[go: up one dir, main page]

WO2008093940A1 - Quinoline derivatives as caspase-3 inhibitor, preparation process for the same and pharmaceutical composition comprising the same - Google Patents

Quinoline derivatives as caspase-3 inhibitor, preparation process for the same and pharmaceutical composition comprising the same Download PDF

Info

Publication number
WO2008093940A1
WO2008093940A1 PCT/KR2008/000202 KR2008000202W WO2008093940A1 WO 2008093940 A1 WO2008093940 A1 WO 2008093940A1 KR 2008000202 W KR2008000202 W KR 2008000202W WO 2008093940 A1 WO2008093940 A1 WO 2008093940A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
amino
quinoline
nitro
Prior art date
Application number
PCT/KR2008/000202
Other languages
French (fr)
Inventor
Je Wook Han
Sung Gyu Kim
Min Ki Shin
Sang Kwon Sohn
Yoon Sung Jung
Ni Na Ha
Jong Hwan Kim
Original Assignee
Yungjin Pharmaceutical 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 Yungjin Pharmaceutical Co., Ltd. filed Critical Yungjin Pharmaceutical Co., Ltd.
Publication of WO2008093940A1 publication Critical patent/WO2008093940A1/en

Links

Classifications

    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with 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

Definitions

  • the present invention relates to a quinoline derivative with inhibitory effects against caspase-3 activity, a pharmaceutically acceptable salt thereof, a method for preparing the quinoline derivative or the pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.
  • necrosis a form of cell death caused by traumatic or cellular injury. Such necrosis causes damage to other tissues e.g., induction of inflammation. In contrast to necrosis, the other pathological form of cell death processes in an orderly regulated pattern. Such a form of cell death is often referred to as “apoptosis” (Barr, et al . , Bio/Technology, 12:487-497, 1994; whilr, et al., 267:1445-1449, 1995).
  • Apoptosis is programmed cell death and is capable of removing exhausted or aged cells without causing any damage to other tissues. Accordingly, apoptosis is a physiologically essential and important process which maintains normal development and homeostasis of organisms by killing damaged or overgrown cells.
  • caspases are proteins which play the most important roles in apoptosis and fourteen types of caspases have been so far identified. These caspases are cysteine proteases and use a varierty of main cellular proteins as substrates.
  • Apoptosis involves a process in which cells fragmentized by a class of caspase are absorbed in the form of small particles in other cells or are killed by cells such as macrophages without undesired phenomena e.g. inflammation .
  • Caspases are divided into two main groups, i.e. initiator caspases and effector caspases.
  • the initiator caspases serve to initiatilly receive apoptosis signals and then transmit the signals to effector caspases and representative examples thereof include caspase-8 and -9.
  • the effector caspases serve to cleave various cellular components and representative examples thereof include caspase-3, -6 and -7. Of these, caspase-3 has been the most actively researched, which serves as the final acceptor in signal transduction cascades . A great deal of research ascertained that apoptosis can be suppressed by inhibiting expression level or activity of caspase-3.
  • Caspase-3 is a cysteine protease of 32kDa and is an effector caspase which plays a critical role during morphogenetic cell death in mammalian brains. Defective mechanism of caspase-related apoptosis is implicated in a variety of diseases, representatively cancers. Namely, cancer is one of disesases caused by failure of apoptosis. On the other hand, excessive apoptosis causes various neurologic disorders.
  • caspase-3 mediated diseases include Alzheimer's disease (Gervais F. G. et al., Cell, 97 (3) : 395-406, 1999; Walter J. et al., Proc
  • caspase-3 inhibitors for use in treating caspase-mediated diseases such as Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury and osteoarthritis.
  • caspase-mediated diseases such as Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury and osteoarthritis.
  • aspartic acid-based, peptide-based and gamma-keto acid-based compounds were reported as caspase-
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci_ 6 alkyl, C L - 6 alkoxy, Ci-6 alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, C ⁇ - 6 halogenoalkyl or 5- to 15-membered aryl; R is in which R 2 is C or
  • R 3 is - (CH 2 ) n ⁇ in which n is 0, 1, 2, 3 or 4;
  • R 4 is C, N, O or S; and
  • R 5 is hydrogen, halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, C ⁇ _ 6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, Ci_ 6 halogenoalkyl or 5- to 15-membered aryl;
  • A is C, N, O or S
  • Y is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, C ⁇ -6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof.
  • the quinoline derivative or a pharmaceutically acceptable salt thereof has a structure of Formula 1 wherein Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, nitro or Ci-6
  • R is or in which R 2
  • R 3 is N;
  • R 4 is C, N, 0 or S; and
  • R 5 is hydrogen, C ⁇ - 6 alkyl or C ⁇ - 6 alkoxyalkyl;
  • A is N; and
  • Y is hydrogen.
  • the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof may be 5-fluoro-3- [ (7-nitro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-8-trifluoromethyl-quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifiuoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoro
  • the caspase-mediated disease that may employ the quinoline derivative of the Formula 1 or a pharmaceutically acceptable salt thereof may be Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
  • the quinoline derivative of the Formula 1 or a pharmaceutically acceptable salt may be hydrochloride, bromate, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, p-toluenesulfonate, tartrate, trifluoroacetate, acetate, citrate, methanesulfonate, formate, benzoate, malonate, naphthalene-2-sulfonate, benzensulfonate, an alkali-metal salt or an alkaline earth metal salt.
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci-6 alkyl, Ct-e alkoxy, d- ⁇ alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, C ⁇ - 6 halogenoalkyl or 5- to 15-membered aryl;
  • R is , or in which R 2 is C or
  • R 3 is -(CH 2 ) n - in which n is 0, 1, 2, 3 or 4; R 4 is C, N, O or S; and R 5 is hydrogen, halogen, C 1 - 6 alkyl, Ci- 6 alkoxy, Ci- ⁇ alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and
  • Y is hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci- 6 alkyl, Ci_ 6 alkoxy, Ci- 6 alkoxyalkyl , C 3 - 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to
  • R is in which
  • Ri is or in which R 2 and R 3 are defined as above, to obtain a compound represented by Formula 10 below:
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, C 1 - 6 alkyl, C ⁇ - 6 alkoxy, Ci_ 6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, C ⁇ - 6 halogenoalkyl or 5- to
  • R is , or in which
  • a pharmaceutical composition containing a pharmaceutically effective amount of the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof for use in treating a caspase- mediated disease based on inhibition of caspase-3 activity.
  • the caspase-mediated disease using the pharmaceutical composition may be Alzheimer' s disease, Huntington's disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
  • the present invention is directed to a quinoline derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof, for use in treating caspase-mediated diseases based on inhibition of caspase-3 activity:
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci_ 6 alkyl, C ⁇ - 6 alkoxy, Ci- 6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to
  • R is , or in which
  • R. 2 is C or N;
  • R 3 is - (CH 2 ) n ⁇ in which n is O, 1, 2, 3 or 4;
  • R 4 is C, N, 0 or S;
  • R 5 is hydrogen, halogen, Ci-6 alkyl, Ci- 6 alkoxy, Ci- 6 alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, Ci_ 6 halogenoalkyl or 5- to 15-membered aryl;
  • A is C, N, 0 or S;
  • Y is hydrogen, halogen, Ci- 6 alkyl, C ⁇ -6 alkoxy, Ci- 6 alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl.
  • the present inventors ascertained that the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof exhibit considerably excellent inhibitory activity against caspase-3. Accordingly, the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof is suitable for use in treating caspase-3 mediated diseases. Meanwhile, a definition of the terms used herein will be given below.
  • halogen refers to a radical such as fluorine, chlorine or bromine.
  • alkyl refers to a straight-chained or branched hydrocarbon radical and examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and the like.
  • halogenoalkyl refers to a group in which at least one hydrogen atom contained in the alkyl is substituted by halogen.
  • alkoxy refers to a straight-chained or branched alkyl radical linked to oxygen and examples thereof include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy and the like.
  • alkoxyalkyl refers to a radical in which at least one hydrogen atom contained in the alkyl is substituted by alkoxy.
  • the alkoxy may be straight-chained or branched.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • aryl refers to a mono- or poly-cyclic aromatic ring, and in particular is intended to include not only homoaromatic rings having carbon atoms exclusively, but also heteroaromatic rings having nitrogen, sulfur or oxygen atoms in addition to carbon atoms.
  • aryl used herein includes (hetero) aromatic rings in which one or more hydrogen are substituted by the following group selected from acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy and guanido.
  • aryl examples include phenyl, napthyl, pyridinyl pyrimidinyl, quinolinyl, benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, cinnolinyl, carbazolyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, be
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, nitro
  • R 2 is C or N; R 3 is -(CH 2 ) 2-; R4 is C, N, O or S; and R 5 is hydrogen, Ci- 6 alkyl or Ci- 6 alkoxyalkyl; A is N; and Y is hydrogen.
  • the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof may be 5-fluoro-3- [ (7-nitro-4 ⁇ piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-8-trifluoromethyl -quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5-
  • the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof exhibit superior inhibitory activity against caspase-3 and is thus more suitable for use in treating caspase-mediated diseases.
  • caspase-mediated diseases that may employ the quinoline derivative of Formula 1 or pharmaceutically acceptable salt thereof include Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury, osteoarthritis and the like. Owing to potent inhibitory activity against caspase-3, the quinoline derivative of Formula 1 or pharmaceutically acceptable salt thereof may be used to treat any caspase-related disease known to be mediated by caspase-3, in addition to the exemplified disesases .
  • the quinoline derivative of Formula 1 may be a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt may be a salt of pharmaceutically acceptable organic acid, inorganic acid or base.
  • suitable organic and inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycollic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid.
  • suitable bases include alkali metal e.g. sodium, alkaline earth metal e.g. magnesium and ammonium.
  • the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below:
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, C 1 - 6 alkyl, C]_ 6 alkoxy, C ⁇ - 6 alkoxyalkyl, C3- 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to
  • R is , or in which
  • the compound of Formula 2 is reacted with diethylethoxymethylenemalonate to obtain the compound represented by Formula 3.
  • the compound of Formula 3 may be prepared by reacting the compound of Formula 2 with diethylethoxymethylenemalonate without using any additional solvent while heating at 100-150°C.
  • the compound of Formula 3 may be prepared by reacting the compound of Formula 2 with diethylethoxymethylenemalonate, while heating in an organic solvent such as toluene, chlorobenzene or xylene at a boiling point of the organic solvent.
  • the compound of Formula 3 is cyclized in the presence of diphenylether to obtain the compound of Formula 4.
  • the compound of Formula 4 may be prepared by cyclizing the compound of Formula 3 while heating in the presence of diphenylether as an organic solvent at 26O 0 C to a melting point of the organic solvent .
  • the compound of Formula 4 is halogenated to obtain the compound of Formula 5.
  • the compound of Formula 5 is prepared by reacting the compound of Formula 4 with a halogenating agent such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride .
  • the compound of Formula 5 is reacted with RH to obtain the compound of Formula 6.
  • the compound of Formula 6 is prepared by reacting the compound of Formula 5 with RH in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent.
  • the reaction of the compound of Formula 5 with RH may be carried out in the presence of an amine compound and examples of suitable amine compounds include triethylamine, diisopropylethylamine, dimethylaniline, pyridine and quinoline.
  • the compound of Formula 6 is hydrolyzed to obtain the compound of Formula 7.
  • the compound of Formula 7 is prepared by hydrolyzing the compound of Formula 6 with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium bicarbonate in the presence of a mixed solvent of water and an organic solvent such as methanol, ethanol, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent.
  • a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium bicarbonate
  • an organic solvent such as methanol, ethanol, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent.
  • the compound of Formula 7 is reacted with the compound of Formula 8 to obtain the compound of Formula 9.
  • the compound of Formula 9 is prepared by reacting the compound of Formula 7 with the compound of Formula 8 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent.
  • reaction of the compound of Formula 7 with the compound of Formula 8 may be carried out in the presence of 1- hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) .
  • HOBt 1- hydroxybenzotriazole
  • NMM N-methylmorpholine
  • EDC l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • the compound of Formula 9 is carbonylated to obtain the quinoline derivative of Formula 1.
  • the quinoline derivative of Formula 1 is prepared by carbonylating the compound of Formula 9 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide .
  • the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below:
  • Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, C ⁇ -6 alkoxyalkyl, C 3 _ 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to
  • R is , or in which
  • R 1 is or in which R 2 and R 3 are defined as above, to obtain a compound represented by Formula 10 below:
  • the compound of Formula 5 is prepared from the compound of Formula 2 in the same manner as in the aforementioned another aspect. Then, for example, the compound of Formula 5 is reacted with RiH in which a protective group e.g. tert- butoxy is introduced at a R 5 position, to obtain the compound of Formula 10.
  • a protective group e.g. tert- butoxy is introduced at a R 5 position
  • the compound of Formula 10 is prepared by reacting the compound of Formula 5 with RiH in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of an amine compound such as triethylamine, diisopropylethylamine, dimethylaniline, pyridine or quinoline at ambient temperature to the boiling point of the organic solvent.
  • an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide
  • an amine compound such as triethylamine, diisopropylethylamine, dimethylaniline, pyridine or quinoline at ambient temperature to the boiling point of the organic solvent.
  • the compound of Formula 11 is prepared by hydrolyzing the compound of Formula 10 under the same conditions as in the preparation of the compound of Formula 7 of the aforementioned another aspect.
  • the compound of Formula 12 in which a protective group II such as tert-butyl is introduced at a Y position is reacted with the compound of Formula 11 to obtain the compound of Formula 13.
  • the compound of Formula 13 is prepared by reacting the compound of Formula 11 with the compound of Formula 12 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of 1- hydroxybenzotriazole (HOBt) , N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) at ambient temperature to the boiling point of the organic solvent.
  • an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or
  • the compound of Formula 13 is carbonylated to the compound of Formula 14.
  • the quinoline derivative of Formula 14 is prepared by carbonylating the compound of Formula 13 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide .
  • protective groups I and II of the compound of Formula 14 are deprotected to obtain the compound of Formula 1.
  • the deprotection of the protective groups I and II is carried out by reacting the compound of Formula 14 with acid e.g. trifluoroacetic acid. Such deprotection may be performed in an organic solvent e.g. dichloromethane.
  • a quinoline derivative of Formula 1 wherein R 4 is N, and R 5 and Y are hydrogen, or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below: wherein Xi, X 2 , X 3 and X 4 are each independently hydrogen, halogen, Ci_ 6 alkyl, Ci_6 alkoxy, C ⁇ - 6 alkoxyalkyl , C 3 - 6 cycloalkyl, nitro, amino, C1-6 halogenoalkyl or 5- to
  • R is or in which
  • R.2 is C or N;
  • R 3 is -(C ⁇ ) n - in which n is 0, 1, 2, 3 or 4;
  • R 4 is C, N, 0 or S; and
  • R 5 is hydrogen, halogen, C ⁇ - ⁇ alkyl, Ci- 6 alkoxy, C ⁇ - 6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, Ci- 6 halogenoalkyl or 5- to 15-membered aryl;
  • A is C, N, 0 or S;
  • Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
  • the compound of Formula 7 is prepared from the compound of Formula 2 in the same manner as in the aforementioned other aspects.
  • the compound of Formula 12 in which a protective group II e.g. tert-butyl is introduced at a Y position is reacted with the compound of Formula 7 to obtain the compound of Formula 15.
  • the compound of Formula 15 is prepared by reacting the compound of Formula 7 with the compound fo Formula 12 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of 1- hydroxybenzotriazole (HOBt) , N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) at ambient temperature to the boiling point of the organic solvent.
  • an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethyl
  • the compound of Formula 15 is carbonylated to obtain the compound of Formula 16.
  • the quinolone derivative of Formula 16 is prepared by carbonylating the compound of Formula 15 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide, formamide or dimethylsulfoxide .
