is the same as defined in formula (1);
  • R4 is the same as defined in formula (1);
  • R12 represents C 1 -C 6 -alkyl
  • R13 represents NO 2 or R1;
  • R14 represents p-MeOBn or Ph 3 C
  • each of R15 and R16 independently represents H, C 1 -C 6 -alkyl, 6 to 12-membered aryl or 5 to 12-membered heteroaryl; or R15 and R16 may be linked with each other to form 3 to 10-membered ring;
  • R15 represents H, C 1 -C 6 -alkyl, 6 to 12-membered aryl or 5 to 12-membered heteroaryl, and R16 is not present;
  • W is a leaving group, for example, halogen such as chloride, bromide, iodide and the like, or sulfonyl such as methanesulfonyl, p-toluenesulfonyl and the like.
  • Compound (5) may be prepared by the method described in Reaction Scheme (7) or (8).
  • Compound (6) may be prepared by hydrolysis reaction of Compound (5) by using a base.
  • the base that can be used is lithium hydroxide, sodium hydroxide, potassium hydroxide, metal bicarbonate, metal carbonate and the like.
  • the use amount of base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (5).
  • the hydrolysis reaction may be carried out in an inert solvent, for example, alkyl alcohol such as methanol, ethanol and the like; ether such as tetrahydrofuran, diethyl ether and the like.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 25 to 120 ⁇ , and reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (8) may be prepared by a coupling reaction of carboxylic acid group of Compound (6) and amine group of Compound (7).
  • Known coupling agents that can be used in the coupling reaction include, but not limited thereto, carboimide such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or 1,1′-dicarbonyldiimidazole (CDI) in a mixed form with 1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), or bis-(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), diphenylphosphoryl azide (DPPA) or N-[dimethylamino-1H-1,2,3-triazole [4,5-b]-pyridin-1-ylmethylene]-N-methylmethaneaminium (HA
  • the use amount of coupling agent is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (6).
  • the use amount of HOBT or HOAT is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (5).
  • acid should be removed with a base.
  • the base that can be used for this is an organic base such as triethylamine, diisopropylethylamine and the like.
  • the use amount of base is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (7).
  • the coupling reaction may be carried out in an inert solvent such as tetrahydrofuran, diethylether, N,N-dimethylformamide, and the like.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 25 to 120 ⁇ , and reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (9) may be prepared by a cyclization reaction of Compound (8) according to literatures (Journal of Organic Chemistry, 68(24), 2003, 9506-9509; Tetrahedron, 55(34), 1999, 10271-10282, etc.).
  • R14 is p-methoxybenzyl (p-MeOBn) group
  • the cyclization reaction is carried out by using phosphorus pentachloride (PCl 5 ) in dichloromethane solvent.
  • PCl 5 phosphorus pentachloride
  • the use amount of PCl 5 is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (8).
  • the temperature of reaction is conventionally ⁇ 10 to 50 ⁇ , preferably 0 to 25 ⁇ , and reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • R14 is triphenylmethyl (Ph 3 C) group
  • the cyclization reaction is carried out by using trifluoromethanesulfonic anhydride (Tf 2 O) and triphenyl phosphinoxide (Ph 3 PO) in dichloromethane solvent.
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Ph 3 PO triphenyl phosphinoxide
  • the use amount of each of them is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (8).
  • the temperature of reaction is conventionally ⁇ 10 to 50 ⁇ , preferably 0-25 ⁇
  • reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (10) may be prepared by using a dehydrogenation agent or a metal catalyst to Compound (9), or by an introduction of a leaving group therein and its subsequent removal by using a base.
  • the dehydrogenation agent may be sulfur, selenium, various quinones ⁇ e.g., 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) ⁇ and the like, and the dehydrogenation metal catalyst may be palladium (conventionally, Pd/C), platinum, nickel (conventionally, NiO 2 ), manganese (conventionally, MnO 2 ) and the like.
  • the use amount of dehydrogenation agent is conventionally 1-20 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (9).
  • the use amount of dehydrogenation metal catalyst is conventionally 0.001-10 equivalents, preferably 0.1-1 equivalent to 1 equivalent of Compound (9).
  • a solvent that can be used is benzene, toluene, decalin, quinoline and the like.
  • the temperature of reaction is conventionally 25 to 400 ⁇ , preferably 25 to 200 ⁇ , and reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • a reagent that can be used in the introduction of leaving group includes cooper (II) bromide (CuBr 2 ), bromotrichloromethane (BrCCl 3 ), N-bromosuccinimide (NBS) and the like.
  • the use amount is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (9).
  • the base that can be used is, for example, inorganic base such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like; organic base such as triethylamine, pyridine, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) and the like; preferably sodium carbonate or DBU.
  • the use amount of base is conventionally 0-10 equivalents, preferably 0-3 equivalents to 1 equivalent of Compound (9).
  • the solvent that can be used is an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; chloroalkane such as dichloromethane, dichloroethane, chloroform and the like, and preferably dichloromethane or chloroform.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 0 to 100 ⁇ , and the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (11) may be prepared through the hydrolysis reaction, reduction reaction, coupling reaction of amine and acid and substitution reaction of amine, etc. of Compound (10) by using the synthesis method of Compounds (6), (15) and (16).
  • Compound (12) may be prepared through the hydrolysis reaction of Compound (9) by using the synthesis method of Compound (6).
  • Compound (14) may be prepared through the coupling reaction of carboxylic acid of Compound (12) and Compound (13) by using the synthesis method of Compound (8).
  • Compound (15) may be prepared by modifying ester group of Compound (9) to alcohol group and introducing leaving group X.
  • a reducing agent to be used for reducing ester group to alcohol group is, for example, sodium borohydride, lithium borohydride, borane, lithium aluminum hydride, diisobutylaluminium hydride (DIBAL-H) and the like.
  • the use amount of reducing agent is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (9).
