Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to an SPLA2 inhibitor compound having high bioavailability.
• sPLA2 human non- pancreatic secretory phospholipase A2
• sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids .
• compounds -2 - which inhibit SPL 2 mediated release of fatty acids (e.g., arachidonic acid) and are highly bioavailable in mammals, especially humans.
• Such compounds are of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2 ; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc .
• Therapeutic agents that may be given orally are, in general, greatly preferred and have enhanced commercial potential because of their inherent ease of use.
• U.S. Patent No. 5,654,326 describes certain indole type SPLA2 inhibitors and related ester prodrugs .
• this patent exemplifies the methyl ester of ( (3- (2-amino- 1, 2-dioxoethyl) -2-methyl-l- (phenylmethyl) -lH-indol-4- yl) oxy) acetic acid.
• This invention is the novel compound, ( (3- (2-amino-l, 2- dioxoethyl) -2-methyl-l- (phenylmethyl) -lH-indol-4- yl) oxy) acetic acid N-morpholino ethyl ester; which is highly bioavailable by oral administration.
• This invention is a pharmaceutical formulation comprising ( (3- (2-amino-l , 2-dioxoethyl) -2-methyl-l- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid, N-morpholino ethyl ester in combination with a carrier or diluent. -3 -
• the compound of the invention ( (3- (2-amino-l , 2- dioxoethyl) -2-methyl-l- (phenylmethyl) -lH-indol-4- yl) oxy) acetic acid, N-morpholino ethyl ester; is represented by the structural formula (I) ;
• N-morpholino ethyl ester (I) is an ester form of known SPLA2 inhibitor ( (3- (2-amino-l, 2-dioxoethyl) -2-methyl- 1- (phenylmethyl) -lH-indol-4-yl) oxy) acetic acid, represented by the structural formula (II), below;
• the compound of formula (II) is described in Example 1 of U.S. Patent No. 5,654,326 (the disclosure of which is incorporated herein by reference) and European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ., 4 October 1995). It is a discovery of this invention that the compound of formula (I) is highly bioavailable upon oral administration compared to other SPLA2 inhibitors .
• This starting material may be prepared by the reaction schemes or method of Example 1 of U.S. Patent No. 5,654,326 (the disclosure of which is incorporated herein by reference) . Similar methods are shown in European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ., 4 October 1995). Other conventional methods may also be used for preparing the starting material. Procedures useful for the synthesis of the compound of this invention are specified in Example 1 set out below:
• Part B Preparation of 4-Methoxy-2-methyl-lH-indole .
• a solution of 280 mL (0.36 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert- butoxycarbonyl-3-methoxy-2-methylaniline (43g, 0.18 mol) in 300 mL of THF keeping the temperature below -40°C with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -20°C and then the bath replaced. After the temperature had cooled to -60°C, 18.5g (0.18 mol) of N- methoxy-N-methylglyoxylamide in an equal volume of THF was - 6 - added dropwise.
• reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 1 hour. It was then poured into a mixture of 600 mL of ether and 600 mL of IN HC1. The organic layer was separated, washed with water, dried over MgS0 , and concentrated at reduced pressure to give 39.5g of a mixture of l-(2-(tert- butoxycarbonylamino) -6-methoxyphenyl) -2-propanone and starting anilide. This mixture was dissolved in 100 mL of methylene chloride and 40 mL of trifluoroacetic acid and stirred for a total of 26 hours. The mixture was washed with water, dried (MgSO ⁇ ) and concentrated at reduced pressure.
• Cynomolgus monkeys were used in a single dose pharmacokinetic study.
• the monkeys (3 per treatment) were administered a single oral lOmg/kg dose of one of six indole prodrug compounds including the compound of this invention.
• Serial blood samples were obtained up to 24 hours after dose administration.
• Plasma was analyzed for the corresponding free acid using an LC/MS method. Also area under the curve (auc) values were computed at 8 and 24 hours .
• the purpose of this assay was to evaluate and compare the oral delivery for selected SPLA2 inhibitors.
• the amount of SPLA2 inhibitor was corrected for free acid equivalents . -10-
• the purpose of this assay was to evaluate and compare the oral delivery for selected SPLA2 inhibitors.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pulmonology (AREA)
• Immunology (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (16)

Applications Claiming Priority (2)

Publications (1)

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Cited By (6)

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• 1999
  • 1999-04-20 ID IDW20002216A patent/ID27812A/id unknown
  • 1999-04-20 HU HU0201636A patent/HUP0201636A1/hu unknown
  • 1999-04-20 AU AU36525/99A patent/AU755901B2/en not_active Ceased
  • 1999-04-20 KR KR1020007012114A patent/KR20010071197A/ko not_active Withdrawn
  • 1999-04-20 HR HR20000738A patent/HRP20000738A2/hr not_active Application Discontinuation
  • 1999-04-20 DE DE69921314T patent/DE69921314T2/de not_active Expired - Lifetime
  • 1999-04-20 BR BR9910149-1A patent/BR9910149A/pt not_active IP Right Cessation
  • 1999-04-20 EP EP99918666A patent/EP1073440B1/en not_active Expired - Lifetime
  • 1999-04-20 PL PL99344571A patent/PL344571A1/xx not_active IP Right Cessation
  • 1999-04-20 CA CA002331036A patent/CA2331036A1/en not_active Abandoned
  • 1999-04-20 TR TR2000/03198T patent/TR200003198T2/xx unknown
  • 1999-04-20 ES ES99918666T patent/ES2230847T3/es not_active Expired - Lifetime
  • 1999-04-20 WO PCT/US1999/008538 patent/WO1999056752A1/en not_active Ceased
  • 1999-04-20 JP JP2000546777A patent/JP4459441B2/ja not_active Expired - Fee Related
  • 1999-04-20 AT AT99918666T patent/ATE280155T1/de not_active IP Right Cessation
  • 1999-04-20 CN CN99805672A patent/CN1303290A/zh active Pending
  • 1999-04-20 EA EA200001141A patent/EA003277B1/ru not_active IP Right Cessation
  • 1999-04-20 IL IL13920399A patent/IL139203A0/xx unknown
  • 1999-04-20 NZ NZ507391A patent/NZ507391A/en unknown
  • 1999-04-20 SK SK1633-2000A patent/SK16332000A3/sk unknown
• 2000
  • 2000-10-10 ZA ZA200005561A patent/ZA200005561B/en unknown
  • 2000-10-31 NO NO20005477A patent/NO315940B1/no not_active IP Right Cessation

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