  • a protective group II of the compound of Formula 16 is deprotected to obtain the quinoline derivative of Formula 1.
  • the deprotection of the protective group II is carried out by reacting the compound of Formula 16 with acid e.g. trifluoroacetic acid. Such deprotection may be performed in an organic solvent e.g. dichloromethane.
  • a quinoline derivative of Formula 1 wherein Y is hydrogen, or a pharmaceutically acceptable salt thereof.
  • Y is hydrogen, or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a pharmaceutical composition containing a pharmaceutically effective amount of the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof, for use in treating a caspase-mediated disease based on inhibition of caspase-3 activity.
  • the pharmaceutical composition comprises the quinoline derivative of Formula 1 with potent inhibitory activity against caspase-3 or a pharmaceutically acceptable salt thereof as an active ingredient and is thus more suitable for use in treating caspase-mediated diseases e.g. Alzheimer's disease, Huntington's disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury, osteoarthritis and the like.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient.
  • excipients that can be used for the pharmaceutical composition include, but are particularly not limited to: ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g.
  • buffer substances e.g. phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids
  • water salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts)
  • colloidal silica e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts
  • colloidal silica e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts
  • colloidal silica e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts
  • colloidal silica e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts
  • the pharmaceutical composition may be administered to subjects such as mammals, e.g. humans by means of oral, parenteral, suction, topical, rectal, intranasal, buccal or intravaginal route.
  • the pharmaceutical composition may be contained in an implant depot.
  • the parenteral administration may be carried out by subcutaneous, intradermal, intravenous, intramuscular, intraarterial, intrasynovial, intracisternal, intrathecal, intratumoral or intracranial injection, or suction.
  • the pharmaceutical composition may be in the form of a sterile injectable preparation e.g. sterile injectable aqueous or oleaginous suspension.
  • the suspension may be formulated using suitable dispersing agents, wetting agents (e.g.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the sterile injectable preparation may comprise vehicles or solvents such as mannitol, water, Ringer's solution or aqueous isotonic salt solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any fixed oil product may be used, including synthetic mono- or diglycerides .
  • fatty acids such as oleic acid or glyceride derivatives thereof may be also useful for injectable preparations, in addition to pharmaceutically acceptable natural oils (in particular, polyoxyethylated natural oils) such as olive oil or castor oil.
  • natural oils in particular, polyoxyethylated natural oils
  • These oil solutions or suspensions may contain a long chain-alcohol diluent or dispersant.
  • the pharmaceutical composition may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, the commonly used excipient is lactose and corn starch. In addition, the tablets may contain lubricants e.g. magnesium stearate.
  • usable diluents are lactose and anhydrous corn starch.
  • active ingredients may be mixed with emulsifying agent and suspending agents.
  • aqueous suspensions may contain specific sweetening, flavoring or coloring agents .
  • the pharmaceutical composition may also be formulated in the form of suppositories for rectal administration.
  • the pharmaceutical composition can be prepared by mixing the active ingredients with a suitable non-irritating excipient which is solid at ambient temperature but liquid at the rectal temperature. Examples of non-irritating excipients include cocoa butter, beeswax, polyethylene glycol and the like.
  • the topical administration of the pharmaceutical composition is particularly useful for the treatment of readily topically applicable sites or organs.
  • the pharmaceutical composition may be formulated in the form of suitable ointments containing the pharmaceutical composition suspended or dissolved in carriers, or be in the form of sprays.
  • suitable ointments containing the pharmaceutical composition suspended or dissolved in carriers, or be in the form of sprays.
  • carriers for topical administration include mineral oils, liquid vaseline, white vaseline, compounds such as propylene glycol, polyoxyethylene or polyoxypropylene, emulsion wax, water and the like.
  • the pharmaceutical composition may be formulated in the form of suitable lotions or creams containing the pharmaceutical composition suspended or dissolved in carriers.
  • suitable carriers include, but are not limited to mineral oils, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, water and the like.
  • the pharmaceutical composition may be also formulated in the form of rectal suppositories or suitable enemata clysters so that it can be topically administered through lower intestinal tracts.
  • the pharmaceutical composition may be formulated as topically-applicable transdermal patches or ocular drops .
  • the pharmaceutical composition may be also administered by nasal aerosols or suction.
  • the pharmaceutical composition is prepared in accordance with a technique well-known in pharmaceutics.
  • the pharmaceutical composition may be prepared as a solution in saline employing suitable preservatives such as benzyl alcohol, absorption promoters to improve bioavailability, fluorocarbon or other solubilizing agents or dispersing agents .
  • the amount of the active ingredient administered through the pharmaceutical composition will vary depending upon a varierty of factors such as the subject in need of, the disease severity, the particular mode of administration, sex and doctor's prescription.
  • An effective amount of the active ingredient will be readily determined by those skilled in the art.
  • the effective amount may be generally in the range of 0.001 to 100 mg/kg/day, preferably 0.001 to LO mg/kg/day.
  • the present invention is directed to the use of a quinoline derivative of the following Formula 1 or a pharmaceutically acceptable salt thereof, for preparing drugs for treating caspase- mediated diseases based on inhibition of caspase-3 activity.
  • Xi, X 2 , X 3 and X4 are each independently hydrogen, halogen, Ci- 6 alkyl, Ct-6 alkoxy, Ci- 6 alkoxyalkyl, C 3 - 6 cycloalkyl, nitro, amino, Ci-e halogenoalkyl or 5- to 15-membered aryl;
  • R is in which R 2 is C or
  • R 3 is - (CH 2 ) n - in which n is 0, 1, 2, 3 or 4; R 4 is C, N, O or S; and R 5 is hydrogen, halogen, Ci_ 6 alkyl, Ci- 6 alkoxy, Ci- 6 alkoxyalkyl, C 3 -S cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
  • A is C, N, 0 or S
  • Y is hydrogen, halogen, Ci- 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 alkoxyalkyl, C 3 - 6 cycloalkyL, nitro, amino, Ci_ 6 halogenoalkyl or 5- to 15-membered aryl.
  • the caspase-mediated diseases include Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury and osteoarthritis.
  • Example 1 Preparation of 5-fluoro-3- [ (7-nitro-4- piperazin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (8)
  • Phosphorus oxychloride (123 g, 800 mmol, 10 eq) was added to the compound 2 (20 g, 80 mmol, 1 eq) and the mixture was stirred under reflux for 12 hours . The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was cooled, neutralized with 20% NaOH and extracted with chloroform.
  • Preparation process 6 Preparation of 4- [3- (1-tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propyl carbamoyl) -7-nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (6) N-methylmorpholine (5.7 g, 56 mmol, 5 eq) , 1- hydroxybenzotriazole (2.3 g, 16.8 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.6 g, 13.4 mmol, 1.2 eq) were added to a solution of the compound 5 (4.5 g, 11.2 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour.
  • Preparation process 7 Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl) -7- nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (7)
  • N-methylmorpholine (0.6 g, 5.9 iranol, 5 eq) , 1- hydroxybenzotriazole (0.24 g, 1.77 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • Preparation process 7 Preparation of 4- [3- (1-fcert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -7- trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (15)
  • Preparation process 8 Preparation of 5-fluoro-4- oxo-3- [ (4-piperazin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid (16)
  • Preparation process 6 Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) - 8-trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (22) N-methylmorpholine (0.6 g, 5.9 mmol, 5 eq) , 1- hydroxybenzotriazole (0.24 g, 1.77 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g, 1.41 mmol, 1.2 eq) were added to a solution of the compound 21 (0.5 g, 1.18 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour.
  • Preparation process 7 Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl) -8- trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (23)
  • a Dess Martin reagent (0.3 g, 0.74 mmol, 1.5 eq) was added to a solution of the compound 22 (0.3 g, 0.49 mmol, 1 eq) in dichloromethane (30 ml) and the mixture was then stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography.
  • N-methylmorpholine (0.78 g, 7.7 mmol, 5 eq)
  • 1- hydroxybenzotriazole (0.31 g, 2.31 mmol, 1.5 eq)
  • 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g, 2.31 mmol, 1.5 eq) were added to a solution of the compound 26 (0.5 g, 1.54 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was then stirred for one hour.
  • An amine reactant (0.32 g, 1.18 mmol, 1 eq) indicated in Reaction Scheme 4 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours.
  • Preparation process 4 Preparation of 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid tert-butyl ester (28)
  • N-methylmorpholine (0.78 g, 7.7 mmol, 5 eq)
  • 1- hydroxybenzotriazole (0.31 g, 2.30 mmol, 1.5 eq)
  • 1- ethyl-3- (3-dimethylaminopropyl ) carbodiimide hydrochloride (0.44 g, 2.3 mmol, 1.5 eq) were added to a solution of the compound 31 (0.5 g, 1.53 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour.
  • An amine reactant (0.32 g, 1.53 mmol, 1 eq) indicated in Reaction Scheme 5 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours.
  • Preparation process 4 Preparation of 5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl-quinoline-3- carbonyl ) -amino] -4-oxo-pentanoic acid tert-butyl ester (33)
  • N-methylmorpholine (0.74 g, 7.3 mmol, 5 eq)
  • 1- hydroxybenzotriazole (0.30 g, 2.19 mmol, 1.5 eq)
  • 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.19 mmol, 1.5 eq) were added to a solution of the compound 36 (0.5 g, 1.46 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour.
  • An amine reactant (0.3 g, 1.46 mmol, 1 eq) indicated in Reaction Scheme 6 was added to the reaction mixture and the resulting mixture was stirred for 1 hours.
  • Preparation process 4 Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-nitro-quinoline ⁇ 3- carboxylic acid ethyl ester (50) Tert-butoxy piperazine (1.3 g, 6.77 mmol) and triethylamine (1.1 g, 11.2 mmol) were added to a solution of the compound 49 (1.6 g, 5.64 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 10 hours. The completion of the reaction was confirmed by thin-layer chromatography. Water (15 ml) was added to the reaction mixture with stirring.
  • Preparation process 6 Preparation of 4- [3- ( I- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) - 8-nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (52) Methylmorpholine (0.38 g, 1.49 mmol), 1- hydroxybenzotriazole (0.2 g, 1.49 mmol) and l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 1.49 mmol) were added to a solution of the compound 51 (0.5 g, 1.24 mmol) in dimethylformamide (5 ml) and the mixture was stirred for 30 minutes.
  • Preparation process 7 Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2--oxo-propylcarbamoyl ) -8- nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (53)
  • a Dess Martin reagent (0.29 g, 0.68 mmol) was added to a solution of the compound 52 (0.34 g, 0.57 mmol) in dichloromethane (3.5 ml) and the mixture was stirred for 10 minutes. The completion of the reaction was confirmed by thin-layer chromatography.
  • Trifluoroacetic acid (1 ml) was added to a solution of the compound 53 (0.2 g, 0.34 mmol) in dichloromethane
  • the target compound 56 was obtained from 2- fluoroaniline 55 in the similar manner as in Preparation process 1 of Example 7.
  • the target compound 57 was obtained from the compound 56 in the similar manner as in Preparation process 2 of Example 7.
  • the target compound 58 was obtained from the compound 57 in the similar manner as in Preparation process 3 of Example 7.
  • Preparation process 4 Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-fluoro-quinoline-3- carboxylic acid ethyl ester (59)
  • the target compound 59 was obtained from the compound 58 in the similar manner as in Preparation process 4 of Example 7.
  • Preparation process 5 Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-fluoro-quinoline-3- carboxylic acid (60)
  • the target compound 60 was obtained from the compound 59 in the similar manner as in Preparation process 5 of Example 7.
  • the target compound 61 was obtained from the compound 60 in the similar manner as in preparation process 6 of Example 7.
  • Preparation process 7 Preparation of 4- [3- ( 1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -8- fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (62)
  • the target compound 62 was obtained from the compound 61 in the similar manner as in Preparation process 7 of Example 7.
  • the target compound 63 was obtained from the compound 62 in the similar manner as in Preparation process 8 of Example 7.
  • the target compound 65 was obtained from 3- fluoroaniline 64 in the similar manner as in Preparation process 1 of Example 7.
  • the target compound 66 was obtained from the compound 65 in the similar manner as in Preparation process 2 of Example 7.
  • the target compound 67 was obtained from the compound 66 in the similar manner as in Preparation process 3 of Example 7.
  • Preparation process 4 Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -7-fluoro-quinoline-3- carboxylic acid ethyl ester (68)
  • the target compound 68 was obtained from the compound 67 in the similar manner as in Preparation process 4 of Example 7.
  • the target compound 69 was obtained from the compound 68 in the similar manner as in Preparation process 5 of Example 7.
  • Preparation process 7 Preparation of 4- [3- (1-tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -7- fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (71)
  • the target compound 71 was obtained from the compound 70 in the similar manner as in Preparation process 7 of Example 7.
  • the target compound 72 was obtained from the compound 71 in the similar manner as in Preparation process 8 of Example 7.
  • the target compound 74 was obtained from the compound 73 in the similar manner as in Preparation process 8 of Example 7.
  • the target compound 76 was obtained from the compound 75 in the similar manner as in Preparation process 8 of Example 7.
  • Example 12 Preparation of 5-fluoro-3- ( ⁇ 4- [4- (2- meth.oxy-eth.yl) —piperazin-1-yl] -8-nitrO-qpiinoline—3- carbonyl ⁇ -amino) -4-oxo-pentanoic acid trifluoroacetic acid (78)
  • the target compound 78 was obtained from the compound 77 in the similar manner as in Preparation process 8 of Example 7.
  • the target compound 80 was obtained from the compound 79 in the similar manner as in Preparation process 8 of Example 7.
  • Inhibitory activity against caspase-3 was evaluated for oxygen-glucose deprivation (OGD) -induced in vitro models of simulated cerebral ischemia.
  • OGD oxygen-glucose deprivation
  • cerebrum cortex was separated from embryo and then centrifuged at 900 rpm for 9 minutes.
  • the resulting precipitate was completely separated into single cells by addition of Dulbecco' s modified Eagle medium (DMEM) containing 10% FBS, 5% HS and 1% PS, and the single cells were seeded on PEI/laminin-coated plates at IxIO 6 cells/ml.
  • DMEM Dulbecco' s modified Eagle medium
  • glucose-free DMEM was gas-bubbled with 95% NO 2 and 5% CO 2 for 20 minutes to remove oxygen present in the medium and then replaced with the medium containing culture cells. Then, the medium was incubated in a hypoxia chamber at 37 0 C for 1.5 hours so that it was exposed to oxygen-glucose deprivation and then treated with a glucose-containing DMEM. At 4 hours following the treatment, in-vivo caspase-3 assay was performed. IxIO 6 cells were collected with a 100 ul cell lysis buffer. The lysate thus obtained was directly reacted with 20 uM DEVD-AFC as a substrate of caspase-3 at 35 0 C for 30 minutes.
  • Caspase-3 known as a cystein protease was obtained by a series of processes involving expression, purification and activation in accordance with the method reported by Rotonda et al. (Nat Struct Biol., 1996, 3(7): 619). Enzyme-level inhibitory activity against caspase-3 of the experimental compounds was evaluated employing the caspase-3 thus obtained.
  • P12 and pl7 subunits were expressed in Escherichia coli, purified by nickel column and anion exchange chromatography and then recombined. Enzyme inactivity of the compounds was measured with Ac-DEVD-AFC as a fluorescent substrate.
  • the caspase-3 was reacted with 10 nM Ac-DEVD-AFC at 37 0 C in the presence of a buffer containing 50 mM NaCl, 10 mM DTT, 1 mM EDTA, 10% glycerol and 0.1% CHAPS, Synergy HT ® available from BIO TEK Instruments, Inc. was used as a fluorescence spectrometer, and the excitation and emission wavelengths herein used were 400 nm and 508 nm, respectively.
  • the present invention provides a quinoline derivative with superior inhibitory activity against caspase-3 or a pharmaceutically acceptable salt thereof. Accordingly, with the quinoline derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one of them, it is possible to prepare a potent drug for treating a caspase-3 related disease e.g. Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
  • a caspase-3 related disease e.g. Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Provided is a quinoline derivative represented by the following Formula (1) for use in treating a caspase- mediated disease by inhibition of caspase-3 activity. Further provided are a method for preparing the quinoline derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same.