  • the reaction may be carried out in an inert solvent, for example, alcohol such as methanol, ethanol and the like; ether such as tetrahydrofuran, diethyl ether and the like; and preferably tetrahydrofuran or ether.
  • the reaction temperature is conventionally ⁇ 78 to 1000, preferably ⁇ 10 to 50 ⁇
  • the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • the method to introduce a leaving group to alcohol group is a halogenation or sulfonylation reaction.
  • the halogenation reaction may be carried out by using a reagent such as iodine, bromine, N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), carbon tetrachloride (CCl 4 ), carbon tetrabromide (CBr 4 ) and the like in the presence of a base such as imidazole, dimethylaminopyridine (DMAP), etc. and phosphine such as triphenylphosphine (Ph 3 P), tributylphosphine (Bu 3 P), etc.
  • a base such as imidazole, dimethylaminopyridine (DMAP), etc.
  • phosphine such as triphenylphosphine (Ph 3 P), tributylphosphine (Bu 3 P), etc.
  • each of the halogenation agent, base and phosphine compound is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (9).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; dichloromethane; chloroform; acetonitrile and the like.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 0 to 50 ⁇ , and the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • the sulfonylation reaction may be carried out by using a reagent such as methanesulfonyl chloride, p-toluenesulfonyl chloride and the like in the presence of an organic base such as pyridine, triethylamine and the like.
  • a reagent such as methanesulfonyl chloride, p-toluenesulfonyl chloride and the like in the presence of an organic base such as pyridine, triethylamine and the like.
  • the use amount of each of the sulfonylation agent and base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (9).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; chloroalkane such as dichloromethane, dichloroethane, chloroform and the like, and preferably dichloromethane or dichloroethane.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • chloroalkane such as dichloromethane, dichloroethane, chloroform and the like, and preferably dichloromethane or dichloroethane.
  • the temperature of reaction using metal catalyst is conventionally ⁇ 10 to 200 ⁇ , preferably 0 to 50 ⁇ , and the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (16) may be prepared by the coupling reaction of Compound (13) and Compound (15) by using a base.
  • the base that can be used is, for example, inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate and the like; organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU) and the like, and preferably potassium carbonate, cesium carbonate or DBU.
  • the use amount of base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (13).
  • the solvent that can be used is an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; alkylnitrile such as acetonitrile, propionitrile and the like; amide such as N,N-dimethylformamide, and preferably tetrahydrofuran, acetonitrile or N,N-dimethylformamide.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • alkylnitrile such as acetonitrile, propionitrile and the like
  • amide such as N,N-dimethylformamide, and preferably tetrahydrofuran, acetonitrile or N,N-dimethylformamide.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 25 to 120 ⁇
  • the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • a is a coupling agent (e.g., EDC, CDI, BOP-Cl);
  • b is PCl 5 or Tf 2 O and Ph 3 PO;
  • c is metal hydroxide (e.g., NaOH, LiOH);
  • d is I 2 or MsCl or the like
  • R4 is the same as defined in Reaction Scheme (1);
  • R12, R13, R14, R15, R16 and Q are the same as defined in Reaction Scheme (2).
  • Compound (17) may be prepared by the method described in Reaction Scheme (10).
  • Compound (18) may be prepared by using Compound (6) and Compound (17) according to the synthesis method of Compound (8) in Reaction Scheme (2).
  • Compound (19) may be prepared by using Compound (18) according to the synthesis method of Compound (9) in Reaction Scheme (2).
  • Compound (20) may be prepared by using Compound (19) according to the synthesis method of Compound (6) in Reaction Scheme (2).
  • Compound (21) may be prepared by using Compound (20) according to the synthesis method of Compound (16) in Reaction Scheme (2).
  • a is SOCl 2 or (COCl) 2 ; and aqueous NH 4 OH solution;
  • R2 is the same as defined in formula (1);
  • R4 is the same as defined in Reaction Scheme (1);
  • R13 is the same as defined in Reaction Scheme (2);
  • W is a leaving group, for example, halogen such as chloride, bromide, iodide and the like, or sulfonyl such as methanesulfonyl, p-toluenesulfonyl.
  • Compound (22) may be prepared by modifying carboxylic acid of Compound (6) to amide and then converting amide to thioamide with Lawesson's reagent.
  • the method of modifying carboxylic acid of Compound (6) to amide is carried out through preparing acid chloride by using thionyl chloride (SOCl 2 ) or oxalyl chloride ((COCl) 2 ) and then reacting it with ammonia water.
  • the use amount of chlorination agent is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (6).
  • the use amount of ammonia water is conventionally 1-5 equivalents.
  • the reaction may be carried out in an inert solvent such as dichloromethane, dichloroethane, chloroform and the like.
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably ⁇ 10 to 100 ⁇ , and reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Thioamide group may be prepared by reacting amide with Lawesson's reagent.
  • the use amount of Lawesson's reagent is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (6).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; chloroalkane such as dichloromethane, dichloroethane, chloroform and the like, aromatic hydrocarbon such as benzene, toluene and the like, and preferably tetrahydrofuran or toluene, etc.
  • the temperature of reaction is conventionally ⁇ 25 to 200 ⁇ , preferably 25 to 150 ⁇ , and the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • Compound (23) is commercially available or may be prepared by known methods such as that disclosed in WO 1999/02501.
  • Compound (24) may be prepared by the coupling reaction of Compound (22) and Compound (23), with using a base if necessary.
  • the base that can be used is, for example, inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate and the like; organic base such as diisopropylethylamine, DBU and the like, and preferably potassium carbonate or cesium carbonate.
  • the use amount of base is conventionally 0-10 equivalents, preferably 0-5 equivalents to 1 equivalent of Compound (22).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; alkylnitrile such as acetonitrile, propionitrile and the like; amide such as N,N-dimethylformamide, and preferably tetrahydrofuran or N,N-dimethylformamide.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • alkylnitrile such as acetonitrile, propionitrile and the like
  • amide such as N,N-dimethylformamide, and preferably tetrahydrofuran or N,N-dimethylformamide.
