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WO1993016698A1 - FURO[3',4':6,7]INDOLIZINO[1,2-b]QUINOLINONES SUBSTITUEES - Google Patents

FURO[3',4':6,7]INDOLIZINO[1,2-b]QUINOLINONES SUBSTITUEES Download PDF

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Publication number
WO1993016698A1
WO1993016698A1 PCT/US1993/001027 US9301027W WO9316698A1 WO 1993016698 A1 WO1993016698 A1 WO 1993016698A1 US 9301027 W US9301027 W US 9301027W WO 9316698 A1 WO9316698 A1 WO 9316698A1
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WIPO (PCT)
Prior art keywords
nrr
lower alkyl
compound
formula
pharmaceutically acceptable
Prior art date
Application number
PCT/US1993/001027
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English (en)
Inventor
David Alan Berges
Robert Philip Hertzberg
Randall Keith Johnson
William Dennis Kingsbury
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Smithkline Beecham Corporation
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.)
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Publication date
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Publication of WO1993016698A1 publication Critical patent/WO1993016698A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • This invention relates to antiviral compounds, pharmaceutical compositions thereof, and a method of treating viral infections. More specifically, this invention relates to certain furoindolizino[l,2-b]-quinolinyl derivatives which have antiviral activity.
  • Camptothecin is an example of one such compound. It is a water-insoluble, cytotoxic alkoloid produced by Camptotheca acuminate trees indigenous to China and Nothapodytes foetida trees indigenous to India. Camptothecin and a few close congeners are the only class of compounds known to inhibit eukaryotic topoisomerase I. The cytotoxic and antitumor activity of camptothecin and its close congeners is due to inhibition of eukaryotic topoisomerase I (Cancer Res. 1988, 48, 1722; Molec.
  • Camptothecin has been shown to have an effect on viruses by a number of investigators in laboratory settings. Although camptothecin has demonstrated antiviral activity in in vitro tissue culture systems, camptothecin and its close analogs that have an E-ring hydroxylactone moiety cannot be considered as useful in vivo antiviral agents because they inhibit mammalian topoisomerase I, inhibit host cell DNA replication, and are cytotoxic to mammalian cells. Furthermore, camptothecin is not expected to be attractive for drug development as an antiviral agent because of unacceptable dose- limiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability.
  • the present invention provides a method for treating viral infections, which method comprises administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier, diluent or excipient
  • R 9 is -H; -OR, -NO2; -NRR 1 ; -CN, halo; -(CH 2 )o-3CH 2 V;
  • R ! 0 is -H, -OR; -OCH2OCH2CH2OCH3; -NO2, -NRR 1 ; -CN, -COR 12 ; -CH(OH)R 12 ; -OC(O)R 12 ; -OC(O)OR 12 ⁇ -OC(O)CH2CH 2 COOR 13 ; -O-(CH 2 )i-5CH2NRR 1 ; -OC(0)NRR 1 ; l,4'-bipiperidine-l'-carboxy; -(CH 2 )o-3CH2V;
  • V is -OH, -OCi- ⁇ alkyl, -OCOR 12 -OCOOR 13 , -OCONRR 1 , -NRR 1 , or -CN;
  • R 11 is -H, -CN, or -OR;
  • R 12 is -H or lower alkyl;
  • R 13 is lower alkyl
  • R and R 1 are independently selected from the group consisting of -H, lower alkyl, and, R and R 1 taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen on which R and R- ⁇ are substituted;
  • Q is CR and T is CH;
  • the dotted lines represent a single bond between carbons 3a and 13a, a double bond between carbons 1 and 13a, and a double bond between carbons 3 and 3a, when Q is CR and T is CH;
  • R 2 is -H, -OR, or -OC(O)R;
  • R 7 , R 9 , R 10 or R 11 is other than -H, only one of the others may be other than -H; and only one of R 7 , R 9 , R 10 or R 11 may be -NO2 or -NRR 1 .
  • this invention relates to certain novel compounds of Formula II, or a pharmaceutically acceptable salt thereof
  • R 7 , R 9 , R 10 or R 11 is other than -H, only one of the others may be other than -H;
  • R 7 , R 9 or R 10 may be -NO2, or -NRR 1 ;
  • R 7 , R 9 , R i O and R 11 are not all -H when T is CH 2 and Q is C(OH)(CH 2 CH 3 ).
  • the present invention provides novel compounds of Formula DI,or a pharmaceutically acceptable salt thereof
  • R 7 , R 9 , R 10 or R 11 is other than -H, only one of the others may be other than -H;
  • R 7 , R 9 , R 10 or R 11 may be -NO2 or -NRR 1 .
  • compositions comprising a compound of either Formula II or HI in combination with an acceptable carrier, excipient, or diluent, particularly a pharmaceutically acceptable carrier, excipient, or diluent.
  • Aliphatic is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono- or poly- unsaturated chains where both double and triple bonds may be present in any combination.
  • lower alkyl refers to an alkyl group of 1 to 6 carbon atoms in any isomeric form, particularly the normal or linear form.