Description

[DESCRIPTION] [Invention Title]
QUINOLINE DERIVATIVES AS CASPASE-3 INHIBITOR, PREPARATION PROCESS FOR THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
[Technical Field]
The present invention relates to a quinoline derivative with inhibitory effects against caspase-3 activity, a pharmaceutically acceptable salt thereof, a method for preparing the quinoline derivative or the pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.
[Background Art]
The regulation over the number of mammalian cells is known to be determined by the balance between cell proliferation and cell death. One type of cell death called "necrotic cell death" (also called "necrosis") is characterized as a pathological form of cell death caused by traumatic or cellular injury. Such necrosis causes damage to other tissues e.g., induction of inflammation. In contrast to necrosis, the other pathological form of cell death processes in an orderly regulated pattern. Such a form of cell death is often referred to as "apoptosis" (Barr, et al . , Bio/Technology, 12:487-497, 1994; Steller, et al., 267:1445-1449, 1995). Apoptosis is programmed cell death and is capable of removing exhausted or aged cells without causing any damage to other tissues. Accordingly, apoptosis is a physiologically essential and important process which maintains normal development and homeostasis of organisms by killing damaged or overgrown cells.
There are many causes of apoptosis. Of these, caspases are proteins which play the most important roles in apoptosis and fourteen types of caspases have been so far identified. These caspases are cysteine proteases and use a varierty of main cellular proteins as substrates. Apoptosis involves a process in which cells fragmentized by a class of caspase are absorbed in the form of small particles in other cells or are killed by cells such as macrophages without undesired phenomena e.g. inflammation .
Caspases are divided into two main groups, i.e. initiator caspases and effector caspases. The initiator caspases serve to initiatilly receive apoptosis signals and then transmit the signals to effector caspases and representative examples thereof include caspase-8 and -9. The effector caspases serve to cleave various cellular components and representative examples thereof include caspase-3, -6 and -7. Of these, caspase-3 has been the most actively researched, which serves as the final acceptor in signal transduction cascades . A great deal of research ascertained that apoptosis can be suppressed by inhibiting expression level or activity of caspase-3. Caspase-3 is a cysteine protease of 32kDa and is an effector caspase which plays a critical role during morphogenetic cell death in mammalian brains. Defective mechanism of caspase-related apoptosis is implicated in a variety of diseases, representatively cancers. Namely, cancer is one of disesases caused by failure of apoptosis. On the other hand, excessive apoptosis causes various neurologic disorders.
Representative examples of caspase-3 mediated diseases include Alzheimer's disease (Gervais F. G. et al., Cell, 97 (3) : 395-406, 1999; Walter J. et al., Proc
Natl Acad Sci U S A 96 ( 4 ) : 1391 -6, 1999; Barnes N. Y. et al., J Neurosci 18 (15) : 5869-80, 1998; Kim T. W. et al.,
Science 277 (5324 ): 373-6, 1997), Huntington' s disease
(Goldberg Y. P. et al., Nat Genet. 13(4):442-9, 1996; Wellington C. L. et al., J Biol Chem. 273 (15) : 9158-67, 1998; Sanchez I. et al., Neuron. 22 (3) : 623-33, 1999), Parkinson's disease (Dodel R. C. et al., MoI Brain Res 64(l):141-8, 1999; Takai N. et al., J Neurosci Res 54 (2) :214-22, 1998), ALS (amyltrophic lateral sclerosis) (Pasinelli P. et al., Proc Natl Acad Sci U S A. 95 (26) :15763-8, 1998), AIDS (Kruman I. I. et al., Exp Neurol. 154 (2) : 276-88, 1998), stroke/ischemia (Hara H. et al., Proc Natl Acad Sci U S A. 94 (5) : 2007-12, 1997; Namura S. et al., J Neurosci. 18 (10) : 3659-68, 1998; Schulz J. B. et al., Ann Neurol. 45(4):421-9, 1999), traumatic brain injury (Yakovlev A. G. et al., J Neurosci. 17 (19) : 7415-24 , 1997; Kermer P. et al., J Neurosci. 18 (12 ): 4656-62, 1998; Chaudhary P. et al, MoI Brain Res. 67(l):36-45, 1999), spinal cord injury (Crowe M. J. et al., Nat Med. 3(l):73-6, 1997; Shuman S. L. et al., J Neurosci Res. 50 (5) : 798-808 , 1997), osteoarthritis and the like.
Accordingly, there have been continuous attempts to develop potent drugs employing caspase-3 inhibitors, for use in treating caspase-mediated diseases such as Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury and osteoarthritis. Up to date, aspartic acid-based, peptide-based and gamma-keto acid-based compounds were reported as caspase-
3 inhibitors (WO 93/05071, WO 96/03982, U.S. Pat. No.
5,585,357, WO 00/32620, WO 00/55157 and U.S. Pat. No. 6,153,591) .
However, these compounds cannot exhibit sufficient inhibitory activity against caspase-3. Accordingly, there is a continuous need to develop a material that exhibits more superior inhibitory activity against caspase-3.
[Disclosure] [Technical Problem]
It is one aspect of the present invention to provide a quinoline derivative with superior inhibitory activity against caspase-3 or a pharmaceutically acceptable salt thereof.
It is another aspect of the present invention to provide a method for preparing the quinoline derivative or pharmaceutically acceptable salt thereof.
It is another aspect of the present invention to provide a pharmaceutical composition comprising the quinoline derivative or the pharmaceutically acceptable salt thereof. It is yet another aspect of the present invention to provide the use of the quinoline derivative or pharmaceutically acceptable salt thereof for preparing a drug for treating caspase-mediated diseases based on inhibition of caspase-3 activity.
[Technical Solution]
The present invention has been made to solve the foregoing problems and in accordance with one aspect of the present invention, there is provided a quinoline derivative of the following Formula 1 for use in treating caspase-mediated diseases by inhibition of caspase-3 activity:
Figure imgf000007_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, CL-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000008_0001
R is in which R2 is C or
N; R3 is - (CH2) n~ in which n is 0, 1, 2, 3 or 4; R4 is C, N, O or S; and R5 is hydrogen, halogen, Ci_6 alkyl, Ci_6 alkoxy, Cχ_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl;
A is C, N, O or S; and
Y is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof.
Preferably, the quinoline derivative or a pharmaceutically acceptable salt thereof has a structure of Formula 1 wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, nitro or Ci-6
Figure imgf000008_0002
halogenoalkyl; R is or in which R2
is N; R3 is -(CH2J2-; R4 is C, N, 0 or S; and R5 is hydrogen, Cχ-6 alkyl or Cχ-6 alkoxyalkyl; A is N; and Y is hydrogen.
More preferably, the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof may be 5-fluoro-3- [ (7-nitro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-8-trifluoromethyl-quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifiuoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5- fluoro-3- [ (8-fluoro-4-piperidin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl- quinoline-3-carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro--4-oxo-3- [ (4-thiomorpholin- 4-yl-7-trifluoromethyl-quinoline-3-carbonyl) -amino] - pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (8- nitro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] -4- oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- ({ 4- [4- (2-methoxy-ethyl) -piperazin-1-yl] -8-nitro-quinoline-3- carbonyl } -amino) -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ ( 8-fluoro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (7-fluoro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3-{ [4- (4-methyl-piperazin-l-yl) -8-nitro- quinoline-3-carbonyl] -amino}-4-oxo-pentanoic acid trifluoroacetic acid or 3-{ [4- (4-ethyl-piperazin-l-yl) -8- nitro-quinoline-3-carbonyl] -amino } -5-fluoro-4-oxo- pentanoic acid trifluoroacetic acid.
The caspase-mediated disease that may employ the quinoline derivative of the Formula 1 or a pharmaceutically acceptable salt thereof may be Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
In addition, the quinoline derivative of the Formula 1 or a pharmaceutically acceptable salt may be hydrochloride, bromate, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, p-toluenesulfonate, tartrate, trifluoroacetate, acetate, citrate, methanesulfonate, formate, benzoate, malonate, naphthalene-2-sulfonate, benzensulfonate, an alkali-metal salt or an alkaline earth metal salt.
In accordance with another aspect of the present invention, there is provided a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000011_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Ct-e alkoxy, d-β alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000011_0002
R is , or in which R2 is C or
N; R3 is -(CH2)n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, O or S; and R5 is hydrogen, halogen, C1-6 alkyl, Ci-6 alkoxy, Ci-ε alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and
Y is hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000012_0001
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000012_0002
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000012_0003
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000012_0004
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula 6 below:
Figure imgf000013_0001
wherein Xi, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula 6 to obtain a compound represented by Formula 7 below:
Figure imgf000013_0002
wherein Xi, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 8 to obtain a compound represented by Formula 9 below:
Figure imgf000013_0003
wherein A and Y are defined as above;
Figure imgf000014_0001
wherein Xi, X2, X3, X4, R, A and Y are defined as above; and carbonylating the compound of Formula 9 to obtain the compound of Formula 1 above.
In accordance with another aspect of the present invention, there is provided a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000014_0002
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Ci_6 alkoxy, Ci-6 alkoxyalkyl , C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to
15-membered aryl; R is
Figure imgf000014_0003
in which
R2 is C or N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is N; and R5 is hydrogen; A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000015_0001
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000015_0002
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000015_0003
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000016_0001
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RiH wherein
Ri is
Figure imgf000016_0002
or in which R2 and R3 are defined as above, to obtain a compound represented by Formula 10 below:
Figure imgf000016_0003
wherein Xi, X2, X3, X4 and Ri are defined as above; hydrolyzing the compound of Formula 10 to obtain a compound represented by Formula 11 below:
Figure imgf000016_0004
wherein Xi, X2, X3, X4 and Ri are defined as above; reacting the compound of Formula 11 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 13 below:
Figure imgf000017_0001
wherein A is defined as above;
Figure imgf000017_0002
wherein X1, X2, X3, X4, Ri and A are defined as above; carbonylating the compound of Formula 13 to obtain a compound represented by Formula 14 below:
Figure imgf000017_0003
wherein X1, X2, X3, X4, Ri and A are defined as above; and deprotecting protective groups I and II of the compound of Formula 14 to obtain the compound of Formula 1 above .
In accordance with another aspect of the present invention, there is provided a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000018_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, C1-6 alkyl, Cχ-6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to
Figure imgf000018_0002
15-membered aryl; R is , or in which
R2 is C or N; R3 is - (CH2) n~ in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Cχ_6 alkyl, Cχ-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000019_0001
(2) wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000019_0002
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000019_0003
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000019_0004
wherein X1, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula 6 below:
Figure imgf000020_0001
wherein X1, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula 6 to obtain a compound represented by Formula 7 below:
Figure imgf000020_0002
wherein X1, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 15 below:
Figure imgf000020_0003
• Protective Group II :i2: wherein A is defined as above;
Figure imgf000021_0001
wherein Xi, X2, X3, X4, R and A are defined as above; carbonylating the compound of Formula 15 to obtain a compound represented by Formula 16 below:
I'
Figure imgf000021_0002
wherein Xi, X2, X3, X4, R and A are defined as above; and deprotecting a protective group II of the compound of Formula 16 to obtain the compound of Formula 1 above. In accordance with another aspect of the present invention, there is provided a pharmaceutical composition containing a pharmaceutically effective amount of the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof for use in treating a caspase- mediated disease based on inhibition of caspase-3 activity.
The caspase-mediated disease using the pharmaceutical composition may be Alzheimer' s disease, Huntington's disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
Hereinafter, the construction and operation of preferred embodiments of the present invention will be explained. However, these embodiments are given for the purpose of illustration and are not intended to limit scope of the present invention.
In one aspect, the present invention is directed to a quinoline derivative represented by the following Formula 1 or a pharmaceutically acceptable salt thereof, for use in treating caspase-mediated diseases based on inhibition of caspase-3 activity:
Figure imgf000022_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Cχ-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to
Figure imgf000022_0002
15-membered aryl; R is , or in which
R.2 is C or N; R3 is - (CH2) n~ in which n is O, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen, halogen, Ci-6 alkyl, Cχ-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl.
As will be mentioned in the following Examples or Experimental Examples, as a result of repeated experiments, the present inventors ascertained that the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof exhibit considerably excellent inhibitory activity against caspase-3. Accordingly, the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof is suitable for use in treating caspase-3 mediated diseases. Meanwhile, a definition of the terms used herein will be given below.
First, the term "halogen" refers to a radical such as fluorine, chlorine or bromine.
The term "alkyl" refers to a straight-chained or branched hydrocarbon radical and examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and the like. The term "halogenoalkyl" refers to a group in which at least one hydrogen atom contained in the alkyl is substituted by halogen.
The term "alkoxy" refers to a straight-chained or branched alkyl radical linked to oxygen and examples thereof include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy and the like.
The term "alkoxyalkyl" refers to a radical in which at least one hydrogen atom contained in the alkyl is substituted by alkoxy. The alkoxy may be straight-chained or branched.
The term "cycloalkyl" refers to a non-aromatic hydrocarbon ring and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "aryl" refers to a mono- or poly-cyclic aromatic ring, and in particular is intended to include not only homoaromatic rings having carbon atoms exclusively, but also heteroaromatic rings having nitrogen, sulfur or oxygen atoms in addition to carbon atoms. Further, the term "aryl" used herein includes (hetero) aromatic rings in which one or more hydrogen are substituted by the following group selected from acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy and guanido.
Examples of the aryl include phenyl, napthyl, pyridinyl pyrimidinyl, quinolinyl, benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, cinnolinyl, carbazolyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazianyl, pteridinyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl , benzoxazinyl, dihydrobenzisothiopyranyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxide, tetrahydroquinolinyl-N- oxide, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N- oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, irαidazolinyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N- oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl- N-oxide, benzothiazolyl-N-oxide, benzoimidazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N- oxide and tetrazolyl-N-oxide .
Preferably, in the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof, Xi, X2, X3 and X4 are each independently hydrogen, halogen, nitro
or Ci-6 halogenoalkyl; R is
Figure imgf000026_0001
xn
which R2 is C or N; R3 is -(CH2) 2-; R4 is C, N, O or S; and R5 is hydrogen, Ci-6 alkyl or Ci-6 alkoxyalkyl; A is N; and Y is hydrogen.