  • a is amine Compound (25), a coupling agent (e.g., EDC, CDI, BOP-Cl);
  • a coupling agent e.g., EDC, CDI, BOP-Cl
  • c is a base (e.g., K 2 CO 3 , Cs 2 CO 3 );
  • R2 is the same as defined in formula (1);
  • R4 is the same as defined in Reaction Scheme (1);
  • R13 is the same as defined in Reaction Scheme (2);
  • W is a leaving group, for example, halogen such as chloride, bromide, iodide and the like, or sulfonyl such as methanesulfonyl, p-toluenesulfonyl and the like.
  • Compound (25) is commercially available or may be prepared by known methods disclosed in literatures (Tetrahydron Letters, 28(48), 6068-6072, 1987; or Organic Process Research & Development 10(3), 472-480, 2006).
  • Compound (26) may be prepared by the sequential process of amide synthesis and thioamide synthesis by using Lawesson's reagent.
  • the amide synthesis through coupling of Compound (6) and Compound (25) may be carried out according to the method of preparing amide Compound (8) in Reaction Scheme (2), and the synthesis of thioamide Compound (26) may be carried out according to the method of preparing Compound (22) in Reaction Scheme (4).
  • Compound (27) may be prepared by the cyclization reaction of Compound (26) by using a base.
  • the base that can be used is potassium carbonate, cesium carbonate, diisopropylethylamine, DBU or the like.
  • the use amount of base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (26).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; alkylnitrile such as acetonitrile, propionitrile and the like; amide such as N,N-dimethylformamide, and preferably tetrahydrofuran, acetonitrile or N,N-dimethylformamide
  • ether such as tetrahydrofuran, diethyl ether and the like
  • alkylnitrile such as acetonitrile, propionitrile and the like
  • amide such as N,N-dimethylformamide, and preferably tetrahydrofuran, acetonitrile or N,N-dimethylformamide
  • the temperature of reaction is conventionally ⁇ 10 to 200 ⁇ , preferably 25 to 120 ⁇
  • the reaction time is conventionally 10 minutes-60 hours, preferably 10 minutes-12 hours.
  • c is a coupling agent (e.g. CDI, BOP-Cl) and Compound (31),
  • R2 is the same as defined in formula (1),
  • R4 is the same as defined in Reaction Scheme (2), and
  • R12 and R13 is the same as defined in Reaction Scheme (2).
  • Compound (28) may be prepared by the reaction of Compound (5) with hydrazine.
  • the use amount of hydrazine is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (5).
  • the reaction may be carried out in an inert solvent, for example, tetrahydrofuran, methanol, ethanol and the like.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 25 to 120° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (30) may be prepared by the coupling reaction of Compound (28) with Compound (29).
  • an acid catalyst may be used.
  • the use amount of Compound (29) is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (28).
  • the acid catalyst that can be used is selected from inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like; organic carbonic acid such as acetic acid, trifluoroacetic acid and the like; amine acid salt such as ammonium chloride; and Lewis acid such as aluminium chloride.
  • the use amount of acid is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (29).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon such as benzene, toluene and the like; saturated hydrocarbon such as cyclohexane, hexane and the like; or amide such as N,N-dimethylamide.
  • ether such as tetrahydrofuran, diethyl ether and the like
  • aromatic hydrocarbon such as benzene, toluene and the like
  • saturated hydrocarbon such as cyclohexane, hexane and the like
  • amide such as N,N-dimethylamide.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 25 to 120° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (31) is commercially available or may be prepared by the method disclosed in US 2004/0019215.
  • Compound (32) may be prepared by the coupling reaction of Compound (6) with Compound (31) and subsequent dehydration reaction.
  • the use amount of coupling agent for the coupling reaction is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (6).
  • the reaction may be carried out in an inert solvent such as tetrahydrofuran or N,N-dimethyl amide.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • the dehydration reaction after the coupling reaction may be carried out by optionally using an acid catalyst. It may be carried out by the method for the preparation of Compound (30).
  • a is sodium nitrate (NaNO 2 ); tin chloride (SnCl 2 ),
  • b is ketone Compound (38), a base (e.g. NaOAc),
  • c is an acid (e.g., polyphosphoric acid (PPA)),
  • PPA polyphosphoric acid
  • e is Compound (42), a base (e.g. NaOH),
  • R3 is the same as defined in formula (1),
  • R11, R4 and R12 are the same as defined in Reaction Scheme (1), and
  • R13 is the same as defined in Reaction Scheme (2).
  • Compound (36) is commercially available or may be prepared by the methods disclosed in literatures [Heterocycles, 68(11), 285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 903-4906, 2004].
  • Compound (37) is commercially available or may be prepared by modifying an amine group of Compound (36) to hydrazine group according to the method disclosed in literature [Journal of the America Chemical Society, 198(48), 15374-75, 2006].
  • Hydrazine compound (37) may be prepared by reacting amine group with NaNO 2 in the presence of hydrochloric acid to obtain diazonium salt (42), and without separation, reducing the diazonium salt by using SnCl 2 .
  • the use amount of NaNO 2 is conventionally 1-10 equivalents, preferably 2-5 equivalents to 1 equivalent of Compound (36).
  • the use amount of SnCl 2 is conventionally 1-10 equivalents, preferably 2-5 equivalents to 1 equivalent of Compound (36).
  • the reaction may be carried out in aqueous solution of hydrochloric acid with a concentration of 1-12N, preferably 4-8N.
  • the reaction temperature is conventionally ⁇ 10 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-6 hours.
  • Hydrazone compound (39) may be prepared by the coupling reaction of Compound (37) with ketone Compound (38). If Compound (37) is in a neutral form, a base is not used, but if Compound (37) is in an acid form, a base should be used for making a neutral form.
  • the base that can be used is, for example, metal hydroxide such as sodium hydroxide, lithium hydroxide, etc.; metal carbonate such as sodium bicarbonate, potassium carbonate, etc.; metal acetate such as sodium acetate; or an organic base such as triethylamine, pyridine, etc.
