WO2009116801A2 - Caspase inhibitor prodrug - Google Patents

Caspase inhibitor prodrug Download PDF

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Publication number
WO2009116801A2
WO2009116801A2 PCT/KR2009/001368 KR2009001368W WO2009116801A2 WO 2009116801 A2 WO2009116801 A2 WO 2009116801A2 KR 2009001368 W KR2009001368 W KR 2009001368W WO 2009116801 A2 WO2009116801 A2 WO 2009116801A2
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WO
WIPO (PCT)
Prior art keywords
formula
compounds
pharmaceutically acceptable
acceptable salts
composition
Prior art date
Application number
PCT/KR2009/001368
Other languages
English (en)
French (fr)
Other versions
WO2009116801A3 (en
Inventor
Hyun Ik Shin
Jae Hoon Lee
Yeong Soo Oh
Kyu Woong Lee
Original Assignee
Lg Life Sciences 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 Lg Life Sciences Ltd. filed Critical Lg Life Sciences Ltd.
Publication of WO2009116801A2 publication Critical patent/WO2009116801A2/en
Publication of WO2009116801A3 publication Critical patent/WO2009116801A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the present invention relates to isoxazoline derivatives of the following formula (1):
  • R 1 represents isoquinolinyl, quinolinyl or naphthyl
  • R 2 represents C 1-8 alkyl, as a prodrug of the caspase inhibitors of the following formula (2):
  • R 1 and R 2 are as defined above, and pharmaceutically acceptable salts thereof.
  • the present invention also relates to a process for preparing the compounds of formula (1), and caspase inhibitor compositions which comprises the compounds of formula (I) or pharmaceutically acceptable salts thereof as an active ingredient, specifically to compositions for anti-inflammation and the prevention or treatment of apoptosis.
  • Caspase is a new kind of cysteine protease recently discovered. About 14 kinds thereof have been known up to now. They are cysteine proteases existing as a tetramer in the form of ⁇ 2 ⁇ 2 .
  • Caspase inhibitors mean those compounds that inhibit the activity of caspase, thereby control such symptoms as inflammation, apoptosis, etc. caused by the caspase activity.
  • Diseases or symptoms that may be treated or alleviated by administering the inhibitors include the following: dementia, cerebral stroke, brain impairment due to AIDS, diabetes, gastric ulcer, cerebral injury by hepatitis virus, hepatitis-induced hepatic diseases, acute hepatitis, human fulminant hepatic failure, sepsis, organ transplantation rejection, rheumatic arthritis, ischemic cardiac diseases, and liver cirrhosis.
  • isoxazoline derivatives have been filed as WO 2006/090997 and WO 2005/021516. Further, caspase inhibitor prodrugs on the basis of isoxazoline derivatives are disclosed in WO 2007/015931 (filed by Vertex Pharmaceuticals Incorporated, USA ).
  • the present inventors have tried to develop new prodrugs of the excellent caspase inhibitors having the isoxazoline structure of formula (2), in order to improve the inhibitors' bioavailability.
  • the present invention is to provide the compounds of formula (1) or pharmaceutically acceptable salts thereof.
  • the present invention also provides a process for preparing the compounds of formula (1).
  • the present invention also provides a caspase inhibitor composition, more specifically a composition for anti-inflammation and the prevention or treatment of apoptosis, which comprises the compounds of formula (1) or pharmaceutically acceptable salts thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • Figure 1 represents the X-ray crystalline structure of the compound of formula (1a);
  • Figure 2 represents the XRD data of the compound of formula (1a);
  • the present invention relates to new compounds of the following formula (1):
  • R 1 represents isoquinolinyl, quinolinyl or naphthyl
  • R 2 represents C 1-8 alkyl, having a caspase-inhibiting activity.
  • preferred compounds are those wherein R 1 represents isoquinolinyl, quinolinyl or naphthyl, and R 2 represents methyl, ethyl, propyl, isopropyl or butyl. More preferred compound is 3a-(fluoromethyl)-2-[(5R)-5-isopropyl-3-isoquinolin-1-yl-4,5-dihydro-isoxazol-5-yl]-6,6a-dihydropuro[3,2-d][1,3]oxazol-5(3aH)-one of the following formula (1a):
  • R 1 represents isoquinolinyl and R 2 represents isopropyl.
  • the compound of formula (1a) was identified by the X-ray crystallography experiment to have the crystalline structure of Figure 1.
  • Figure 2 represents the XRD data showing the crystallinity of the compound of formula (1a).
  • the compounds of formula (1) may be used in the form of a pharmaceutically acceptable salt which includes the acid or base addition salt typically known in the art.
  • the compounds of formula (1) can be prepared by reacting the compounds of formula (2) with trifluoroacetic anhydride in an organic solvent, as depicted in the following Reaction Scheme (1):
  • R 1 and R 2 are as defined above.
  • the isoxazoline derivatives of formula (2), the caspase inhibitors are dissolved in an organic solvent such as dichloromethane at 10 ⁇ 40 °C , and trifluoroacetic anhydride is added in an amount of 1 to 5 molar ratio with respect to the isoxazoline derivatives of formula (2) at the same temperature.
  • the resulting mixture is reacted for 1 to 48 h to give the compounds of formula (1).