More preferably, the quinoline derivative of Formula 1 or the pharmaceutically acceptable salt thereof may be 5-fluoro-3- [ (7-nitro-4~piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-8-trifluoromethyl -quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid, 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoroacetic acid, 5- fluoro-3- [ (8-fluoro-4-piperidin~l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl- quinoline-3-carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-4-oxo-3- [ (4-thiomorpholin- 4-yl-7-trifluoromethyl-quinoline-3-carbonyl) -amino] - pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (8- nitro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] -4- oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- ({ 4- [4- (2-methoxy-ethyl) -piperazin-1-yl] -δ-nitro-quinoline-3- carbonyl} -amino) -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3-[ (8-fluoro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3- [ (7-fluoro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid, 5-fluoro-3-{ [4- (4-methyl-piperazin-l-yl) -8-nitro- quinoline-3-carbonyl] -amino} -4-oxo-pentanoic acid trifluoroacetic acid or 3-{ [4- (4-ethyl-piperazin-l-yl) -8- nitro-quinoline-3-carbonyl] -amino } -5-fluoro-4-oxo- pentanoic acid trifluoroacetic acid.
The quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof exhibit superior inhibitory activity against caspase-3 and is thus more suitable for use in treating caspase-mediated diseases.
Representative examples of caspase-mediated diseases that may employ the quinoline derivative of Formula 1 or pharmaceutically acceptable salt thereof include Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury, osteoarthritis and the like. Owing to potent inhibitory activity against caspase-3, the quinoline derivative of Formula 1 or pharmaceutically acceptable salt thereof may be used to treat any caspase-related disease known to be mediated by caspase-3, in addition to the exemplified disesases . In addition, the quinoline derivative of Formula 1 may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt may be a salt of pharmaceutically acceptable organic acid, inorganic acid or base. Examples of suitable organic and inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycollic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Examples of suitable bases include alkali metal e.g. sodium, alkaline earth metal e.g. magnesium and ammonium.
In another aspect, the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000029_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, C1-6 alkyl, C]_6 alkoxy, Cχ-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to
Figure imgf000029_0002
15-membered aryl; R is , or in which
R.2 is C or N; R3 is -(CH2)n~ in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3--6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen, halogen, Ci_6 alkyl, Ci_6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000030_0001
wherein X1, X2, X3 and X4 are defined as above;
Figure imgf000030_0002
wherein X1, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000030_0003
wherein X1, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below :
Figure imgf000031_0001
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula 6 below:
Figure imgf000031_0002
wherein Xi, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula 6 to obtain a compound represented by Formula 7 below:
Figure imgf000031_0003
wherein Xi, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 8 to obtain a compound represented by Formula 9 below:
Figure imgf000032_0001
wherein A and Y are defined as above;
Figure imgf000032_0002
wherein X1, X2, X3, X4, R, A and Y are defined as above; and carbonylating the compound of Formula 9 to obtain the compound of Formula 1 above.
The respective processes of the preparation method will be illustrated below.
First, the compound of Formula 2 is reacted with diethylethoxymethylenemalonate to obtain the compound represented by Formula 3. In this process, the compound of Formula 3 may be prepared by reacting the compound of Formula 2 with diethylethoxymethylenemalonate without using any additional solvent while heating at 100-150°C. Alternatively, the compound of Formula 3 may be prepared by reacting the compound of Formula 2 with diethylethoxymethylenemalonate, while heating in an organic solvent such as toluene, chlorobenzene or xylene at a boiling point of the organic solvent. Then, the compound of Formula 3 is cyclized in the presence of diphenylether to obtain the compound of Formula 4. In this process, the compound of Formula 4 may be prepared by cyclizing the compound of Formula 3 while heating in the presence of diphenylether as an organic solvent at 26O0C to a melting point of the organic solvent .
Subsequently, the compound of Formula 4 is halogenated to obtain the compound of Formula 5. In this process, the compound of Formula 5 is prepared by reacting the compound of Formula 4 with a halogenating agent such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride .
Then, the compound of Formula 5 is reacted with RH to obtain the compound of Formula 6. In this process, for example, the compound of Formula 6 is prepared by reacting the compound of Formula 5 with RH in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent. Alternatively, the reaction of the compound of Formula 5 with RH may be carried out in the presence of an amine compound and examples of suitable amine compounds include triethylamine, diisopropylethylamine, dimethylaniline, pyridine and quinoline.
Then, the compound of Formula 6 is hydrolyzed to obtain the compound of Formula 7. In this process, for example, the compound of Formula 7 is prepared by hydrolyzing the compound of Formula 6 with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium bicarbonate in the presence of a mixed solvent of water and an organic solvent such as methanol, ethanol, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent.
Then, the compound of Formula 7 is reacted with the compound of Formula 8 to obtain the compound of Formula 9. In this process, for example, the compound of Formula 9 is prepared by reacting the compound of Formula 7 with the compound of Formula 8 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide at ambient temperature to the boiling point of the organic solvent. Alternatively, the reaction of the compound of Formula 7 with the compound of Formula 8 may be carried out in the presence of 1- hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) .
Then, the compound of Formula 9 is carbonylated to obtain the quinoline derivative of Formula 1. In this process, for example, the quinoline derivative of Formula 1 is prepared by carbonylating the compound of Formula 9 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide . In another aspect, the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000035_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Ci_6 alkoxy, Cχ-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to
Figure imgf000036_0001
15-membered aryl; R is , or in which
R2 is C or N; R3 is -(CHa)n" in which n is 0, 1, 2, 3 or 4; R4 is N; and R5 is hydrogen; A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethyl enemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000036_0002
wherein X1, X2, X3 and X4 are defined as above;
Figure imgf000036_0003
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000037_0001
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RiH wherein
R1 is
Figure imgf000037_0003
or in which R2 and R3 are defined as above, to obtain a compound represented by Formula 10 below:
Figure imgf000037_0004
wherein Xi, X2, X3, X4 and Ri are defined as above; hydrolyzing the compound of Formula 10 to obtain a compound represented by Formula 11 below:
Figure imgf000038_0001
wherein Xi, X2, X3, X4 and Ri are defined as above; reacting the compound of Formula 11 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 13 below:
Figure imgf000038_0002
OtouB U (12)
wherein A is defined as above;
Figure imgf000038_0003
wherein Xi, X2, X3, X4, Ri and A are defined as above; carbonylating the compound of Formula 13 to obtain a compound represented by Formula 14 below:
Figure imgf000039_0001
wherein Xi, X2, X3, X4, Ri and A are defined as above; and deprotecting protective groups I and II of the compound of Formula 14 to obtain the compound of Formula 1 above .
In this preparation method, the compound of Formula 5 is prepared from the compound of Formula 2 in the same manner as in the aforementioned another aspect. Then, for example, the compound of Formula 5 is reacted with RiH in which a protective group e.g. tert- butoxy is introduced at a R5 position, to obtain the compound of Formula 10. In this process, for example, the compound of Formula 10 is prepared by reacting the compound of Formula 5 with RiH in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of an amine compound such as triethylamine, diisopropylethylamine, dimethylaniline, pyridine or quinoline at ambient temperature to the boiling point of the organic solvent.
Then, the compound of Formula 11 is prepared by hydrolyzing the compound of Formula 10 under the same conditions as in the preparation of the compound of Formula 7 of the aforementioned another aspect.
Then, for example, the compound of Formula 12 in which a protective group II such as tert-butyl is introduced at a Y position, is reacted with the compound of Formula 11 to obtain the compound of Formula 13. In this process, for example, the compound of Formula 13 is prepared by reacting the compound of Formula 11 with the compound of Formula 12 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of 1- hydroxybenzotriazole (HOBt) , N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) at ambient temperature to the boiling point of the organic solvent.
Then, the compound of Formula 13 is carbonylated to the compound of Formula 14. In this process, for example, the quinoline derivative of Formula 14 is prepared by carbonylating the compound of Formula 13 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide . Then, protective groups I and II of the compound of Formula 14 are deprotected to obtain the compound of Formula 1. In this process, the deprotection of the protective groups I and II is carried out by reacting the compound of Formula 14 with acid e.g. trifluoroacetic acid. Such deprotection may be performed in an organic solvent e.g. dichloromethane.
In the preparation method according to the aforementioned another aspect, there is prepared a quinoline derivative of Formula 1 wherein R4 is N, and R5 and Y are hydrogen, or a pharmaceutically acceptable salt thereof. By introducing any substituent at a R5 or Y position of the quinoline derivative or a pharmaceutically acceptable salt thereof, it is possible to prepare other quinoline derivatives or pharmaceutically acceptable salts thereof that fall within the scope of the compound of Formula 1.
In another aspect, the present invention is directed to a method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000042_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Ci_6 alkoxy, Cχ-6 alkoxyalkyl , C3-6 cycloalkyl, nitro, amino, C1-6 halogenoalkyl or 5- to
Figure imgf000042_0002
15-membered aryl; R is or in which
R.2 is C or N; R3 is -(C^)n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, C±-β alkyl, Ci-6 alkoxy, Cχ-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000042_0003
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000043_0001
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000043_0002
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000043_0003
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula 6 below:
Figure imgf000044_0001
wherein Xi, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula β to obtain a compound represented by Formula 7 below:
Figure imgf000044_0002
wherein Xi, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 15 below:
Figure imgf000044_0003
' Protective Group II :i2: wherein A is defined as above;
Figure imgf000044_0004
wherein Xi, X2, X3, X4, R and A are defined as above; carbonylating the compound of Formula 15 to obtain a compound represented by Formula 16 below:
Figure imgf000045_0001
wherein X1, X2, X3, X4, R and A are defined as above; and deprotecting a protective group II of the compound of Formula 16 to obtain the compound of Formula 1 above.
In this preparation method, the compound of Formula 7 is prepared from the compound of Formula 2 in the same manner as in the aforementioned other aspects.
Then, the compound of Formula 12 in which a protective group II e.g. tert-butyl is introduced at a Y position, is reacted with the compound of Formula 7 to obtain the compound of Formula 15. In this process, for example, the compound of Formula 15 is prepared by reacting the compound of Formula 7 with the compound fo Formula 12 in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide or dimethylsulfoxide in the presence of 1- hydroxybenzotriazole (HOBt) , N-methylmorpholine (NMM) or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) at ambient temperature to the boiling point of the organic solvent.
Then, the compound of Formula 15 is carbonylated to obtain the compound of Formula 16. In this process, for example, the quinolone derivative of Formula 16 is prepared by carbonylating the compound of Formula 15 via oxidation with a Dess Martin reagent in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, anisole, acetonitrile, propionitrile, dimethylformamide, formamide or dimethylsulfoxide .
Then, a protective group II of the compound of Formula 16 is deprotected to obtain the quinoline derivative of Formula 1. In this process, the deprotection of the protective group II is carried out by reacting the compound of Formula 16 with acid e.g. trifluoroacetic acid. Such deprotection may be performed in an organic solvent e.g. dichloromethane. In this preparation method according to the aforementioned another aspect, there is prepared a quinoline derivative of Formula 1 wherein Y is hydrogen, or a pharmaceutically acceptable salt thereof. By introducing any substituent at a Y position of the quinoline derivative or a pharmaceutically acceptable salt thereof, it is possible to prepare other quinoline derivatives or pharmaceutically acceptable salts thereof that fall within the scope of the compound of Formula 1. In another aspect, the present invention is directed to a pharmaceutical composition containing a pharmaceutically effective amount of the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof, for use in treating a caspase-mediated disease based on inhibition of caspase-3 activity.
The pharmaceutical composition comprises the quinoline derivative of Formula 1 with potent inhibitory activity against caspase-3 or a pharmaceutically acceptable salt thereof as an active ingredient and is thus more suitable for use in treating caspase-mediated diseases e.g. Alzheimer's disease, Huntington's disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury, osteoarthritis and the like. In addition to the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition may further comprise a pharmaceutically acceptable excipient. Examples of excipients that can be used for the pharmaceutical composition include, but are particularly not limited to: ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g. human serum albumin), buffer substances (e.g. phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, wool fat and the like.
In addition, the pharmaceutical composition may be administered to subjects such as mammals, e.g. humans by means of oral, parenteral, suction, topical, rectal, intranasal, buccal or intravaginal route. Alternatively, the the pharmaceutical composition may be contained in an implant depot. The parenteral administration may be carried out by subcutaneous, intradermal, intravenous, intramuscular, intraarterial, intrasynovial, intracisternal, intrathecal, intratumoral or intracranial injection, or suction. The pharmaceutical composition may be in the form of a sterile injectable preparation e.g. sterile injectable aqueous or oleaginous suspension. The suspension may be formulated using suitable dispersing agents, wetting agents (e.g. tween 80) or suspending agents in accordance with a method well-known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. The sterile injectable preparation may comprise vehicles or solvents such as mannitol, water, Ringer's solution or aqueous isotonic salt solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any fixed oil product may be used, including synthetic mono- or diglycerides . In addition, fatty acids such as oleic acid or glyceride derivatives thereof may be also useful for injectable preparations, in addition to pharmaceutically acceptable natural oils (in particular, polyoxyethylated natural oils) such as olive oil or castor oil. These oil solutions or suspensions may contain a long chain-alcohol diluent or dispersant. The pharmaceutical composition may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, the commonly used excipient is lactose and corn starch. In addition, the tablets may contain lubricants e.g. magnesium stearate. In the case of capsules for oral administration, usable diluents are lactose and anhydrous corn starch. In the case of aqueous suspensions for oral administration, active ingredients may be mixed with emulsifying agent and suspending agents. In addition, if necessary, aqueous suspensions may contain specific sweetening, flavoring or coloring agents . The pharmaceutical composition may also be formulated in the form of suppositories for rectal administration. The pharmaceutical composition can be prepared by mixing the active ingredients with a suitable non-irritating excipient which is solid at ambient temperature but liquid at the rectal temperature. Examples of non-irritating excipients include cocoa butter, beeswax, polyethylene glycol and the like.