  • the use amount of base is conventionally 1-5 equivalents, preferably 1-2 equivalents to 1 equivalent of Compound (37).
  • the reaction may be carried out in an inert solvent such as tetrahydrofuran, methanol, ethanol, etc.
  • the reaction temperature is conventionally ⁇ 10 to 100° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (39) may be prepared by reacting diazonium salt (41) and Compound (42) in the presence of a base according to Japp-Klingemann rearrangement method disclosed in literature [Organic Process Research & Development, 2, 1988, 214-220].
  • the use amount of hydrochloric acid for the preparation of diazonium salt (41) is conventionally 1-10 equivalents, preferably 2-4 equivalents to 1 equivalent of Compound (36).
  • the base used for the reaction between Compounds (41) and (42) is sodium hydroxide.
  • the use amount of the base is conventionally 1-20 equivalents, preferably 1-10 equivalents to 1 equivalent of Compound (42).
  • Aqueous solution of 50% ethanol may be used as a solvent.
  • the reaction temperature is conventionally ⁇ 10 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (40) can be prepared by using an acid catalyst and Compound (39).
  • the acid used in the synthesis is polyphosphoric acid, hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, acetic acid, etc., and preferably poylphosphoric acid.
  • Polyphosphoric acid may be used alone or in combination with aromatic hydrocarbon such as benzene, toluene, etc.
  • the reaction temperature is conventionally ⁇ 25 to 150° C.
  • the reaction time is conventionally 5 minutes-60 hours and preferably 5 minutes-12 hours.
  • Compound (42) is commercially available or may be prepared by the methods disclosed in literatures [WO 2007040289, WO 200601079 or Organic Letters 9(3), 397-400, 2007].
  • d is trimethylsilylacetylene or 2-methyl-3-butyn-2-ol, Pd, Cu(I), a base (e.g., Et 3 N or Et 2 NH),
  • e is tetrabutylammonium fluoride (Bu 4 NF) or NaOH,
  • f is Compound (48), Pd(II), Cu(I), a base (e.g., Et 3 N or Et 2 NH),
  • R11 and R4 are the same as defined in Reaction Scheme (1), and
  • R13 is the same as defined in Reaction Scheme (2).
  • Compound (36) is commercially available or may be prepared by the methods disclosed in literatures [Heterocycles, 68(11), 285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 903-4906, 2004].
  • Compound (43) may be prepared by iodination reaction of Compound (36).
  • the iodination agent for iodination reaction may be selected from iodine, iodine monobromide and iodine monochloride, and silver ion, for example, silver nitrate (AgNO 3 ), silver carbonate
  • the use amount of iodination agent is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (36).
  • the use amount of silver ion is conventionally 0-10 equivalents, preferably 0-3 equivalents to 1 equivalent of Compound (36).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether, etc.; alkylalcohol such as methanol, ethanol, etc.; alkylnitrile such as acetonitrile, propionitril, etc.; or an organic acid such as acetic acid.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (44) is commercially available or may be prepared by the methods disclosed in literatures [Synthesis, 59-61, 2004 or Bioorganic & Medicinal Chemistry Letters, 13, 197-209, 2003] or the synthesis method of Compound (47).
  • Compound (45) may be prepared by the coupling reaction of iodide group of Compound (43) and acetylene group of Compound (44) according to the method disclosed in literature [Tetrahedron, 59, 2003, 1571-1587].
  • the coupling reaction may be carried out with the use of Pd (0) or Pd (II) catalyst [e.g., Pd(Ph 3 P) 4 , PdCl 2 (Ph 3 P) 2 )], Cu(I) catalyst (e.g., CuI) and a base (e.g., triethylamine, diethylamine, etc.).
  • Pd catalyst is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (43).
  • the use amount of Cu(I) catalyst is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (43).
  • the use amount of base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (43).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl lether, etc.; aromatic hydrocarbon such as benzene, toluene, etc.; or N,N-dimethylformamide.
  • ether such as tetrahydrofuran, diethyl lether, etc.
  • aromatic hydrocarbon such as benzene, toluene, etc.
  • N,N-dimethylformamide N,N-dimethylformamide.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 25 to 120° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (46) may be prepared by the cyclization reaction of Compound (45) according to the methods disclosed in literatures [JP 2001/233855; Tetrahedron, 59, 2003, 1571-1587; Tetrahedron Letters, 47(36), 2006, 6485-6388; or Heterocycles, 64, 2004, 475-482, etc.].
  • the cyclization reaction may be carried out by using a base, Cu (I), Pd (II), etc.
  • the base that can be used is, for example, potassium hydride (KH), potassium t-butoxide (KOBu t ), etc., and the use amount of base is conventionally 1-10 equivalents, preferably 1-2 equivalents to 1 equivalent of Compound (45).
  • each of Cu (I) and Pd (II) is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (45).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether, etc.; aromatic hydrocarbon such as benzene, toluene, etc.; alkyl nitrile such as acetonitrile, propionitrile, etc.; N,N-dimethylformamide or N-methyl-pyrrolidinone (NMP). If a base is used, the preferred solvent is NMP.
  • the preferred solvent is acetonitrile, toluene, N,N-dimethylformamide, etc.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 120° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (46) may also be prepared by modifying the amine group of Compound (43) to trifluoroacetamide group and then cyclizing with using Pd (II) according to the method disclosed in literature [Tetrahedron, 60, 2006, 10983-10992].
  • Compound (47) may be prepared by the coupling reaction of Compound (43) and acetylene in the presence of Pd (II), Cu(I) and a base according to the method disclosed in literature [Journal of Organic Chemistry, 71, 2006, 167-175].
  • the acetylene used is trimethylsilylacetylene or 2-methyl-3-butyn-2-ol, and the use amount of acetylene is conventionally 1-10 equivalents, preferably 1-3 equivalents to 1 equivalent of Compound (43).