  • the compounds of formula (1) according to the present invention act as a prodrug for the caspase inhibitor, which is demonstrated by the results of the following Experiments.
  • the compounds of formula (1) are administered into the body, they are converted to their active forms, the compounds of formula (2), and then metabolized in the body. According to this, the compounds of formula (1) can exert the anti-inflammation effect or blocking effect against apoptosis.
  • the present invention provides a caspase inhibitor composition, more specifically a composition for anti-inflammation and the prevention or treatment of apoptosis, which comprises the compounds of formula (1) or pharmaceutically acceptable salts thereof as an active ingredient together with a pharmaceutically acceptable carrier. More specifically, the composition of the present invention exhibits the therapeutic or preventive effect against dementia, cerebral stroke, brain impairment due to AIDS, diabetes, gastric ulcer, cerebral injury by hepatitis virus, hepatitis-induced hepatic diseases, acute hepatitis, human fulminant hepatic failure, sepsis, organ transplantation rejection, rheumatic arthritis, necrosis of cardiac cell due to ischemic cardiac diseases, and liver cirrhosis.
  • the compounds of the present invention can be formulated as various pharmaceutical dosage forms according to the desired purpose.
  • therapeutically effect amounts of the compounds of formula (1) or pharmaceutically acceptable salts thereof are mixed together with various pharmaceutically acceptable carriers which can be selected according to the formulation to be prepared.
  • the caspase inhibitor compounds of the present invention can be formulated as injectable, percutaneous or oral preparation according to the desired purpose. It is especially advantageous to prepare the formulation in a unit dosage form for ease of administration and uniformity of dosage.
  • any usual pharmaceutical carrier may be used for the oral preparation.
  • water, glycols, oils, alcohols and the like may be used for oral liquid preparations such as suspensions, syrups, elixirs and solutions; or starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be used for solid preparations such as powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules are the most advantageous dosage unit forms. It is also desirable for tablets and pills to be formulated into enteric-coated preparation.
  • injections for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent.
  • Solvents that can be used for preparing injections include water, Ringer's fluid, and isotonic NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acids such as oleic acid may also be used for injections.
  • the carrier may include a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives having no significant skin irritation.
  • Said additives may be selected from those which facilitate the administration through the skin and/or assist preparation of a desired composition.
  • the compounds of the present invention are preferably administered to the subject patient in a total daily dosage ranging from 5 to 500 mg per kg of body weight.
  • the total daily dosage may be administered in a single or multiple dosage.
  • specific administration dosage for an individual patient can be varied with body weight, sex, hygienic condition, or diet of subject patient, time or method of administration, excretion rate, mixing ratio of agent, severity of disease to be treated, etc.
  • the compound of formula (1a) When the compound of formula (1a) is administered, it is immediately converted to the corresponding active compound of formula (2a), and thus the compound of formula (1a) was not detected in plasma at all. Accordingly, the metabolites of the compound of formula (2a), i.e., compounds of formulas (3) ⁇ (6) were quantitatively analyzed, along with the compound of formula (2a). But, the compound of formula (4) among them was not detected.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/KR2009/001368 2008-03-18 2009-03-18 Caspase inhibitor prodrug WO2009116801A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020080025123A KR20090099886A (ko) 2008-03-18 2008-03-18 캐스파제 저해제의 프로드럭
KR10-2008-0025123 2008-03-18

Publications (2)

Publication Number Publication Date
WO2009116801A2 true WO2009116801A2 (en) 2009-09-24
WO2009116801A3 WO2009116801A3 (en) 2009-12-17

Family

ID=41091396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2009/001368 WO2009116801A2 (en) 2008-03-18 2009-03-18 Caspase inhibitor prodrug

Country Status (2)

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KR (1) KR20090099886A (ko)
WO (1) WO2009116801A2 (ko)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021600A1 (en) * 1999-09-17 2001-03-29 Lg Chem Investment Ltd. Caspase inhibitor
KR100594544B1 (ko) * 2003-08-27 2006-06-30 주식회사 엘지생명과학 이소옥사졸린 구조를 갖는 캐스파제 저해제
KR100774999B1 (ko) * 2005-02-26 2007-11-09 주식회사 엘지생명과학 이소옥사졸린 유도체 및 그의 제조 방법
NZ566022A (en) * 2005-07-28 2011-04-29 Vertex Pharma Caspase inhibitor prodrugs

Also Published As

Publication number Publication date
WO2009116801A3 (en) 2009-12-17
KR20090099886A (ko) 2009-09-23

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