The topical administration of the pharmaceutical composition is particularly useful for the treatment of readily topically applicable sites or organs. For example, upon topical application to the skin, the pharmaceutical composition may be formulated in the form of suitable ointments containing the pharmaceutical composition suspended or dissolved in carriers, or be in the form of sprays. Examples of carriers for topical administration that can be used for the pharmaceutical composition include mineral oils, liquid vaseline, white vaseline, compounds such as propylene glycol, polyoxyethylene or polyoxypropylene, emulsion wax, water and the like.
The pharmaceutical composition may be formulated in the form of suitable lotions or creams containing the pharmaceutical composition suspended or dissolved in carriers. Suitable carriers include, but are not limited to mineral oils, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, water and the like.
The pharmaceutical composition may be also formulated in the form of rectal suppositories or suitable enemata clysters so that it can be topically administered through lower intestinal tracts. In addition, the pharmaceutical composition may be formulated as topically-applicable transdermal patches or ocular drops .
The pharmaceutical composition may be also administered by nasal aerosols or suction. The pharmaceutical composition is prepared in accordance with a technique well-known in pharmaceutics. For example, the pharmaceutical composition may be prepared as a solution in saline employing suitable preservatives such as benzyl alcohol, absorption promoters to improve bioavailability, fluorocarbon or other solubilizing agents or dispersing agents .
The amount of the active ingredient administered through the pharmaceutical composition will vary depending upon a varierty of factors such as the subject in need of, the disease severity, the particular mode of administration, sex and doctor's prescription. An effective amount of the active ingredient will be readily determined by those skilled in the art. The effective amount may be generally in the range of 0.001 to 100 mg/kg/day, preferably 0.001 to LO mg/kg/day.
In another aspect, the present invention is directed to the use of a quinoline derivative of the following Formula 1 or a pharmaceutically acceptable salt thereof, for preparing drugs for treating caspase- mediated diseases based on inhibition of caspase-3 activity.
Figure imgf000053_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Ct-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-e halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000053_0002
R is in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, O or S; and R5 is hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3-S cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
A is C, N, 0 or S; and
Y is hydrogen, halogen, Ci-6 alkyl, Ci_6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyL, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl.
The caspase-mediated diseases include Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury and osteoarthritis.
[Mode for Invention] Example 1: Preparation of 5-fluoro-3- [ (7-nitro-4- piperazin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (8)
[Reaction Scheme 1]
ether
Figure imgf000054_0001
Figure imgf000054_0002
Preparation process 1: Preparation of 2- [ (3-nitro- phenylamino) -methylene] -malonic acid diethyl ester (1)
Diethylethoxymethylenemalonate (150 g, 694 mmol, 1.1 eq) was added to a solution of 3-nitroaniline (87 g, 631 mmol, 1 eq) in xylene (600 ml) and the mixture was stirred at 13O0C for 4 hours. The completion of the reaction was confirmed by thin-layer chromatography. The reaction product was cooled and filtered to obtain the target compound 1 (155 g, yield = 80 %) . 1H NMR (CDCl3, 300 MHz) δ: 11.06 (d, J = 9.8 Hz,
IH), 8.49 (d, J = 13.2 Hz, IH), 8.00 - 7.96 (m, 2H), 7.56 - 7.51 (m, IH), 7.43 - 7.24 (m, IH), 4.35 - 4.24 (m, 4H), 1.41 - 1.28 (m, 6H) .
Preparation process 2: Preparation of 7-nitro~4- oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester
(2)
The compound 1 (85 g, 280 mmol, 1 eq) was slowly added to refluxing diphenyl ether (250 ml) and the mixture was stirred for one hour. After cooling, the mixture was decanted and filtered to obtain the target compound 2 (6O g, yield = 82 %) . 1H NMR (DMSO, 300 MHz) δ: 8.75 - 8.50 (m, IH) , 838 - 8.13 (m, IH) , 7.88 - 7.84 (m, 2H) , 7.66 - 7.62 (m, IH) , 4.25 - 4.19 (m, 2H), 1.38 - 1.18 (m, 3H) .
Preparation process 3: Preparation of 4-chloro-7- nitro-quinoline-3-carboxylic acid ethyl ester (3)
Phosphorus oxychloride (123 g, 800 mmol, 10 eq) was added to the compound 2 (20 g, 80 mmol, 1 eq) and the mixture was stirred under reflux for 12 hours . The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was cooled, neutralized with 20% NaOH and extracted with chloroform.
The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 3 (8.4 g, yield =
37 %) .
1H NMR (CDCl3, 400 MHz) δ: 9.30 (s, IH), 9.00 (s, IH), 8.59 - 8.56 (m, IH), 8.45 - 8.42 (m, IH), 4.53 (q, J = 7.2 Hz, 2H), 1.49 (t, J= 7.2 Hz, 3H). aaa
Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl ) ~7-nitro-quinoline-3- carboxylic acid ethyl ester (4) Tert-butoxy piperazine (5 g, 27.7 mmol, 1.1 eq) and trimethylamine (5.1 g, 50.4 mmol, 2 eq) were added to a solution of the compound 4 (7 g, 25.2 mmol, 1 eq) in dichloromethane (100 ml) and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate: hexane = 1 : 2) to obtain the target compound 4 (10.2 g, yield = 92 %) .
1H NMR (CDCl3, 300 MHz) δ : 9.01 (s, 0.5H), 8.95 (s, 0.5H), 8.31 (s, IH), 8.31 - 8.30 (m, IH), 7.33 - 7.31 (m, IH), 7.26 (s, IH), 4.49 (q, J = 7.1 Hz, 2H), 3.73 - 3.70 (m, 4H), 3.31 - 3.28 (m, 4H), 1.52 - 1.43 (m, 12H).
Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -7-nitro-quinoline-3- carboxylic acid (5) Lithium hydroxide (1.18 g, 27.9 mmol, 1.5 eq) was added to a solution of the compound 4 (8 g, 18.6 mmol, 1 eq) in ethanol (40 ml) and water (40 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 5 (6.8 g, yield = 90 %) .
1H NMR (CD3OD, 300 MHz) δ: 8.92 - 8.77 (m, 2H), 8.50 - 8.41 (m, IH), 8.33 - 8.29 (m, IH), 3.71 - 3.70 (m, 4H), 3.43 - 3.30 (m, 4H), 1.50 (s, 9H).
Preparation process 6: Preparation of 4- [3- (1-tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propyl carbamoyl) -7-nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (6) N-methylmorpholine (5.7 g, 56 mmol, 5 eq) , 1- hydroxybenzotriazole (2.3 g, 16.8 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.6 g, 13.4 mmol, 1.2 eq) were added to a solution of the compound 5 (4.5 g, 11.2 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour. An amine reactant (2.3 g, 11.2 mmol, 1 eq) indicated in Reaction Scheme 1 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 6 (3 g, yield = 46 %) .
1H NMR (CDCl3, 300 MHz) δ: 8.97 - 8.41 (m, 2H), 8.34 - 8.21 (m, 2H), 7.40 - 7.33 (m, IH), 4.67 - 4.50 (m, 3H), 4.51 - 4.48 (m, IH), 3.70 (brs, 4H), 3.33 - 3.29 (m, 4H), 2.82 - 2.73 (m, 2H), 1.50 - 1.45 (m, 18H).
Preparation process 7: Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl) -7- nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (7)
A Dess Martin reagent (2.6 g, 6.1 mmol, 1.2 eq) was added to a solution of the compound 6 (3 g, 5.1 mmol, 1 eq) in dichloromethane (30 ml) and the mixture was stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 7 (1.8 g, yield = 60 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.93 (d, J = 1.9 Hz, IH),
8.91 (s, IH), 8.31 - 8.26 (m, 2H), 7.46 (d, J = 7.4 Hz, IH), 5.25 - 5.19 (m, 2H), 5.16 - 5.06 (m, IH), 3.71 (s,
4H), 3.30 (t, J = 4.9 Hz, IH), 3.15 - 3.07 (m, 2H), 1.51
(s, 9H) , 1.44 (s, 9H) .
Preparation process 8 : Preparation of 5-fluoro-3- [ (7-nitro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] - 4-oxo-pentanoic acid trifluoroacetic acid (8)
Trifluoroacetic acid (10 ml, 38 eq) was added to a solution of the compound 7 (1.8 g, 3.05 mmol, 1 eq) in dichloromethane (10 ml) and the mixture was stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 8 (1.3 g, yield = 77 %) . 1H NMR (CD3OD, 500 MHz) δ: 8.89 - 8.83 (m, 2H), 8.45
- 8.40 (m, 2H), 5.20 - 5.05 (m, IH), 4.65 - 4.35 (m, 2H), 3.65 -3.49 (m, 8H), 3.00 - 2.55 (m, 2H). Example 2: Preparation of 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-7-trifluoromethyl-quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid (16)
[Reaction Scheme 2]
Figure imgf000061_0001
Preparation process 1: Preparation of 2-[(3- trifluoromethyl-phenylamino) -methylene] -malonic acid diethyl ester (9)
Diethylethoxymethylenemalonate (19.3 g, 89.4 mmol, 1.2 eq) was added to 3- (trifluoromethyl) aniline (10 g, 62.1 mmol, 1 eq) and the mixture was stirred at 1300C for 4 hours . The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was filtered to obtain the compound 9 (20 g, yield = 97 %) . 1H NMR (CDCl3, 500 MHz) δ: 11.1 (d, J = 13.3 Hz, IH), 8.51 (d, J = 13.4 Hz, IH), 7.60 - 7.49 (m, IH), 7.41 - 7.28 ( (m, 2H), 4.33 - 4.26 (m, 6H), 1.40 - 1.35 (m, 9H) .
Preparation process 2: Preparation of 4-oxo-7- trifluoromethyl-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (10)
The compound 9 (10 g, 30.2 mmol, 1 eq) was slowly added to refluxing diphenyl ether (30 ml) and the mixture was stirred for one hour. After cooling, the reaction mixture was slowly decanted and filtered to obtain the compound 10 (6 g, yield = 70 %) .
1H NMR (DMSO, 500 MHz) δ: 8.70 - 8.53 (m, IH), 8.34 (d, J = 8.6 Hz, 0.5H), 7.97 - 7.67 (m, 2H), 7.41 - 7.38 (m, IH), 7.15 - 7.00 (m, IH), 4.24 - 4.20 (m, 2H), 1.30 - 1.23 (m, 3H) .
Preparation process 3: Preparation of 4-chloro-7- trichloromethyl-quinoline-3-carboxylic acid ethyl ester (11)
Phosphorus oxychloride (26.8 g, 175 mmol, 10 eq) was added to the compound 10 (5 g, 17.5 mmol, 1 eq) and the mixture was stirred under reflux for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was cooled, neutralized with 20% NaOH and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 11 (3 g, yield = 57 %) .
1H NMR (CDCl3, 500 MHz) δ: 1.30 - 1.23 (m, 3H), 8.57 - 8.54 (m, IH), 8.46 (s, IH), 7.77 (t, J = 7.9 Hz, IH), 4.55 - 4.50 (m, 2H), 1.50 - 1.46 (m, 3H).
Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl ) -7-trifluoromethyl- quinoline-3-carboxylic acid ethyl ester (12) Tert-butoxy piperazine (1.4 g, 7.3 mmol, 1.1 eq) and triethylamine (1.3 g, 13.2 mmol, 2 eq) were added to a solution of the compound 11 (2 g, 6.6 mmol, 1 eq) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography and the reaction mixture was then extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate: hexane = 1 : 2) to obtain the target compound 12 (2.2 g, yield = 73 %) .
1H NMR (CDCl3, 500 MHz) δ : 8.98 (s, IH), 8.38 (s, IH), 8.29 (d, J = 8.8 Hz, IH), 7.74 - 7.72 (m, IH), 4.48 (q, J = 7.1 Hz, 2H), 3.71 (s, 4H), 3.29 (s, 4H), 1.51 (s, 9H) , 1.45 (t, J = 7.1 Hz, 3H) .
Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -7-trifluoromethyl- quinoline-3-carboxylic acid (13)
Lithium hydroxide (0.56 g, 13.2 mmol, 3 eq) was added to a solution of the compound 12 (2 g, 4.4 mmol, 1 eq) in ethanol (40 ml) and water (40 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was then neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 13 (1.7 g, yield = 90 %) .
1H NMR (CD3OD, 500 MHz) δ: 8.84 - 8.74 (m, IH), 8.45 - 8.37 (m, IH), 8.18 (d, J = 3.6 Hz, IH), 7.76 - 7.72 (m, IH) , 3 . 67 - 3 . 56 (m, 4H ) , 3 . 38 - 3 . 12 (m, 4H ) , 1 . 48 - 1 . 43 (m, 9H) .
Preparation process 6: Preparation of 4- [3- ( 1- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) - 7-trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (14)
N-methylmorpholine (0.6 g, 5.9 iranol, 5 eq) , 1- hydroxybenzotriazole (0.24 g, 1.77 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
(0.27 g, 1.41 mmol, 1.2 eq) were added to a solution of the compound 13 (0.5 g, 1.18 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour. An amine reactant (0.25 g, 1.18 mmol, 1 eq) indicated in Reaction Scheme 2 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 14 (0.4 g, yield = 55 %) . 1H NMR (CDCl3, 500 MHz) δ : 8.89 - 8.83 (m, IH) ,
8.36 - 8.01 (m, 2H) , 7.72 - 7.70 (m, IH) , 7.37 - 7.35 (m,
IH) , 4.62 - 4.50 (m, 3H) , 4.16 - 4.15 (m, IH) , 3.70 -
3.62 (m, 4H) , 3.31 (s, 4H) , 2.96 - 2.79 (m, 2H) , 1.51 - 1.42 (m, 18H) .
Preparation process 7: Preparation of 4- [3- (1-fcert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -7- trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (15)
A Dess Martin reagent (0.3 g, 0.74 πunol, 1.5 eq) was added to a solution of the compound 14 (0.3 g, 0.49 itimol, 1 eq) in dichloromethane (30 ml) and the mixture was stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 15 (0.2 g, yield = 67 %) .
1H NMR (CDCl3, 500 MHz) δ : 8.89 (s, IH), 8.38 (s, IH), 8.26 (d, J = 8.7 Hz, IH), 7.73 - 7.70 (m, IH), 7.50 (d, J = 7.4 Hz, IH), 5.25 - 5.06 (m, 3H), 3.70 (s, 4H), 3.30 (s, 4H), 3.15 - 3.04 (m, 2H), 1.51 - 1.26 (m, 18H) .
Preparation process 8: Preparation of 5-fluoro-4- oxo-3- [ (4-piperazin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid (16)
Trifluoroacetic acid (0.73 ml, 38 eq) was added to a solution of the compound 15 (0.15 g, 0.25 mmol, 1 eq) in dichloromethane (0.73 ml) and the mixture was stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 16 (0.1 g, yield = 71 %) .
1H NMR (CD3OD, 500 MHz) δ: 8.86 - 8.80 (m, IH), 8.42 (t, J = 8.6 Hz, IH), 8.33 (d, J = 8.8 Hz, IH), 7.90 - 7.87 (m, 3H), 4.87 - 4.51 (m, 3H), 3.59 - 3.45 (m, 8H), 2.97 - 2.62 (m, 2H) .
Example 3: Preparation of 5-fluoro-4-oxo-3- [ (4- piperazin-l-yl-8-trifluoromethyl-quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid (24) [Reaction Scheme 3]
ether
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Preparation process 1: Preparation of 2-[(2- trifluoromethyl-phenylamino) -methylene] -malonic acid diethyl ester (17)
Diethylethoxymethylenemalonate (19.3 g, 89.4 mmol, 1.2 eq) was added to 2- (trif Luoromethyl) aniline (10 g, 62.1 mmol, 1 eq) , the mixture was stirred at 130°C for 4 hours . The completion of the reaction was confirmed by thin-layer chromatography. The reaction product was cooled and filtered to obtain the target compound 17 (19 g, yield = 93 %) .
1H NMR (CDCl3, 500 MHz) δ: 11.36 (d, J = 12.6 Hz, IH), 8.47 (d, J = 12.8 Hz, IH), 7.66 - 7.59 (m, 2H), 7.38 (d, J = 8.3 Hz, IH), 7.28 - 7.24 (m, IH), 4.37 - 4.19 (m, 4H) , 1.39 - 1.27 (m, 6H) .
Preparation process 2: Preparation of 4-oxo-8- trifluoromethyl-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (18)
The compound 17 (10 g, 30.2 mmol, 1 eq) was slowly added to refluxing diphenyl ether (30 ml) and the mixture was stirred for one hour. After cooling, the mixture was slowly decanted and filtered to obtain the target compound 18 (7.5 g, yield = 87 %).
1H NMR (DMSO, 500 MHz) δ: 11.67 (brs, IH), 8.49 - 8.47 (m, 2H), 8.21 (d, J = 7.4 Hz, IH), 7.58 (t, J = 7.8 Hz, IH), 4.24 (d, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H) .
Preparation process 3: Preparation of 4-chloro-8- trichloroirtethyl-quinoline-3-carboxylic acid ethyl ester (19) Phosphorus oxychloride (26.8 g, 175 mmol, 10 eq) was added to the compound 18 (5 g, 17.5 mmol, 1 eq) and the mixture was stirred under reflux for 12 hours . The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was cooled, neutralized with 20% NaOH and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 19 (4 g, yield = 76 %) .
1H NMR (CDCl3, 500 MHz) δ: 9.36 (s, IH), 8.65 (d, J = 8.5 Hz, IH), 8.28 (d, J = 7.3 Hz, IH), 7.77 (t, J = 7.9 Hz, IH), 4.54 (q, J = 7.1 Hz, IH), 1.47 (d, J = 7.1 Hz, 3H) .
Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-trifluoromethyl- quinoline-3-carboxylic acid ethyl ester (20)
Tert-butoxy piperazine (1.4 g, 7.3 mmol, 1.1 eq) and triethylamine (1.3 g, 13.2 mmol, 2 eq) were added to a solution of the compound 19 (2 g, 6.6 mmol, 1 eq) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography and the reaction mixture was extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 20 (2.2 g, yield = 73 %) .
1H NMR (CDCl3, 500 MHz) δ : 9.06 (s, IH), 8.40 (d, J = 8.5 Hz, IH), 8.10 (d, J = 7.1 Hz, IH), 7.61 (t, J = 7.9 Hz, IH), 4.47 (d, J = 7.1 Hz, 2H), 3.70 (s, 4H), 3.28 (s, 4H), 1.51 (s, 9H), 1.43 (t, J= 7.1 Hz, 3H).
Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-l-yl) -8-trifluoromethyl- quinoline-3-carboxylic acid (21)
Lithium hydroxide (0.56 g, 13.2 mmol, 3 eq) was added to a solution of the compound 20 (2 g, 4.4 mmol, 1 eq) in ethanol (40 ml) and water (40 ml), and the mixture was then stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 21 (1.7 g, yield = 90 %) . 1H NMR (CD3OD, 500 MHz) δ: 8.89 (s, IH), 8.77 (d, J = 1.8 Hz, IH), 8.48 (d, J = 4.2 Hz, IH), 8.04 (d, J = 3.6 Hz, IH), 7.65 - 7.61 (m, IH), 3.67 (s, 4H), 3.36 - 3.16 (m, 4H) , 1.48 - 1.26 (m, 9H) .