  • the use amount of each of Cu (I) and Pd (II) is conventionally 0.001-5 equivalents, preferably 0.01-1 equivalent to 1 equivalent of Compound (46).
  • the base used is diethylamine, triethylamine, diisopropylethylamine, etc. and the use amount of base is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (43).
  • the reaction may be carried out in an inert solvent, for example, ether such as tetrahydrofuran, diethyl ether, etc., or aromatic hydrocarbon such as benzene, toluene, etc.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 120° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (48) is commercially available or may be prepared by the methods disclosed in literatures [Journal of Organic Chemistry, 70, 2005, 6519-6522 or Tetrahedron, 60(48), 2004, 10983-10992].
  • a is p-methoxybenzylchloride (PMBC1) or triphenylmethylchloride (TrCl), a base (e.g., NaOH),
  • alkylalcohol e.g., methanol, ethanol
  • c is di-t-butyloxy-dicarbonyl (Boc 2 O), a base (e.g., NaOH, K 2 CO 3 ),
  • d is alkylchloroformate (e.g., EtOCOCl), a base (e.g., N-methylmorpholine),
  • e is diazomethane (CH 2 N 2 ), a base (e.g., KOH),
  • f is silver ion (e.g., silver benzoate)
  • h is MsCl, Et 3 N,
  • i is p-methoxybenzylthiol (PMBSH), NaH,
  • R12 represents C 1 -C 6 alkyl
  • R14 represents p-MeOBn or Ph 3 C.
  • Compound (49) may be prepared by protecting thiol group of cysteine with p-methoybenzylchloride (PMBC1) or triphenylmethylchloride (TrCl) in the presence of a base.
  • PMBC1 p-methoybenzylchloride
  • TrCl triphenylmethylchloride
  • the use amount of PMBC1 or TrCl for the protection of thiol group is conventionally 1-5 equivalents, preferably 1-2 equivalents to 1 equivalent of cysteine.
  • the base used is sodium hydroxide, potassium carbonate, etc., and its use amount is conventionally 1-5 equivalents, preferably 1-2 equivalents to 1 equivalent of cysteine.
  • the reaction may be carried out in an inert solvent such as tetrahydrofuran, methanol, ethanol, water, etc.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (51) may be prepared by protecting amine group of Compound (49) with BOC group.
  • the use amount of Boc 2 O for the protection of amine group is conventionally 1-5 equivalents, preferably 1-2 equivalents to 1 equivalent of cysteine.
  • the used base is, for example, hydroxide such as sodium hydroxide, lithium hydroxide etc.; carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; an organic base such as diisopropylethylamine, triethylamine, etc., and preferably potassium carbonate, triethylamine, etc.
  • the reaction may be carried out in an inert solvent such as tetrahydrofuran, methanol, ethanol, water, etc.
  • the reaction temperature is conventionally ⁇ 10 to 200° C. and preferably 0 to 50° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (50) may be prepared by the esterification of carboxyl group of Compound (49).
  • the esterification reaction may be carried out with the use of acetylchloride or thionylchloride in an alkylalcohol solvent.
  • the use amount of acetylchloride or thionylchloride is conventionally 1-10 equivalents, preferably 1-5 equivalents to 1 equivalent of Compound (49).
  • the reaction temperature is conventionally ⁇ 25 to 200° C. and preferably 25 to 100° C.
  • the reaction time is conventionally 10 minutes-60 hours and preferably 10 minutes-12 hours.
  • Compound (52) may be prepared by the method disclosed in literature [Helvetica Chimica Acta, 87, 2004, 3131-3159].
  • anhydride compound is reacted with 1-5 equivalents of diazomethane and 1-5 equivalents of aqueous potassium hydroxide solution in diethyl ether solvent at 0° C., and then reacted with Ag ion (e.g., silver trifluoroacetate (CF 3 CO 2 Ag), silver benzoate, etc.) at room temperature in the absence of light, to prepare an alkyl ester.
  • Ag ion e.g., silver trifluoroacetate (CF 3 CO 2 Ag), silver benzoate, etc.
  • the BOC protection group of the prepared compound may be reacted with an acid (e.g., hydrochloric acid, trifluoroacetic acid) in a solvent such as dioxane, tetrahydrofuran or dichloromethane at room temperature for deprotection, and then Compound (52) may be obtained.
  • an acid e.g., hydrochloric acid, trifluoroacetic acid
  • a solvent such as dioxane, tetrahydrofuran or dichloromethane
  • Compound (53) may be prepared by the method disclosed in literatures [Synlett, 15, 2005, 2397-2399 or Journal of Organic Chemistry, 66(5), 2001, 1919-1923] with using glutamic acid or aspartic acid as a starting material.
  • Compound (54) may be prepared by modifying an alcohol group of Compound (53) to a leaving group and then reacting with p-methoxybenzylthiol (PMBSH), as in the method for preparation of Compound (21) in Reaction Scheme (3).
  • PMBSH p-methoxybenzylthiol
  • Compound (53) is reacted with 1-5 equivalents of triethylamine and 1-3 equivalents of MsCl in a dichloromethane solvent at 0° C. to obtain a sulfonate compound.
  • the sulfonate compound may be reacted at 25 to 100° C. with PMBSNa solution, which is prepared by adding 2-5 equivalents of NaH and 2-5 equivalents of PMBSH in DMF, to prepare Compound (54).
  • Compound (17) of the present invention may be prepared by the method specifically illustrated in the following Reaction Scheme (10).
  • b is a reducing agent (e.g., NaBH 4 ),
  • c is t-butylcarbonylchloride (t BuCOCl), a base (e.g., Et 3 N),
  • R12 represents C 1 -C 6 alkyl
  • R14 represents p-MeOBn or Ph 3 C.
  • Compound (17) may be prepared by subsequently protecting an amine group with BOC group, reducing ester group to an alcohol, protecting the alcohol group with an ester group, and deprotecting the BOC group.