  • Lower alkoxy means the group lower alkyl-O-.
  • ' ⁇ alo means fluoro, chloro, bromo or iodo.
  • Acyl means the radical having a terminal carbonyl carbon.
  • 5-7 membered saturated heterocyclic ring containing the nitrogen is intended to include saturated rings such as piperidine, pyrrolidine, morpholine, piperazine, and N-alkyl piperazine.
  • Salts of any sort may be made from the present compounds, provided there is an acidic group present or a sufficiently basic nitrogen.
  • Particularly preferred are the pharmaceutically acceptable salts of the instant compounds. These latter salts are those which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions are prepared in a standard manner.
  • the parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts of a base moiety, or an excess of organic or inorganic base in the case where there is an acid group.
  • Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid.
  • Cationic salts are readily prepared from metal bases such as sodium, potassium, calcium, magnesium, zinc, copper or the like and ammonia.
  • Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, and the like.
  • a chiral center or some other form of an isomeric center is created by some combination of substituents in a compound of the present invention, all forms of such isomer(s) are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture or the mixture may be separated and an individual enantiomer may be used alone.
  • the present invention provides a method for the treatment of viral infections comprising administering to an infected host, including humans, in need thereof an effective amount of a compound of Formula I as described hereinabove, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier, excipient or diluent.
  • the present invention also provides compounds, and pharmaceutically acceptable salts thereof, which exhibit antiviral activity, said compounds having the structure represented by either Formula II or HI, as described hereinabove.
  • These compounds and the present method are useful for treating viral infections caused by a broad variety of viruses in both animals and plants.
  • the present compounds and the present method are particularly useful in treating DNA replicating animal virus infections. More specifically, these compounds and the present method are especially useful in treating the following pathogens in humans:
  • Herpes Simplex virus types 1 and 2 Cytomegalovirus
  • Animal pathogens which arc treatable with these compounds and by the present method include, but are not limited to:
  • Equine Herpes virus Porcine Herpes virus
  • a preferred method of treating viral infections according to the present invention uses compounds of Formula I where T is CH2, Q is C(OR)(Ci-6alkyl), R 7 is -H, R 9 is -H, R 11 is -H, and R 10 is -H, -OR, or -OCH2OCH2CH2OCH3.
  • Yet another preferred method of treating viral infections according to the present invention uses compounds of Formula I where T is CH, Q is CR, where R is Ci ⁇ alkyl, and R 7 R 9 , R 10 , and R 11 are all -H.
  • Preferred compounds of the present invention include those of Formula II where T is CH2, Q is C(OR)(Ci-6alkyl), R?, R 9 , R 11 are -H, and R 10 is -H, -OR, or
  • Yet another group of preferred compounds are those of Formula HI where R is
  • R 7 , R 9 , R 10 , and R 11 are all -H.
  • Camptothecin, 10-hydroxycamptothecin and 9-hydroxycamptothecin are natural products. Camptothecin and 10-hydroxycamptothecin are publicly available from sources in the People's Republic of China.
  • a 9-hydroxycamptothecin compound which can be used as starting material for making some of the inventive compounds is described in Japanese Patent Application No. 59-51289.
  • the synthesis of 9- nitrocamptothecin is described in Wall, et al., J. Med. Chem., 1986, 29, 2358.
  • a total synthesis of camptothecin is described in Wall, et al., /. Med. Chem., 1980, 23, 554.
  • the 1980 Wall synthesis is useful for introducing one or more R 7 -R n substituents into precursors of the compounds of Formula I. To do so, the Wall synthesis is modified, using well-known methods, at the appropriate step to provide for insertion of the desired substituent.
  • the furan ring may be formed by a two step process comprising: i) treating a 1H- pyrano-[3',4':6,7]indolizino[l,2-b]quinolin-14(4H,12H)-one with an oxidizing agent to form an 8-formyloxymethyl-7-(l-oxopropylindolzino[l,2-b]quinolin-9(llH)-one; and ii), forming a ring by treating the quinolin-9(HH)-one with base, for example potassium carbonate.
  • the 3-hydroxy group can be derivatized. In particular, protection of this group with an ether derivative allows the introduction of other substitutents onto the quinoline portion of the molecule.
  • a and B ring substituents may also be introduced into the molecule prior to formation of the furan ring, so long as these substituents are not degraded or modified by the oxidizing agent or base used the in the formation of the fiiran ring.
  • Compounds of the present invention having desired A/B ring substitutents can be prepared by introducing the substitutents onto the camptothecin starting material either prior to or after formation of the furan ring.
  • compounds of the present invention having the desired substituents may be conveniently prepared from 4- ethyl-3,4-d__hydroxy-lH-pyrano-[3 ⁇ 4':6,7]indoUzino[l,2-b]quinolin-14(4H,12H)-ones, the syntheses of which are disclosed in a co-pending application, U.S . Ser. No. 07/783,063, the specification of which is incorporated herein by reference.