Preparation process 6: Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) - 8-trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (22) N-methylmorpholine (0.6 g, 5.9 mmol, 5 eq) , 1- hydroxybenzotriazole (0.24 g, 1.77 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.27 g, 1.41 mmol, 1.2 eq) were added to a solution of the compound 21 (0.5 g, 1.18 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour. An amine reactant (0.25 g, 1.18 mmol, 1 eq) indicated in Reaction Scheme 3 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 22 (0.5 g, yield = 69 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.97 - 8.67 (m, IH), 8.38
- 8.36 (m, IH), 8.09 - 8.00 (m, IH), 7.61 - 7.58 (m, IH), 7.30 - 7.26 (m, IH), 4.54 - 4.49 (in, 3H), 4.15 (s, IH),
3.69 (s, 4H), 3.32 - 3.29 (m, 4H), 3.03 - 2.71 (m, 2H),
1.55 - 1.44 (m, 18H) .
Preparation process 7: Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl) -8- trifluoromethyl-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (23)
A Dess Martin reagent (0.3 g, 0.74 mmol, 1.5 eq) was added to a solution of the compound 22 (0.3 g, 0.49 mmol, 1 eq) in dichloromethane (30 ml) and the mixture was then stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography.
After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound
23 (0.17 g, yield = 57 %) . 1H NMR (CDCl3, 500 MHz) δ: 8.97 (s, IH), 8.38 - 8.37 (m, IH), 8.11 - 8.04 (m, IH), 7.60 (t, J = 7.9 Hz, IH), 7.43 - 7.37 (m, IH), 5.21 - 5.06 (m, 3H), 3.70 (s, 4H), 3.29 (s, 4H), 3.15 - 3.01 (m, 2H), 1.52 - 1.41 (m, 18H).
Preparation process 8: Preparation of 5-fluoro-4- oxo-3- [ (4-piperazin-l-yl-8-trif Luoromethyl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid (24) Trifluoroacetic acid (0.73 ml, 38 eq) was added to a solution of the compound 23 (0.15 g, 0.25 mmol, 1 eq) in dichloromethane (0.73 ml) and the mixture was then stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 24 (0.1 g, yield = 71 %) .
1H NMR (CD3OD, 300 MHz) δ: 8.82 (d, J = 4.3 Hz, IH), 8.50 (t, J = 7.9 Hz, IH), 8.18 (t, J = 8.3 Hz, IH), 7.78 - 7.73 (m, IH), 4.87 - 4.58 (m, 3H), 3.56 - 3.46 (m, 8H), 2.93 - 2.67 (m, 2H) . Example 4: Preparation of 5-fluoro-4-oxo-3- [ (4- piperidin-l-yl-7-trifluoromethyl-quinoline-3-carbonyl) - amino] -pentanoic acid trifluoroacetic acid (29)
[Reaction Scheme 4]
Figure imgf000075_0001
Preparation process 1: Preparation of 4-piperidin- l-yl-7-trifluoromethyl-quinoline-S-carboxylic acid ethyl ester (25)
Piperidine (0.62 g, 7.3 mmol, 1.1 eq) and triethylamine (1.3 g, 13.2 mmol, 2 eq) were added to a solution of the compound 11 (prepared in Preparation process 3 of Example 2; 2 g, 6.6 mmol, 1 eq) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography and the reaction mixture was then extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 25 (2 g, yield = 87 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.91 (s, IH), 8.33 (s, IH), 8.27 (d, J = 8.8 Hz, IH), 7.70 - 7.68 (m, IH), 4.46 (q, J = 7.2 Hz, 2H), 3.31 - 3.29 (m, 2H), 1.86 - 1.73 (m, 6H) , 1.45 (t, J = 7.1 Hz, 3H) .
Preparation process 2: Preparation of 4-piperidin- l-yl-7-trifluoromethyl-quinoline-3-carboxylic acid (26)
Lithium hydroxide (0.68 g, 16.2 mmol, 3 eq) was added to a solution of the compound 25 (1.9 g, 5.4 mmol, 1 eq) in ethanol (20 ml) and water (10 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 26 (1.6 g, yield = 90 %) . 1H NMR (CD3OD, 500 MHz) δ: 8.66 (s, IH) , 8.31 (d, J = 8.8 Hz, IH) , 8.13 (s, IH) , 7.71 - 7.69 (m, IH) , 3.39 - 3.37 (m, 4H) , 1.81 - 1.70 (m, 6H) .
Preparation process 3: Preparation of 5-fluoro-4- hydroxy-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline- 3-carbonyl) -amino] -pentanoic acid tert-butyl ester (27)
N-methylmorpholine (0.78 g, 7.7 mmol, 5 eq) , 1- hydroxybenzotriazole (0.31 g, 2.31 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g, 2.31 mmol, 1.5 eq) were added to a solution of the compound 26 (0.5 g, 1.54 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was then stirred for one hour. An amine reactant (0.32 g, 1.18 mmol, 1 eq) indicated in Reaction Scheme 4 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 27 (0.38 g, yield = 48 %) . 1H NMR (CDCl3, 500 MHz) δ : 8.84 - 8.79 (m, IH),
8.31 (s, IH) , 8.21 (d, J = 8.8 Hz, IH) , 7.67 - 7.65 (m,
IH) , 7.43 (d, J = 8.1 Hz, IH) , 4.59 - 4.49 (m, 3H) , 4.18
- 4.15 (m, IH) , 2.87 - 2.81 (m, 2H) , 1.83 - 1.76 (m, 6H) , 1.46 (s, 9H) .
Preparation process 4 : Preparation of 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid tert-butyl ester (28) A Dess Martin reagent (0.35 g, 0.83 mmol, 1.5 eq) was added to a solution of the compound 27 (0.28 g, 0.55 mmol, 1 eq) in dichloromethane (10 ml) and the mixture was stirred for two hours . The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 28 (0.2 g, yield = 70 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.86 (s, IH), 8.35 (s, IH), 8.25 (d, J = 5 Hz, IH), 7.71 - 7.69 (m, IH), 7.44 - 7.43 (m, IH), 5.27 - 5.08 (m, 3H), 3.32 - 3.30 (m, 6H), 3.11 - 307 (m, 2H), 1.85 - 1.77 (m, 6H), 1.45 (s, 9H). Preparation process 5: Preparation of 5-fluoro-4- oxo-3- [ (4-piperidin-l-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoroacetic acid (29) Trifluoroacetic acid (0.5 ml, 38 eq) was added to a solution of the compound 28 (0.09 g, 0.18 mitiol, 1 eq) in dichloromethane (0.5 ml) and the mixture was stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 29 (0.04 g, yield = 40 %) .
1H NMR (CD3OD, 500 MHz) δ : 8.59 (m, 0.5H), 8.55 - 8.43 (m, 0.5H), 8.21 (d, J = 5.0 Hz, IH), 5.20 - 5.00 (m, IH), 4.60 - 4.40 (m, 0.5H), 4.58 - 4.45 (m, 1.5H), 3.64 - 3.45 (m, 4H), 2.94 - 2.90 (m, 1.5H), 2.62 - 2.55 (m, 0.5H) , 1.90 - 1.82 (m. 6H) .
Example 5: Preparation of 5-fluoro-3- [ (4-morpholin- 4-yl-7-trifluoromethγl-quinoline-3-carbonyl) -amino] -4- oxo-pentanoic acid trifluoroacetic acid (34)
[Reaction Scheme 5]
Figure imgf000080_0001
Preparation process 1: Preparation of 4-morpholin- 4-yl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (30)
Morpholine (0.64 g, 7.3 iranol, 1.1 eq) and triethylamine (1.3 g, 13.2 mmol, 2 eq) were added to a solution of the compound 11 (prepared in Preparation process 3 of Example 2; 2 g, 6.6 mmol, 1 eq) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography and the reaction mixture was then extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 4) to obtain the target compound 30 (2 g, yield = 86 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.97 (s, IH), 8.38 (s, IH), 8.30 (d, J = 5 Hz, IH), 7.74 - 7.72 (m, IH), 4.49 (q, J = 5 Hz, 2H), 3.98 - 3.97 (m, 4H), 3.37 - 3.35 (m, 4H) , 1.47 (t, J = 5 Hz, 3H) .
Preparation process 2: Preparation of 4-morpholin- 4-yl-7-trifluoromethyl-quinoline-3-carboxylic acid (31) Lithium hydroxide (0.68 g, 16.2 mmol, 3 eq) was added to a solution of the compound 30 (1.9 g, 5.4 mmol, 1 eq) in ethanol (20 ml) and water (10 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 31 (1.6 g, yield = 90 %) .
1H NMR (CD3OD, 500 MHz) δ: 8.66 (s, IH), 8.31 (d, J = 8.8 Hz, IH), 8.13 (s, IH), 7.71 - 7.69 (m, IH), 3.39 - 3.37 (m, 4H), 1.81 - 1.70 (m, 6H). Preparation process 3: Preparation of 5-fluoro-4- hydroxy-3- [ (4-morpholin-4-yl-7-trifluoromethyl-quinoline- 3-carbonyl) -amino] -pentanoic acid tert-butyl ester (32)
N-methylmorpholine (0.78 g, 7.7 mmol, 5 eq) , 1- hydroxybenzotriazole (0.31 g, 2.30 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl ) carbodiimide hydrochloride (0.44 g, 2.3 mmol, 1.5 eq) were added to a solution of the compound 31 (0.5 g, 1.53 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour. An amine reactant (0.32 g, 1.53 mmol, 1 eq) indicated in Reaction Scheme 5 above was added to the reaction mixture and the resulting mixture was stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 32 (0.5 g, yield = 69 %) . 1H NMR (CDCl3, 500 MHz) δ: 8.92 - 8.82 (m, IH), 8.36
- 8.22 (m, 2H), 8.00 - 7.80 (m, IH), 7.72 - 7.68 (m, IH), 7.60 - 7.40 (m, 0.5H), 4.64 - 4.53 (s, 4H), 3.96 (s, 4H), 3.39 (s, 4H), 2.88 - 2.57 (m, 3H), 1.46 - 1.37 (m, 9H). Preparation process 4 : Preparation of 5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl-quinoline-3- carbonyl ) -amino] -4-oxo-pentanoic acid tert-butyl ester (33) A Dess Martin reagent (0.51 g, 1.2 mmol, 1.5 eq) was added to a solution of the compound 32 (0.42 g, 0.81 mmol, 1 eq) in dichloromethane (10 ml) and the mixture was stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 33 (0.29g, yield = 70 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.91 (s, IH), 8.39 (s, IH), 8.28 (d, J = 10 Hz, IH), 7.74 - 7.72 (m, IH), 7.54 (d, J = 5 Hz, IH), 5.25 - 5.07 (m, 3H), 3.99 - 3.97 (m, 2H), 3.38 - 3.36 (m, 2H), 3.16 - 3.09 (m, 2H), 1.46 (s, 9H) .
Preparation process 5: Preparation of 5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid (34)
Trifluoroacetic acid (0.85 ml, 38 eq) was added to a solution of the compound 33 (0.15 g, 0.29 mmol, 1 eq) in dichloromethane (0.85 ml) and the mixture was stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 34 (0.1 g, yield = 59 %) .
1H NMR (CD3OD, 500 MHz) δ: 8.80 - 8.60 (m, IH), 8.48 (d, J = 8.9 Hz, IH), 8.26 (d, J = 7.1 Hz, 3H), 7.94 - 7.92 (m, IH), 5.30 - 5.10 (m, IH), 4.79 - 4.39 (m, 2H), 4.03 - 3.93 (m, 4H), 3.79 - 3.65 (m, 3H), 3.20 - 2.70 (m, 1.5H) , 2.63 - 2.60 (m, 0.5H) .
Example 6: Preparation of 5-fluoro-4-oxo-3- [ (4- thiomorpholin-4-yl-7-trifluoromethyl-quinoline-3- carbonyl) -amino] -pentanoic acid trifluoroacetic acid (39)
[Reaction Scheme 6]
Figure imgf000085_0001
Preparation process 1: Preparation of 4- thiomorpholin-4-yl-7-trifluoromethyl-quinoline-3- carboxylic acid ethyl ester (35)
Thiomorpholine (0.75 g, 7.3 mmol, 1.1 eq) and triethylamine (1.3 g, 13.2 mmol, 2 eq) were added to a solution of the compound 11 (prepared in Preparation process 3 of Example 2; 2 g, 6.6 mmol, 1 eq) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography and the reaction mixture was then extracted with chloroform.
The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 2) to obtain the target compound 35 (2.3 g, yield = 96 %) .
1H NMR (CDCl3, 500 MHz) δ: 8.99 (s, IH), 8.29 (d, J = 8.8 Hz, IH), 7.76 - 7.73 (m, IH), 4.50 (q, J = 7.13 Hz, 2H), 3.58 - 3.56 (m, 4H), 2.91 (s, 4H), 1.48 (t, J = 7.2 Hz, 3H) .
Preparation process 2: Preparation of 4- thiomorpholin-4-yl-7-trifluoromethyl-quinoline-3- carboxylic acid (36)
Lithium hydroxide (0.68 g, 16.2 mmol, 3 eq) was added to a solution of the compound 35 (2 g, 5.4 mmol, 1 eq) in ethanol (40 ml) and water (40 ml) and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The solvent was evaporated under reduced pressure and the residue was neutralized with IN HCl. The resulting solution was extracted with chloroform, evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 36 (1.7 g, yield = 90 %) .
1H NMR (CD3OD3, 300 MHz) δ: 8.73 (s, IH), 8.35 (d, J = 8.8 Hz, IH), 8.17 (s, IH), 7.77 - 7.75 (m, IH), 3.65 - 3.63 (m, 4H) , 2.86 (s, 4H) . Preparation process 3: Preparation of 5~fluoro-4- hydroxy-3- [ (4-thiomorpholin-4-yl~7-trifluoromethyl- quinoline-3-carbonyl) -amino] -pentanoic acid tert-butyl ester (32)
N-methylmorpholine (0.74 g, 7.3 mmol, 5 eq) , 1- hydroxybenzotriazole (0.30 g, 2.19 mmol, 1.5 eq) and 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.19 mmol, 1.5 eq) were added to a solution of the compound 36 (0.5 g, 1.46 mmol, 1 eq) in dimethylformamide (40 ml) and the mixture was stirred for one hour. An amine reactant (0.3 g, 1.46 mmol, 1 eq) indicated in Reaction Scheme 6 was added to the reaction mixture and the resulting mixture was stirred for 1 hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with chloroform. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 37 (0.25 g, yield = 32 %).
1H NMR (CDCl3, 500 MHz) δ : 8.94 - 8.86 (m, IH), 8.37 (s, IH), 8.37 - 8.26 (m, IH), 8.26 - 8.25 (m, IH), 7.74 - 7.72 (m, IH), 7.50 - 7.39 (m, IH), 4.63 - 4.50 (m, 3H) , 4.19 - 4.18 (m, IH) , 3.60 - 3.58 (m, 4H) , 2.91 - 2.84 (m, 4H) , 2.76 - 2.73 (m, 2H) , 1.44 (s, 9H) .
Preparation process 4 : Preparation of 5-fluoro-4- oxo-3- [ (4-thiomorpholin-4-yl-7-trifluoromethyl-quinoline- 3-carbonyl) -amino] -pentanoic acid tert-butyl ester (38)
A Dess Martin reagent (0.28 g, 0.65 mmol, 1.5 eq) was added to a solution of the compound 37 (0.23 g, 0.43 mmol, 1 eq) in dichloromethane (30 ml) and the mixture was stirred for two hours. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate, the resulting mixture was stirred and extracted with dichloromethane. The extract was evaporated under reduced pressure and purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 38 (O.lδg, yield = 75 %) .
Preparation process 5: Preparation of 5-fluoro-4- oxo-3- [ (4-thiomorpholin--4-yl-7-trifluoromethyl-quinoline- 3-carbonyl ) -amino] -pentanoic acid trifluoroacetic acid (39)
Trifluoroacetic acid (0.12 ml, 38 eq) was added to a solution of the compound 38 (0.02 g, 0.04 mmol, 1 eq) in dichloromethane (0.12 ml) and the mixture was stirred for one hour. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was evaporated under reduced pressure and purified by column chromatography (methanol : methylene chloride = 1 : 4) to obtain the target compound 39 (0.1 g, yield = 71 %) .
1H NMR (CD3OD, 500 MHz) δ: 8.52 - 8.48 (m, IH), 8.37 - 8.31 (m, IH), 7.97 (s, IH), 7.88 - 7.86 (m, IH), 4.55 - 4.24 (m, 4H), 3.51 - 3.26 (m, 4H), 3.00 - 2.57 (m, 6H),
Example 7: Preparation of 5-fluoro-3- [ (8-nitro-4- piperazin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (54) [Reaction Scheme 7]
Figure imgf000090_0001
Preparation process 1: Preparation of 2- [ (2-nitro- phenylamino) -methylene] -malonic acid diethyl ester (47)
Diethylethoxymethylenemalonate (34 g, 159.3 mmol) was added to a solution of 2-nitroaniline (20.0 g, 144.8 mmol) in ethanol (100 ml) and the mixture was stirred at 1200C for 6 hours. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was cooled, filtered and washed three times with hexane (100 ml) to obtain the target compound 47 (31 g, yield = 69 %) .
1H NMR (CDCl3, 300 MHz) δ: 12.6-12.53 (m, IH), 8.53 (d, J = 12.0 Hz, IH), 8.13 (d, J = 4.0 Hz, IH), 7.73-7.66 (m, 1 H), 7.52-7.48 (m, IH), 7.27-7.17 (m, IH), 4.48-4.20 (m, 4H), 1.45-1.26 (m, 6H)
Preparation process 2: Preparation of 8-nitro-4- oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (48)
The compound 47 (140.0 g, 450 mmol) was slowly added to refluxing phenyl ether (400 ml) at 2600C and the mixture was stirred for 3 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, and crystallized while stirring in petroleum ether (1.4 L) . After the resulting compound was filtered and washed with petroLeum ether, the solvent was removed under reduced pressure to obtain the target compound 48 (104.4 g, yield = 88 %). 1H NMR (CDCl3, 300 MHz) δ: 9.01 (s, IH), 8.37 (d, J = 8.7 Hz, 1 H), 8.01 (d, J = 7.5 Hz, 1 H), 7.61 (dd, J = 8.4, 7.5 Hz, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 3.72 - 3.69 (m, 4 H), 3.31 - 3.28 (m, 4 H), 1.51 (s, 9 H), 1.43 (t, J = 7.2 Hz, 3 H) . Preparation process 3: Preparation of 4-chloro-8- nitro-quinoline-3-carboxylic acid ethyl ester (49)
Phosphorus oxychloride (175 ml, 1.91 iriol) was added to the compound 48 (50 g, 0.19 mol) and the mixture was stirred under reflux for 5 hours . The completion of the reaction was confirmed by thin-layer chromatography. After the phosphorus oxychloride was removed under reduced pressure, the concentrated compound was stirred in cooling water (00C). The resulting mixture was dissolved in dichloromethane (250 ml) and neutralized with ammonia water. The organic layer was extracted and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The resulting compound was dried over anhydrous magnesium sulfate and stirred in the presence of activated carbon for 30 minutes. After filtering and vacuum concentration, the resulting mixture was crystallized from methanol (500 mL) . The solid compound thus obtained was filtered to obtain the target compound 49 (38 g, yield = 72 %) .
1H NMR (CDCl3, 500 MHz) δ: 9.33 (s, 1 H), 8.66 (d, J = 8.4 Hz, 1 H), 8.65 (d, J = 7.5 Hz, 1 H), 7.80 (t, J = 8.0 Hz, 1 H), 4.53 (q, J = 7.1 Hz, 2 H), 1.47 (t, J = 7.2 Hz, 3 H) . Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-nitro-quinoline~3- carboxylic acid ethyl ester (50) Tert-butoxy piperazine (1.3 g, 6.77 mmol) and triethylamine (1.1 g, 11.2 mmol) were added to a solution of the compound 49 (1.6 g, 5.64 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 10 hours. The completion of the reaction was confirmed by thin-layer chromatography. Water (15 ml) was added to the reaction mixture with stirring. The organic layer was extracted with chloroform and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The resulting mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The obtained concentrate was purified by column chromatography (ethyl acetate : hexane = 1 : 2) to obtain the target compound 50 as a yellow solid (2.13 g, yield = 88 %) . 1H NMR (CDCl3, 300 MHz) δ : 9.01 (s, 1 H), 8.37 (d,
J = 8.7 Hz, 1 H), 8.01 (d, J = 7.5 Hz, 1 H), 7.61 (dd, J = 8.4, 7.5 Hz, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 3.72 - 3.69 (m, 4 H), 3.31 - 3.28 (m, 4 H), 1.51 (s, 9 H), 1.43 (t, J = 7.2 Hz, 3 H) . Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-nitro-quinoline-3- carboxylic acid (51) Lithium hydroxide (0.44 g, 10.46 mmol) was added to a solution of the compound 50 (1.5 g, 3.49 mmol) in a mixed solvent of ethanol and water (4 : 1, 20 ml) and the mixture was stirred at room temperature for 48 hours. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was neutralized with IN HCl and evaporated under reduced pressure to remove the solvent. The obtained concentrate was purified by column chromatography (methanol : ethyl acetate = 1 : 10) to obtain the target compound 51 as a solid (1.01 g, yield = 72 %) .