  • the protection of amine group may be carried out according to the method illustrated in Reaction Scheme (9).
  • ester group may be carried out by reacting with 2-5 equivalents of lithium borohydride for 1-5 hours in tetrahydrofuran solvent at 0° C.
  • the protection of alcohol group may be carried out by the reacting with t-BuCOCl for 10 minutes—12 hours in the presence of 1-5 equivalents of a base such as triethylamine or pyridine etc., in dichloromethane solvent at 0-25° C.
  • a base such as triethylamine or pyridine etc.
  • the deprotection of BOC group may be carried out by dissolving reactants in an inert solvent such as tetrahydrofuran, dioxane, ethyl acetate or dichloromethane and reacting with 1-10 equivalents of hydrochloric acid or acetic acid for 10 minutes-12 hours at 0 to 50° C.
  • an inert solvent such as tetrahydrofuran, dioxane, ethyl acetate or dichloromethane
  • the compound of formula (1) prepared by the above methods may be separated or purified from the reaction products by various methods such as recrystallization, ionic electrophoresis, silica gel column chromatography or ion exchange resin chromatography, etc.
  • the indole or indazole compounds of the present invention may be prepared by various methods.
  • composition of the present invention comprising the above-explained indole or indazole compound of formula (1) as an active component can be used for preserving cells or organs of animals. More specifically, the composition of the present invention can be used for preventing injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion. However, the effects of the composition according to the present invention are not limited to those explained above.
  • Cell as used herein means an animal cell isolated from tissues of human or non-human animals and selected from the group consisting of liver cell, skin cell, mucous membrane cell, Langerhans islet cell, nerve cell, cartilage cell, endothelium cell, epithelial cell, bone cell and muscle cell, or sperm, egg or fertilized egg of livestock or fish.
  • Organ is selected from the group consisting of skin, cornea, kidney, heart, liver, pancreas, intestine, nerve, lung, placenta, umbilical cord and blood vessel system.
  • the indole or indazole compound according to the present invention can be used by further adding it in a conventional solution for preserving organs. If the indole or indazole compound according to the present invention is added in the conventional solution for preserving organs, the preservation period of the above-mentioned organs for transplantation can be greatly extended and organ damage after transplantation can be effectively prevented or treated.
  • liver cells or pancreas cells, etc. of animals can be preserved for a long time even without freezing.
  • preserved animal cells can be utilized for applications in cell or tissue engineering to prepare useful materials.
  • the “pharmaceutical composition” may comprise a pharmaceutically acceptable carrier, diluent, excipient or combination thereof, if needed.
  • a pharmaceutical composition facilitates the administration of the compound into a living organism.
  • administration techniques including oral, injection, aerosol, parenteral and topical administrations, but not limited thereto.
  • Carrier as used herein means a substance which facilitates the incorporation of the compound into cells or tissues.
  • DMSO dimethylsulfoxide
  • carrier is a typical carrier which is used to facilitate the introduction of various organic compounds into cells or tissues of living organisms.
  • “Diluent” as used herein is defined as a substance being diluted in water that dissolves the compound, as well as stabilizing the subject compound in its biologically active form.
  • the salts dissolved in a buffer solution are utilized as diluents in the art.
  • a typical buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents hardly alter biological activities of the compound since the buffer salts can control the pH of solution at low concentration.
  • “Pharmaceutically acceptable” as used herein means the property that does not impair biological activities and properties of the compound.
  • the compounds of the present invention can be formulated in various pharmaceutical dosage forms according to the desired purpose.
  • the active ingredient specifically the compounds of formula (1), pharmaceutically acceptable salt or isomer thereof
  • various pharmaceutically acceptable carriers which can be selected according to the formulation to be prepared.
  • the pharmaceutical composition of the present invention can be formulated as injection preparation, oral preparation, etc.
  • the compounds of the present invention can be formulated by the methods known in the art utilizing known pharmaceutical carriers and excipients, and incorporated into containers of unit dose form or multi-dose form.
  • the form of the preparation can be solutions, suspensions or emulsions in oily or aqueous media, and may contain typical dispersing agents, suspending agents or stabilizers. Further, for example, it can be a form of dry powder which is intended to be reconstructed by dissolving in sterilized, pyrogen-free water prior to use.
  • the compounds of the present invention also can be formulated into suppository forms utilizing typical suppository base such as cocoa butter or other glycerides.
  • solid dosage forms for oral administration capsules, tablets, pills, powder and granules can be prepared, and capsules and tablets are especially useful.
  • tablets and pills are prepared as enteric coated forms.
  • Solid dosage forms can be prepared by mixing the compound of the present invention together with carriers such as one or more inert diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrant, binder, etc.
  • the compound of the present invention or the pharmaceutical compositions containing the same can also be administered in combination with other active agents, for example, other materials that can prevent injury of organs, isolated cell systems or tissues caused by cold storage, transplant operation or post-transplantation reperfusion
  • the dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight and age of the patient, specific nature of the disease and severity of the disease, etc. However, dosage needed for transplanting an organ to an adult is typically from about 1 nM to 100 ⁇ M, and generally a concentration of 10 ⁇ M or less will be a sufficient dosage but for some patients, higher dosage may be preferable.
  • Treatment as used herein means interrupting or delaying the progress of the disease when applied to the subject showing the onset of disease symptoms and “prevention” means interrupting or delaying the sign of the onset of disease when applied to the subject that does not show but is at risk of the onset of disease symptoms.
  • M means molar concentration
  • N means normal concentration
  • FIG. 1 illustrates a hepatocyte-protecting effect of the compound of Example 21 according to the present invention through the results of experiments using rat primary hepatocytes.
  • FIG. 2 illustrates a recovery capacity of the compounds of Examples 126, 127, 137 and 138 according to the present invention in lung cell LB-HEL at 37° C. with the passage of time after cold shock for 24 hours, compared with the control drugs, IM54 and nec-1.
  • FIG. 3 illustrates a protecting effect of the compound of Example 126 according to the present invention against cold preservation injury in rat-isolated perfusion liver model, compared with the conventional preservation solution, HTK solution, through the measurement of LDH, AST and ALT activity.
  • FIG. 4 illustrates a protecting effect of the compound of Example 126 according to the present invention against cold ischemia and warm reperfusion injury in rat-isolated perfusion liver model, compared with the conventional preservation solution, HTK solution, through the measurement of LDH activity.
  • FIG. 5 illustrates a protecting effect of the compound of Example 126 according to the present invention against cold ischemia/warm reperfusion injury in rat-isolated perfusion liver model, compared with the conventional preservation solution, HTK solution, through the measurement of bile output.
  • acetamide compound was dissolved in dichloromethane (200 ml), and fuming nitric acid (13 ml, 0.29 mol) was added in drops at 0 ⁇ . The resulting mixture was stirred for 1 h at 0 ⁇ ⁇ room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate.
  • nitrate compound was dissolved in methanol (100 ml) and tetrahydrofuran (100 ml), and 6N-sodium hydride was added in drops. The mixture was stirred for 6 h at room temperature. After completion of the reaction, 6N-hydrochloric acid solution was added to neutralize the reaction mixture to about pH 7. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give the title compound (44 g, Yield 83%).
  • Step 1 The compound obtained in Step 1 (30.7 g, 127.3 mmol) was dissolved in tetrahydrofuran (150 ml) and water (150 ml). Potassium carbonate (26.4 g, 190 mmol) and di-t-butyloxy-dicarbonyl (27.7 g, 127.3 mmol) were added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was distilled under reduced pressure to remove tetrahydrofuran. The mixture was cooled to 0 ⁇ , and acidified to pH 3 using 3N aqueous hydrochloric acid solution.
  • Step 3 The compound obtained in Step 3 was dissolved in methanol (1000 ml), silver benzoate (7.1 g, 31.1 mmol) was added, and the mixture was reacted for 1 h under sonication. After completion of the reaction, the mixture was concentrated and purified by column chromatography to give (R)-3-t-butoxycarbonylamino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester (35.2 g, 95.3 mmol, Yield 76%).
  • Step 4 The compound obtained in Step 4 (35.2 g) was dissolved in dichloromethane (70 ml), 4N hydrochloric acid/1,4-dioxane solution (71 ml) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was concentrated. The solid produced by adding dichloromethane (30 ml) and diethylether (150 ml) was filtered and dried to give the title compound (25.5 g, 83.3 mmol, Yield 87%).
  • Step 2 The compound obtained in Step 2 (11 g, 62.7 mmol) was dissolved in dichloromethane (200 ml), and 4N hydrochloric acid/ethyl acetate solution (20 ml) was added. The mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was thoroughly concentrated, and diethylether (150 ml) was added. The resulting solid was filtered and dried to give the title compound (20 g, Yield 96%).
  • Step 1 To the compound obtained in Step 1 were added tetrahydrofuran (200 ml) and water (200 ml) to dissolve. Triethylamine (87 ml, 621.6 mmol) was added, and di-t-butyloxy-dicarbonyl (43.0 g, 196.8 mmol) dissolved in tetrahydrofuran (100 ml) was added in drops while stirring. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added.
  • the alcohol compound obtained in Step 3 was dissolved in dichloromethane (300 ml). Triethylamine (58 ml, 414.4 mmol) and trimethylacetylchloride (28 ml, 227.9 mmol) were added, and the mixture was stirred for 6 h at 0 ⁇ . After completion of the reaction, water was added.
  • Step 2 The compound obtained in Step 2 was dissolved in dichloroethane (10 ml) and toluene (10 ml), and Lawesson's reagent (1.29 g, 3.2 mmol) was added. The mixture was refluxed for 4 h, and distilled under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and the concentrate was purified by column chromatography to give the product of cyclization reaction, i.e., the compound 2-(4,5-dihydro-thiazol-2-yl)-7-nitro-1H-indole (100 mg, Yield 22%).
  • the product of cyclization reaction i.e., the compound 2-(4,5-dihydro-thiazol-2-yl)-7-nitro-1H-indole (100 mg, Yield 22%).
  • the thiazoline compound obtained in Step 3 was dissolved in methanol (50 ml). 10% Pd/C was added, and the mixture was stirred for 8 h under hydrogen gas. After completion of the reaction, the mixture was filtered through cellite, distilled under reduced pressure and purified by column chromatography to give the title compound (80 mg, Yield 91%).
  • Example 5 The compound obtained in Example 5 (820 mg, 2.6 mmol) was dissolved in dichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol) and triethylamine (0.81 ml, 3.1 mmol) were added, which was then stirred for 30 min at 0 ⁇ . After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (600 mg, Yield 60%).
  • Step 1 The compound obtained in Step 1 was dissolved in methanol (32 ml), tetrahydrofuran (32 ml) and water (16 ml). 1N sodium hydroxide (7 ml) was added, and stirred for 4 h at room temperature. After completion of the reaction, the mixture was distilled under reduced pressure, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound (700 mg, Yield 78%).
  • Step 1 The compound obtained in Step 1 (2.5 g, 6.12 mmol) was reacted according to the same procedure as Example 4 to give the title compound (2.19 g, 5.76 mmol, Yield 94%).
  • Example 13 The compound obtained in Example 13 (3.7 g, 10.2 mmol) was dissolved in tetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol), triphenylphosphine (4.0 g, 15.3 mmol) and iodine (3.9 g, 15.3 mmol) were added, and stirred for 8 h at 0 ⁇ ⁇ room temperature. After completion of the reaction, ethyl acetate (100 ml) was added, and the reaction mixture was washed with water (100 ml ⁇ 2). The organic layer was concentrated and the residue was purified by column chromatography to give the title compound (2.0 g, 4.07 mmol, Yield 40%).