1H NMR (CD3OD, 300 MHz) δ: 8.73 (s, 1 H), 8.45 (d, J = 8.6 Hz, 1 H), 8.00 (d, J = 7.4 Hz, 1 H), 7.65 (dd, J = 8.4, 7.6 Hz, 1 H), 3.69 (brs, 4 H), 3.42-3.89 (m, 4 H), 1.49 (s, 9H).
Preparation process 6: Preparation of 4- [3- ( I- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) - 8-nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (52) Methylmorpholine (0.38 g, 1.49 mmol), 1- hydroxybenzotriazole (0.2 g, 1.49 mmol) and l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 1.49 mmol) were added to a solution of the compound 51 (0.5 g, 1.24 mmol) in dimethylformamide (5 ml) and the mixture was stirred for 30 minutes. An amine reactant 51- 1 indicated in Reaction Scheme 7 above was added and the resulting mixture was then stirred for 12 hours. The completion of the reaction was confirmed by thin-layer chromatography. The reaction mixture was extracted with dichloromethane (10 ml), washed twice with water (10 ml) and once with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained concentrate was purified by column chromatography (ethyl acetate : hexane = 1 : 2) to obtain the target compound 52 as a light yellow solid (0.42 g, yield = 57 %) .
1H NMR (CD3Cl3, 300 MHz) δ : 8.84 (s, 0.5 H), 8.81 (s, 0.5 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 6.9 Hz, 1 H), 7.56 (t, J = 8.4 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 0.5 H), 7.33 (d, J = 8.7 Hz, 0.5 H), 4.64-4.53 (m, 3 H), 4.17-4.12 (m, 1 H), 3.71-3.67 (m, 4 H), 3.41-3.24 (m, 4 H), 2.79-2.71 (m, 2 H), 1.50 (s, 9H), 1.46 (s, 9 H). Preparation process 7: Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2--oxo-propylcarbamoyl ) -8- nitro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (53) A Dess Martin reagent (0.29 g, 0.68 mmol) was added to a solution of the compound 52 (0.34 g, 0.57 mmol) in dichloromethane (3.5 ml) and the mixture was stirred for 10 minutes. The completion of the reaction was confirmed by thin-layer chromatography. After addition of saturated sodium bicarbonate (3 ml), the resulting mixture was stirred for 30 minutes and extracted with dichloromethane. The extract was washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate thus obtained was purified by column chromatography (ethyl acetate : hexane = 1 : 1) to obtain the target compound 53 as a light yellow solid (0.29 g, yieLd = 85 %).
1H NMR (CD3Cl3, 500 MHz) δ : 8.89 (s, 1 H), 8.33 (dd, J = 10, 1.2 Hz, 1 H), 8.31 (dd, J = 25, 1.2 Hz, 1 H), 7.60 (dd, J = 10, 7.6 Hz, 1 H), 7.35 (d, J = 25 Hz, 1 H), 5.19-5.18 (m, 2 H), 5.09 (q, 1 H), 3.71-3.67 (m, 4 H), 3.30-3.29 (m, 4 H), 3.15-2.84 (m, 2 H), 1.50 (s, 9H), 1.43 (s, 9 H) . Preparation process 8: Preparation of 5-fluoro-3- [ (8-nitro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] - 4-oxo-pentanoic acid trifluoroacetic acid (54)
Trifluoroacetic acid (1 ml) was added to a solution of the compound 53 (0.2 g, 0.34 mmol) in dichloromethane
(1 ml) and the mixture was stirred at 0°C for 10 minutes and at room temperature for two hours . The solvent and trifluoroacetic acid were removed by evaporation under reduced pressure. The residue was purified by column chromatography (methanol : dichloromethane = 1 : 10) to obtain the target compound 54 (0.15 g, yield = 79 %) .
1H NMR (CD3OD, 500 MHz) δ : 8.78 (s, 0.5 H), 8.74
(s, 0.5 H), 8.45 (d, J = 7.4 Hz, 1 H), 8.12 (t, J = 7.4
Hz, 1 H), 7.77-7.73 (m, 1 H), 5.14-5.11 (m, 1 H), 4.83- 4.81 (m, 1 H), 4.60-4.58 (m, 0.5 H), 4.51-4.47 (m, 1 H),
3.62-3.48 (m, 8 H), 2.95-2.55 (m, 2H).
Example 8: Preparation of 5-fluoro-3- [ (8-fluoro-4- piperazin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (63)
[Reaction Scheme 8] P henyl ether
Figure imgf000098_0002
Figure imgf000098_0001
SS S6 Sϊ
POCfj
Figure imgf000098_0003
Figure imgf000098_0004
60 £1
D ess-martin TFA penodinane
CH2CI2 CHjCl2
Figure imgf000098_0006
Figure imgf000098_0005
Preparation process 1: Preparation of 2- [ (2-fluoro- phenylamino) -methylene] -malonic acid diethyl ester (56)
The target compound 56 was obtained from 2- fluoroaniline 55 in the similar manner as in Preparation process 1 of Example 7.
1H NMR (CDCl3, 500 MHz) δ : 11.07 (d, J = 12.9 Hz, IH), 8.51 (d, J = 13.6 Hz, IH), 7.29-7.28 (m, IH), 7.17- 7.28 (m, 2 H), 7.10-7.08 (m, IH), 4.33 (q, J = 7.1 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3 H) .
Preparation process 2: Preparation of 8-fluoro-4- oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (57)
The target compound 57 was obtained from the compound 56 in the similar manner as in Preparation process 2 of Example 7. 1H NMR (CD3OD, 500 MHz) δ: 12.47 (s, IH), 8.63 (s,
IH), 8.12 (d, J = 8.2 Hz, IH), 7.58-7.54 (m, IH), 7.46- 7.42 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H) .
Preparation process 3: Preparation of 4-chloro-8- fluoro-quinoline-3-carboxylic acid ethyl ester (58)
The target compound 58 was obtained from the compound 57 in the similar manner as in Preparation process 3 of Example 7. 1H NMR (CDCl3, 500 MHz) δ: 9.23 (s, IH), 8.21 (d, J = 8.1 Hz, IH), 7.68-7.64 (m, IH), 7.58-7.54 (m, IH), 4.52 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H). Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-fluoro-quinoline-3- carboxylic acid ethyl ester (59)
The target compound 59 was obtained from the compound 58 in the similar manner as in Preparation process 4 of Example 7.
1H NMR (CDCl3, 500 MHz) δ: 8.93 (s, IH), 7.94 (d, J = 8.3 Hz, IH), 7.51-7.42 (m, 2H), 4.47 (q, J = 7.2 Hz, 2H), 3.69 (brs, 4H), 3.29 (brs, 4H), 1.51 (s, 9H), 1.44 (t, J = 7.2 Hz, 3H) .
Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -8-fluoro-quinoline-3- carboxylic acid (60) The target compound 60 was obtained from the compound 59 in the similar manner as in Preparation process 5 of Example 7.
1H NMR (CD3OD, 500 MHz) δ: 8.65 (s, IH), 8.27-8.24 (m, 1 H), 7.53-7.51 (m, IH), 7.39-7.35 (m, IH), 3.65 (brs, 4H), 3.37 (brs, 4 H), 1.46 (s, 9H).
Preparation process 6: Preparation of 4- [3- (1- tert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl) - 8-fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (61)
The target compound 61 was obtained from the compound 60 in the similar manner as in preparation process 6 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.86 (s, 0.5H), 8.79 (s, 0.5 H), 7.56 (t, J = 7.4 Hz, IH), 7.54-7.37 (m, 3H), 4.62-4.49 (m, IH), 3.68 (brs, 4H), 3.31-3.29 (m, 4H), 2.85-2.70 (m, 2H), 1.50 (s, 9H), 1.46 (s, 9H).
Preparation process 7: Preparation of 4- [3- ( 1- tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -8- fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (62) The target compound 62 was obtained from the compound 61 in the similar manner as in Preparation process 7 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.86 (s, 1 H) , 7.90 (d,
J = 8.4 Hz, 1 H), 7.56 (d, J = 7.4 Hz, 1 H), 7.51-7.46 (m, 1 H), 7.44-7.40 (m, 1 H), 5.25-5.06 (m, 3 H), 3.69
(brs, 4 H), 3.32-3.27 (m, 4 H), 3.09 (dq, J = 17.9, 4.7
Hz, 2 H), 1.51 (s, 9H), 1.44 (s, 9 H). Preparation process 8: Preparation of 5-fluoro-3- [ (8-fluoro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] - 4-oxo-pentanoic acid trifluoroacetic acid (63)
The target compound 63 was obtained from the compound 62 in the similar manner as in Preparation process 8 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.75 (s, 0.5 H), 8.70 (d, J = 4.0 Hz, 0.5 H), 8.03-8.00 (m, 1 H), 7.68-7.62 (m, 1 H), 7.59-7.54 (m, 1 H), 4.59-4.45 (m, 1 H), 3.69-3.65 (m, 1 H), 3.59-3.43 (m, 8 H), 2.96-2.93 (m, 2 H).
Example 9: Preparation of 5-fluoro-3- [ (7-fluoro-4- piperazin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (72) [Reaction Scheme 9]
Figure imgf000103_0001
DfS-rtβrtin psflαeinww
CHjCla
Figure imgf000103_0002
« 1!
Preparation process 1: Preparation of 2- [ (3-fluoro- phenylamino) -methylene] -malonic acid diethyl ester (65)
The target compound 65 was obtained from 3- fluoroaniline 64 in the similar manner as in Preparation process 1 of Example 7.
1H NMR (CDCl3, 500 MHz) δ : 11.06 (d, J = 13.2 Hz , 1 H), 8.46 (d, J = 13.5 Hz, 1 H), 7.35-7.32 (m, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.87-6.84 (m, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H), 1.34 (t, J= 7.1 Hz, 3 H). Preparation process 2: Preparation of 7-fluoro-4- oxo-1, 4-dihydro-quinoline-3-carboxylic acid ethyl ester (66)
The target compound 66 was obtained from the compound 65 in the similar manner as in Preparation process 2 of Example 7.
1H NMR (DMSO-d6, 500 MHz) δ: 12.30 (s, 1 H), 8.58 (s, 1 H), 8.12 (dd, J = 8.9, 6.3 Hz, 1 H), 7.40-7.37 (m, 1 H), 7.29-7.25 (m, 1 H), 4.21 (q, J = 7.0 Hz, 2 H), 1.28 (t, J = 7.0 Hz, 3 H) .
Preparation process 3: Preparation of 4-chloro-7- fluoro-quinoline-3-carboxylic acid ethyl ester (67)
The target compound 67 was obtained from the compound 66 in the similar manner as in Preparation process 3 of Example 7.
1H NMR (CDCl3, 500 MHz) δ: 9.22 (s, 1 H), 8.45 (dd, J = 9.4, 5.9 Hz, 1 H), 7.78 (dd, J = 9.5 2.5 Hz, 1 H), 7.51-7.47 (m, 1 H), 4.51 (q, J = 7.2 Hz, 2 H), 1.47 (t, J = 7.2 Hz, 3 H) .
Preparation process 4: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -7-fluoro-quinoline-3- carboxylic acid ethyl ester (68) The target compound 68 was obtained from the compound 67 in the similar manner as in Preparation process 4 of Example 7.
1H NMR (CDCl3, 500 MHz) δ : 8.91 (s, 1 H) , 8.19 (dd, J = 9.2, 6.0 Hz, 1 H), 7.69 (dd, J = 9.7, 2.5 Hz, 1 H),
7.35-7.31 (m, 1 H), 4.46 (q, J = 7.2 Hz, 2 H), 3.69 (brs,
4 H), 3.28 (brs, 4 H), 1.51 (s, 9 H), 1.44 (t, J = 7.2
Hz, 3 H) .
Preparation process 5: Preparation of 4-(4-tert- butoxycarbonyl-piperazin-1-yl) -7-fluoro-quinoline-3- carboxylic acid (69)
The target compound 69 was obtained from the compound 68 in the similar manner as in Preparation process 5 of Example 7.
1H NMR (CD3OD, 500 MHz) δ: 8.67 (s, 1 H) , 8.01 (d, J = 8.6 Hz, 1 H), 7.54-7.49 (m, 1 H), 7.42-7.39 (m, 1 H), 3.67 (brs, 4 H), 3.40-3.38 (m, 4 H), 1.48 (s, 9 H).
Preparation process 6: Preparation of 4- [3- (1-fcert- butoxycarbonylmethyl-3-fluoro-2-hydroxy-propylcarbamoyl ) -
7-fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (70) The target compound 70 was obtained from the compound 69 in the similar manner as in Preparation process 6 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.86 (s, 0.5 H), 8.78 (s, 0.5 H), 8.16-8.12 (m, 1 H), 7.70-7.67 (m, 1 H), 7.47- 7.45 (m, 0.5 H), 7.41-7.39 (m, 0.5 H), 7.34-7.30 (m, 1 H), 4.62-4.48 (m, 3 H), 4.13-4.11 (m, 1 H), 3.68 (brs, 4 H), 3.30-3.29 (m, 4 H), 2.88-2.73 (m, 2 H), 1.51 (s, 9H), 1.45 (s, 9 H) .
Preparation process 7: Preparation of 4- [3- (1-tert- butoxycarbonylmethyl-3-fluoro-2-oxo-propylcarbamoyl ) -7- fluoro-quinolin-4-yl] -piperazine-1-carboxylic acid tert- butyl ester (71) The target compound 71 was obtained from the compound 70 in the similar manner as in Preparation process 7 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.83 (s, 1 H), 8.93
(dd, J = 9.3, 5.9 Hz, 1 H), 7.70 (dd, J = 9.6, 2.6 Hz, 1 H), 7.61 (d, J = 7.4 Hz, 1 H), 7.35-7.31 (m 1 H), 5.26-
5.06 (m, 3 H), 3.69 (brs, 4 H), 3.29-3.28 (m, 4 H), 3.08
(dq, J= 17.0, 4.7 Hz, 2 H), 1.51 (s, 9H), 1.44 (s, 9 H). Preparation process 8: Preparation of 5-fluoro-3- [ (7-fluoro-4-piperazin-l-yl-quinoline-3-carbonyl) -amino] - 4-oxQ-pentanoic acid trifluoroacetic acid (72)
The target compound 72 was obtained from the compound 71 in the similar manner as in Preparation process 8 of Example 7.
1H NMR (CD3Cl3, 500 MHz) δ : 8.74 (s, 0.5 H), 8.69 (d, J = 2.4 Hz, 0.5 H), 8.32-8.28 (m, 1 H), 7.68-7.63 (m, 1 H), 7.53-7.47 (m, 1 H), 5.12-5.95 (in, 1 H), 4.59-4.47 (m, 1 H), 3.59-3.46 (m, 8 H), 2.96-2.93 (m, 2 H).
Example 10: Preparation of 5-fluoro-3-{ [4- (4- methyl-piperazin-1-yl) -8-nitro-quinoline-3-carbonyl] - amino} -4-oxo-pentanoic acid trifluoroacetic acid (74) [Reaction Scheme 10]
Figure imgf000107_0001
The target compound 74 was obtained from the compound 73 in the similar manner as in Preparation process 8 of Example 7. 1H NMR (CD3OD, 500 MHz) δ: 8.73-8.71 (m, 0.5 H),
8.68-8.67 (m, 0.5 H), 8.46-8.44 (m, 1 H), 8.11-8.09 (m, 1 H) , 7.76-7.72 (m, 1 H) , 5.22-5.13 (m, 2 H) , 3.62-3.30 (m, 8 H) , 2.90-2.87 (m, 5 H) .
Example 11: Preparation of 3-{ [4- (4-ethyl- piperazin-1-yl) -8-nitro-quinoline-3~carbonyl] -amino} -5- fluoro-4-oxo-pentanoic acid tπfluoroacetic acid (76)
[Reaction Scheme 11]
Figure imgf000108_0001
The target compound 76 was obtained from the compound 75 in the similar manner as in Preparation process 8 of Example 7.
1H NMR (CD3OD, 500 MHz) δ: 8.79-8.75 (m, 1 H), 8.45- 8.43 (m, 1 H), 8.13-8.11 (m, 1 H), 7.76-7.74 (m, 1 H), 5.11-5.08 (m, 1 H), 3.70-3.57 (m, 10 H), 3.34-3.31 (m, 3 H), 2.95-2.91 (m, 1 H), 1.43-1.39 (m, 3 H).
Example 12: Preparation of 5-fluoro-3- ({4- [4- (2- meth.oxy-eth.yl) —piperazin-1-yl] -8-nitrO-qpiinoline—3- carbonyl} -amino) -4-oxo-pentanoic acid trifluoroacetic acid (78)
[Reaction Scheme 12]
Figure imgf000109_0001
'17 78
The target compound 78 was obtained from the compound 77 in the similar manner as in Preparation process 8 of Example 7.
1H NMR (CD3OD, 500 MHz) δ: 8.79-8.78 (m, 0.5 H), 8.76-8.75 (m, 0.5 H), 8.43-8.41 (m, 1 H), 8.13-8.10 (m, 1 H), 7.77-7.73 (m, 1 H), 5.09-5.07 (m, 1 H), 3.79 (brs, 2 H), 3.69-3.66 (m, 8 H), 3.61 (brs, 2 H), 3.48 (s, 3 H), 2.95-2.92 (m, 2 H), 2.65-2.63 (m, 1 H).
Example 13: Preparation of 5-fluoro-3- [ (8-fluoro-4- piperidin-l-yl-quinoline-3-carbonyl) -amino] -4-oxo- pentanoic acid trifluoroacetic acid (80)
[Reaction Scheme 13]
Figure imgf000109_0002
The target compound 80 was obtained from the compound 79 in the similar manner as in Preparation process 8 of Example 7. 1H NMR (CD3OD, 500 MHz): δ 8.59-8.52 (m, 1 H), 8.01- 8.00 (m, 1 H), 7.62-7.54 (m, 1 H), 5.08 (brs, 1 H), 4.58- 4.56 (m, 1 H), 3.50-3.49 (m, 1 H), 3.41 (brs, 4 H), 3.01- 2.91 (m, 2 H), 1.86-1.78 (m, 6 H).
Experimental Example 1 : Evaluation of inhibitory activity against caspase-3 on OGD models of primary- cultured neuronal cells
Inhibitory activity against caspase-3 was evaluated for oxygen-glucose deprivation (OGD) -induced in vitro models of simulated cerebral ischemia. After 15-20 days pregnant SD rats were sacrificed, cerebrum cortex was separated from embryo and then centrifuged at 900 rpm for 9 minutes. The resulting precipitate was completely separated into single cells by addition of Dulbecco' s modified Eagle medium (DMEM) containing 10% FBS, 5% HS and 1% PS, and the single cells were seeded on PEI/laminin-coated plates at IxIO6 cells/ml. After 10-12 days in vitro (DIV), glucose-free DMEM was gas-bubbled with 95% NO2 and 5% CO2 for 20 minutes to remove oxygen present in the medium and then replaced with the medium containing culture cells. Then, the medium was incubated in a hypoxia chamber at 370C for 1.5 hours so that it was exposed to oxygen-glucose deprivation and then treated with a glucose-containing DMEM. At 4 hours following the treatment, in-vivo caspase-3 assay was performed. IxIO6 cells were collected with a 100 ul cell lysis buffer. The lysate thus obtained was directly reacted with 20 uM DEVD-AFC as a substrate of caspase-3 at 350C for 30 minutes. After the reaction, the cleavage of the substrate by caspase-3 was measured with an ELISA reader at an excitation wavelength of 400 nm and an emission wavelength of 508 nm. IC50 of respective experimental compounds was calculated using a graphPad Prism 4.0 program. The results thus obtained are shown in Table 1 below. TABLE 1
Figure imgf000111_0001
Figure imgf000112_0001
It can be confirmed from Table 1 that the compound 29 of Example 4 had a low IC50 of 10 nM and thus exhibited considerably superior inhibitory activity against caspase-3 and that the compounds' of Examples 1, 2, 3, 7, 8, 9, 12 and 13 had an IC50 in the range of 200 nM to 15 uM and inhibitory activity against caspase-3 of the compounds are thus substantially equivalent to or superior to those of conventional caspase-3 inhibitors.
Experimental Example 2 : Evaluation of enzyme-level inhibitory activity against caspase-3
Caspase-3 known as a cystein protease was obtained by a series of processes involving expression, purification and activation in accordance with the method reported by Rotonda et al. (Nat Struct Biol., 1996, 3(7): 619). Enzyme-level inhibitory activity against caspase-3 of the experimental compounds was evaluated employing the caspase-3 thus obtained.
P12 and pl7 subunits were expressed in Escherichia coli, purified by nickel column and anion exchange chromatography and then recombined. Enzyme inactivity of the compounds was measured with Ac-DEVD-AFC as a fluorescent substrate.
In this process, the caspase-3 was reacted with 10 nM Ac-DEVD-AFC at 370C in the presence of a buffer containing 50 mM NaCl, 10 mM DTT, 1 mM EDTA, 10% glycerol and 0.1% CHAPS, Synergy HT® available from BIO TEK Instruments, Inc. was used as a fluorescence spectrometer, and the excitation and emission wavelengths herein used were 400 nm and 508 nm, respectively.
The IC50 of the experimental compounds is shown in Table 2 below. TABLE 2
Figure imgf000113_0001
Figure imgf000114_0001
[Industrial Applicability]
As apparent from the foregoing, the present invention provides a quinoline derivative with superior inhibitory activity against caspase-3 or a pharmaceutically acceptable salt thereof. Accordingly, with the quinoline derivative, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one of them, it is possible to prepare a potent drug for treating a caspase-3 related disease e.g. Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke/ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.