  • Example 22 The ester compound obtained in Example 22 (500 mg, 1.2 mmol) was reacted according to the same procedures as Example 11 to give the title compound 400 mg (Yield 85%).
  • Step 1 The compound obtained in Step 1 was dissolved in 300 ml of 1:1:1 mixture of water, tetrahydrofuran and methanol. To the mixture added 4.6 g (86.9 mmol) of ammonium chloride and 4.9 g (86.9 mmol) of iron and stirred for 30 minutes at 60° C. The mixture was filtered through celite and distilled under reduced pressure. To the concentrate added saturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The extract was dried with anhydrous magnesium sulfate, filtered. The filtrate was purified by column chromatography to give the title compound 400 mg (Yield 15%).
  • Example 28 The compound obtained in Example 28 (100 mg, 0.27 mmol) was reacted according to the same procedures as Preparation 44 to give the title compound 70 mg (Yield 76%).
  • Example 28 The compound obtained in Example 28 (300 mg, 0.81 mmol) was reacted according to the same procedures as Example 4 to give the title compound 200 mg (Yield 75%).
  • Example 52 The compound obtained in Example 52 (50 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide 3 ml. Glycolic acid (15 mg, 0.20 mmol), triethylamine (0.06 ml, 0.43 mmol), EDC (38 mg, 0.20 mmol) and HOBT (27 mg, 0.20 mmol) were added, and the mixture was stirred at room temperature for 8 hours. To the reaction mixture added 1N HCl solution and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to obtain the title compound 20 mg (Yield 43%).
  • Example 52 The compound obtained in Example 52 was dissolved in dichloromethane 10 ml, and triethylamine (0.02 ml, 0.14 mmol), methanesulfonylchloride (10 mg, 0.09 mmol) were added. The mixture was stirred at 0° C. for 1 hour. To the reaction mixture added 1N HCl solution and extracted with ethylacetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to obtain the title compound 18 mg (Yield 67%).
  • Example 55 The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved in N, N-dimethyl formamide 5 ml. 2-Morpholine-4-yl-ethylamine (22 mg, 0.17 mmol), EDC (25 mg, 0.19 mmol) and HOBT (18 mg, 0.19 mmol) were added. The mixture was stirred for 8 hours at room temperature. Saturated 1N aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound 40 mg (Yield 100%).
  • Step 1 The compound obtained in Step 1 (18.30 g, 78.61 mmol) was dissolved in 300 ml of the 2:1 mixture of methanol and dichloromethane, and 5.44 g (39.3 mmol) of potassium carbonate was added. The mixture was stirred at room temperature for 1 hour. At the end of reaction, the reaction mixture was diluted with water and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to obtain the title compound 11.90 g (Yield 95%).
  • reaction mixture was diluted with water and extracted with ethylacetate.
  • the extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and separated by column chromatography to obtain the title compound 7.6 g (Yield 81%).
  • Example 64 The compound obtained in Example 64 (300 mg, 0.81 mmol) was dissolved in 15 ml of tetrahydrofuran, 5 ml of water and 5 ml of methanol. 100 mg (2.44 mmol) of Lithium hydroxide monohydrate was added. The mixture was stirred at room temperature for 21 hours. At the end of reaction, tetrahydrofurane and methanol were removed by distillation under reduced pressure. To the distillate 1N HCl solution was added the mixture was extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to obtain the title compound 20 mg (Yield 7%).
  • Example 64 The compound obtained in Example 64 (760 mg, 2.06 mmol) was dissolved in 30 ml of tetrahydrofuran and 2M-lithiumborohydride solution in tetrahydrofuran (2.06 ml, 4.12 mmol) was added. The mixture was at 80° C. for 3 hours. Saturated ammoniumchloride solution was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to obtain the title compound 60 mg (Yield 9%).
  • Example 68 The compound obtained in Example 68 (300 mg, 0.81 mmol) was reacted according to the same procedures as Example 65 to give the title compound 120 mg (Yield 42%).
  • Example 68 The compound obtained in Example 68 (300 mg, 0.81 mmol) was reacted according to the same procedures as Example 66 to give the title compound 150 mg (Yield 54%).
  • Example 71 The compound obtained in Example 71 (350 mg, 1.0 mmol) was reacted according to the same procedures as Example 65 to give the title compound 300 mg (Yield 94%).
  • Example 71 The compound obtained in Example 71 (60 mg, 0.17 mmol) was reacted according to the same procedures as Example 66 to give the title compound 21 mg (Yield 40%).

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US8436038B2 (en) * 2007-08-17 2013-05-07 Lg Life Sciences Ltd. Indole and indazole compounds as an inhibitor of cellular necrosis
US9000028B2 (en) 2007-08-17 2015-04-07 Lg Life Sciences Ltd. Indole and indazole compounds as an inhibitor of cellular necrosis
US20110098297A1 (en) * 2008-04-10 2011-04-28 Takeda Pharmaceutical Company Limited Fused ring compounds and use thereof
US8673942B2 (en) 2008-04-10 2014-03-18 Takeda Pharmaceutical Company Limited Fused ring compounds and use thereof
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GB2516178B (en) * 2012-05-21 2018-08-08 Src Inc Methods and systems for the detection of ricin and other ribosome inactivating proteins
US20160200709A1 (en) * 2013-08-22 2016-07-14 Lg Life Sciences Ltd. Indole compound as inhibitor of necrosis
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JP2011509255A (ja) 2011-03-24
RU2010132644A (ru) 2012-02-10
US8349885B2 (en) 2013-01-08
EP2230238A4 (fr) 2012-11-07
WO2009088192A2 (fr) 2009-07-16
JP5188583B2 (ja) 2013-04-24
EP2230238A2 (fr) 2010-09-22
CN101952281A (zh) 2011-01-19
US20120270203A1 (en) 2012-10-25
BRPI0906612A2 (pt) 2015-07-14
KR101098583B1 (ko) 2011-12-26
CN101952281B (zh) 2014-04-02
RU2460525C2 (ru) 2012-09-10

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