Claims

[CLAIMS]
[Claim 1]
A quinoline derivative represented by the following Formula 1 for use in treating a caspase-mediated disease by inhibition of caspase-3 activity:
Figure imgf000115_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000115_0002
R is , or in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, O or S; and R5 is hydrogen, halogen, Ci_6 alkyl, Ci_6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, O or S; and Y is hydrogen, halogen, Cj-e alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof.
[Claim 2]
The quinoline derivative according to claim 1 wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, nitro or Ci-6 halogenoalkyl;
R is , or in which R2 is C or
N; R3 is -(CH2)2~; R4 is C, N, O or S; and R5 is hydrogen, Ci_6 alkyl or Cχ_6 alkoxyalkyl;
A is N; and
Y is hydrogen.
[Claim 3]
The quinoline derivative according to claim 1 wherein the quinoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof is selected from: 5-fluoro-3- [ (7-nitro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid;
5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid;
5-fluoro-4-oxo-3- [ (4-piperazin-l-yl-8- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid; 5-fluoro-4-oxo-3- [ (4-piperidin-l-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid;
5-fluoro-3- [ (8-fluoro-4-piperidin-l-yl-quinoline-3- carbonyl ) -amino] -4-oxo-pentanoic acid trifluoroacetic acid;
5-fluoro-3- [ (4-morpholin-4-yl-7-trifluoromethyl- quinoline-3-carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid;
5-fluoro-4-oxo-3- [ (4-thiomorpholin-4-yl-7- trifluoromethyl-quinoline-3-carbonyl) -amino] -pentanoic acid trifluoroacetic acid;
5-fluoro-3- [ (8-nitro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid; 5-fluoro-3- ( { 4- [4- (2-methoxy-ethyl) -piperazin-1- yl] -δ-nitro-quinoline-3-carbonyL } -amino) -4-oxo-pentanoic acid trifluoroacetic acid;
5-fluoro-3- [ (8-fluoro-4-piperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid;
5-fluoro-3- [ (7-fluoro-4-plperazin-l-yl-quinoline-3- carbonyl) -amino] -4-oxo-pentanoic acid trifluoroacetic acid; 5-fluoro-3-{ [4- (4-methyl-piperazin-l-yl) -8-nitro- quinoline-3-carbonyl] -amino } -4-oxo-pentanoic acid trifluoroacetic acid; and
3- { [4- (4-ethyl-piperazin-1-yl) -8-nitro-quinoline-3- carbonyl] -amino} -5-fluoro-4-oxo-pentanoic acid trifluoroacetic acid.
[Claim 4]
The quinoline derivative according to claim 1 wherein the caspase-mediated disease is Alzheimer' s disease, Huntington' s disease, Parkinson's disease, ALS,
AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
[Claim 5] The quinoline derivative according to claim 1 wherein the quinoline derivative of the Formula 1 or a pharmaceutically acceptable salt is hydrochloride, bromate, sulfate, nitrate, perchlorate, fumarate, maleate, phosphate, glycolate, lactate, salicylate, succinate, p-toluenesulfonate, tartrate, trifluoroacetate, acetate, citrate, methanesulfonate, formate, benzoate, malonate, naphthalene-2-sulfonate, benzensulfonate, an alkali-metal salt or an alkaline earth metal salt.
[Claim 6]
A method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000119_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Ci-e alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_g halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000120_0001
R is , or in which R2 is C or
N; R3 is -(CH2)n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Cj-β halogenoalkyl or 5- to 15-membered aryl; A is C, N, O or S; and
Y is hydrogen, halogen, Cχ-6 alkyl, Ci_6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-.6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000120_0002
(2)
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000121_0001
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000121_0002
(4)
wherein Xi, X2, X3 and X4 are defined as above; halogenizing the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000121_0003
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula β below:
Figure imgf000122_0001
wherein X1, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula 6 to obtain a compound represented by Formula 7 below:
Figure imgf000122_0002
wherein X1, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 8 to obtain a compound represented by Formula 9 below:
Figure imgf000122_0003
(8) wherein A and Y are defined as above;
Figure imgf000122_0004
wherein X1, X2, X3, X4, R, A and Y are defined as above; and carbonylating the compound of Formula 9 to obtain the compound of Formula 1 above.
[Claim 7]
An intermediate compound represented by the following Formula 7 for use in preparing a quinoline derivative represented by the following Formula 1:
Figure imgf000123_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Cχ-6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl; and
Figure imgf000123_0002
R is , or in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci_6 alkoxyalkyl, C3-5 cycloalkyl, nitro, amino, Cχ-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000124_0001
wherein Xi, X2, X3, X4 and R are defined as above;
A is C, N, 0 or S; and
Y is hydrogen, halogen, Ci_6 alkyl, Ci-6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyi, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl, or a pharmaceutically acceptable salt thereof.
[Claim 8]
An intermediate compound represented by the following Formula 9 for use in preparing a quinoline derivative represented by the following Formula 1:
Figure imgf000124_0002
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Ci~6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyi, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000125_0001
R is in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is C,
N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl;
A is C, N, 0 or S; and
Y is hydrogen, halogen, C]-6 alkyl, Ci_6 alkoxy, C]-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000125_0002
wherein Xi, X2, X3, X4, R, A and Y are defined as above .
[Claim 9] A method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000126_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, C1-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxyalkyl, C3_5 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000126_0002
R is or in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is N; and R5 is hydrogen;
A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000126_0003
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000127_0001
wherein X1, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000127_0002
(4)
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000127_0003
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RiH wherein
Protective
Prote Group
Protective
Ri is or
Figure imgf000128_0002
Figure imgf000128_0001
in which R2 and R3 are defined as above, to obtain a compound represented by Formula 10 below:
Figure imgf000128_0003
wherein Xi, X2, X3, X4 and R] are defined as above; hydrolyzing the compound of Formula 10 to obtain a compound represented by Formula 11 below:
Figure imgf000128_0004
wherein Xi, X2, X3, X4 and Ri are defined as above; reacting the compound of Formula 11 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 13 below:
Figure imgf000128_0005
wherein A is defined as above;
Figure imgf000129_0001
wherein Xi, X2, X3, X4, Ri and A are defined as above; carbonylating the compound of Formula 13 to obtain a compound represented by Formula 14 below:
Figure imgf000129_0002
wherein Xi, X2, X3, X4, Ri and A are defined as above; and deprotecting protective groups I and Il of the compound of Formula 14 to obtain the compound of Formula 1 above .
[Claim 10] A method for preparing a quinoline derivative represented by Formula 1 below:
Figure imgf000130_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Cj-β alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000130_0002
R is , or in which R2 is C or
N; R3 is -(CH2)n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Cχ-ς alkoxy, Cχ_6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: reacting a compound represented by the following Formula 2 with diethylethoxymethylenemalonate to obtain a compound represented by Formula 3 below:
Figure imgf000131_0001
wherein Xi, X2, X3 and X4 are defined as above;
Figure imgf000131_0002
wherein Xi, X2, X3 and X4 are defined as above; cyclizing the compound of Formula 3 in the presence of diphenylether to obtain a compound represented by Formula 4 below:
Figure imgf000131_0003
wherein Xi, X2, X3 and X4 are defined as above; halogenating the compound of Formula 4 to obtain a compound represented by Formula 5 below:
Figure imgf000131_0004
wherein Xi, X2, X3 and X4 are defined as above and Z is halogen; reacting the compound of Formula 5 with RH in which R is defined as above, to obtain a compound represented by Formula 6 below:
Figure imgf000132_0001
wherein Xi, X2, X3, X4 and R are defined as above; hydrolyzing the compound of Formula 6 to obtain a compound represented by Formula 7 below:
Figure imgf000132_0002
wherein Xi, X2, X3, X4 and R are defined as above; reacting the compound of Formula 7 with a compound represented by the following Formula 12 to obtain a compound represented by Formula 15 below:
Figure imgf000132_0003
Protective Group II :i2) wherein A is defined as above;
Figure imgf000133_0001
wherein Xi, X2, X3, X4, R and A are defined as above; carbonylating the compound of Formula 15 to obtain a compound represented by Formula 16 below:
Figure imgf000133_0002
wherein Xi, X2, X3, X4, R and A are defined as above; and deprotecting a protective group II of the compound of Formula 16 to obtain the compound of Formula 1 above.
[Claim 11]
A pharmaceutical composition containing a pharmaceutically effective amount of a quinoline derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in treating a caspase- mediated disease based on inhibition of caspase-3 activity:
Figure imgf000134_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci-6 alkyl, Ci-g alkoxy, C1-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000134_0002
R is , or in which R2 is C or
N; R3 is -(CH2)n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, O or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Cχ-6 alkoxy, Ci-6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, 0 or S; and Y is hydrogen.
[Claim 12]
The pharmaceutical composition according to claim 11 wherein the caspase-mediated disease is Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
[Claim 13]
A use of a quinoline derivative of the following Formula 1 or a pharmaceutical] y acceptable salt thereof for preparing a drug for treating a caspase-mediated disease based on inhibition of caspase-3 activity:
Figure imgf000135_0001
wherein Xi, X2, X3 and X4 are each independently hydrogen, halogen, Ci_6 alkyl, Cχ-6 alkoxy, Ci-6 alkoxyalkyl, C3-6 cycloalkyl, nitro, amino, Ci_6 halogenoalkyl or 5- to 15-membered aryl;
Figure imgf000135_0002
R is , or in which R2 is C or
N; R3 is - (CH2) n- in which n is 0, 1, 2, 3 or 4; R4 is C, N, 0 or S; and R5 is hydrogen, halogen, Ci-6 alkyl, Ci_6 alkoxy, Ci_6 alkoxyalkyl, C3_6 cycloalkyl, nitro, amino, Ci-6 halogenoalkyl or 5- to 15-membered aryl; A is C, N, O or S; and Y is hydrogen.
[Claim 14]
The use of the quinoline derivative according to claim 11 wherein the caspase-mediated disease is Alzheimer's disease, Huntington' s disease, Parkinson's disease, ALS, AIDS, stroke, ischemia, traumatic brain injury, spinal cord injury or osteoarthritis.
PCT/KR2008/000202 2007-01-31 2008-01-11 Quinoline derivatives as caspase-3 inhibitor, preparation process for the same and pharmaceutical composition comprising the same WO2008093940A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2007-0010137 2007-01-31
KR1020070010137A KR100844926B1 (en) 2007-01-31 2007-01-31 Quinoline derivatives as caspase-3 inhibitors, methods for their preparation and pharmaceutical compositions comprising them

Publications (1)

Publication Number Publication Date
WO2008093940A1 true WO2008093940A1 (en) 2008-08-07

Family

ID=39674214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/000202 WO2008093940A1 (en) 2007-01-31 2008-01-11 Quinoline derivatives as caspase-3 inhibitor, preparation process for the same and pharmaceutical composition comprising the same

Country Status (2)

Country Link
KR (1) KR100844926B1 (en)
WO (1) WO2008093940A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003093240A1 (en) * 2002-04-30 2003-11-13 Yungjin Pharmaceutical Co., Ltd. Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003093240A1 (en) * 2002-04-30 2003-11-13 Yungjin Pharmaceutical Co., Ltd. Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARECKI P.E. ET AL.: "Synthesis of 4-substituted aminoquinoline-3-carboxylates as potential antimicrobial agents", J. PHARM. SCI., vol. 73, no. 8, August 1984 (1984-08-01), pages 1141 - 1143, XP001057093, DOI: doi:10.1002/jps.2600730828 *

Also Published As

Publication number Publication date
KR100844926B1 (en) 2008-07-09

Similar Documents

Publication Publication Date Title
AU686115B2 (en) Imidazo (I,2-a) pyridine derivatives as bradykinin antagonists, pharmaceuticals and processes for their preparation
CN103153996B (en) As quinoline and the quinoxaline derivatives of kinase inhibitor
AU2006243068B2 (en) Quinoline and quinoxaline derivatives as inhibitors of kinase enzymatic activity
JP4287649B2 (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
TWI488851B (en) Quinazoline as a potassium channel inhibitor
US5994368A (en) Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists
US5744471A (en) Pyridazion quinoline compounds
US20040229889A1 (en) HDAC inhibitor
JP2023527878A (en) LPA receptor antagonist and use thereof
CA2642130C (en) Selective benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors
JPH02300182A (en) Benzopyran derivative and production thereof
JP2001500864A (en) Thrombin inhibitors
KR20190080951A (en) Pyrimido [5,4-b] indolizine or pyrimido [5,4-b] pyrrolizine compounds, their preparation methods and uses
JPWO2004108724A1 (en) Tricyclic compounds
WO2004063202A1 (en) Fused furan compound
CN106749223B (en) Tyrosine kinase inhibitor and preparation method and application thereof
US20040260094A1 (en) Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same
CN116496269B (en) A prolyl hydroxylase inhibitor and its use
WO2013030358A1 (en) Glycine b antagonists
WO2008093940A1 (en) Quinoline derivatives as caspase-3 inhibitor, preparation process for the same and pharmaceutical composition comprising the same
CN111018860A (en) Pyrrolotriazines and application thereof
CN107118209B (en) Pyrido [3,4-b ] indolylurea compounds and application thereof as IDO (intermediate compound) inhibitor
JP4078494B2 (en) Hepatitis C drug
CN118184572A (en) Preparation of a new type of HsClpP agonist and its application in anti-inflammatory and anti-tumor activities
JPH10259184A (en) Production of tricyclic heterocyclic compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08704741

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08704741

Country of ref document: EP

Kind code of ref document: A1