  • the preparative process involves first treating the COrresrx)nding4-ethyl-3,4-dihydroxy-lH-pyrano[3 ⁇ 4':6,7]indoUzino[l,2-b]quinolin- 14(4H,12H)-ones with an oxidizing agent such as sodium metaperiodate to form an 8- formyloxymethyl-7-(l-oxopropyl)indolizino [l,2-b]quinoline-9(l lH)-one from which the formyl group is then cleaved, for example by mild base treatment, resulting in a hydroxy ketone which then spontaneously cyclizes to a 3-ethyl-l, ll-dihydro-3-hydroxy- 3H, 13H-furo[3',4':6,7]indolizino[l,2-b]quinolin-13-one.
  • an oxidizing agent such as sodium metaperiodate
  • the hydroxy group of these compounds can be replaced with an ether moiety by treating the hydroxy compound with an alcohol with acid catalysis.
  • the hydroxy compound can be dehydrated, for example with trifluoroacetic acid, to give the corresponding 3-ethyl-l 1H, 13H- furo ⁇ 4':6,7]indoliz__no[l,2-b]quinolin-13-one.
  • SCHEME 1 The assay used to test the compounds of the present invention for antiviral activity is well-known. A generalized description of the assay follows. Well plates are seeded with the appropriate cells at a concentration of lxlO 5 cells per well suspended in 0.5 mL of Earle's Minimum Essential Medium (EMEM) containing 10% fetal bovine serum (FBS) and antibiotic and antimycotic solution. After the cells are 80-90% confluent (24 hours), old medium is removed and washed with Hank's buffered saline solution (HBSS). Cells are then infected for 1 hour at 37°C with 100-200 plaque forming units per well of a herpes simplex virus suspended in 250 mL HBSS. Following adsorption, the following are added:
  • EMEM Earle's Minimum Essential Medium
  • FBS fetal bovine serum
  • HBSS Hank's buffered saline solution
  • This assay can be used to test compound activity against many other viruses besides herpes simplex by simply modifying the cell type used in the first step to match the virus being tested, and otherwise following the procedure outlined above.
  • Other cell types which can be used in this assay include mouse mammary tumor cells, human lung fibroblasts, sheep chorioplexus cells, and green monkey kidney cells.
  • assays can be used to determine the antiviral activity of the present compounds.
  • assays include the following types: cell count, clonogenic, cytopathic effect, dish-colony formation, microtiter-growth inhibition, thymidine incorporation and yield reduction. Each of these assays is well-known and is available either from the literature or from a commercial testing lab.
  • compositions prepared from the compounds of Formula I have both a human and veterinary utility, and comprise an excipient or carrier which is acceptable for the intended pharmaceutical end use and at least one inventive compound.
  • the carrier may be a liquid, or spray, or may be formulated in a solid, non- degradeable or degradeable form for insertion in the rumen. Selected excipients and carriers may be employed to prepare compositions acceptable or adaptable for human use.
  • the present invention additionally provides compositions prepared from compounds of Formula I which are useful in treating plants, e.g. agricultural or ornamental seeds and plants.
  • the compound can be mixed with a fertilizer, other microbiocides such as fungicides, or insecticides and the like.
  • a fertilizer such as fungicides, or insecticides and the like.
  • present compositions may also be formulated in powders or sprays by methods well-known in the art for application to plant surfaces.
  • compositions of the present invention may be contained in one embodiment, such as in a single pill, capsule, or pre-measured intravenous dose or pre-filled syringe for injection.
  • the composition will be prepared in individual dose forms where one unit, such as a pill, will contain a sub-optimal dose but the user will be instructed to take two or more unit doses per treatment.
  • the composition When the composition is presented as a cream, it will contain a discrete amount of drug and the user will apply some amount of the cream one or more times until the disease is in remission or has been effectively treated. Concentrates for later dilution by the end user may also be prepared, for instance for IV formulations and multi-dose injectable formulations.
  • Carriers or diluents contemplated for use in these compositions are generally known in the pharmaceutical formulary arts. Reference to useful materials can be found in well known compilations such as Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pa.
  • the nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example whether by intravenous and intramuscular injection, parenterally, topically, orally, or by inhalation.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for administration to the skin, eye, ear, nose or genitalia.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems: ethanol, glycerin, propylene glycol, olive oil, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins, and mixtures thereof with water, for solid systems: lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, kaolin and mannitol; and for aerosol systems: dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram.
  • a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampule or vial or nonaqueous liquid suspension.
  • a pharmaceutically acceptable salt of the compound of Formula I is dissolved in an aqueous solution of an organic or inorganic acid or base. If a soluble salt form is not available, the compound of Formula I may be dissolved in a suitable co-solvent or combinations thereof.
  • suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. It will be appreciated that the actual preferred dosages of the compounds used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated.
  • Example 4 (+V3-Ethyl-1H. 3H-fiiror3'.4':6.71indolizinori.2-blquinolin-1.13OlH)-dione.
  • This compound was prepared by the method of R. P. ⁇ ertzberg, M. J. Caranfa, K. G. ⁇ olden, D. R. Jakas, G. Gallagher, M. R. Mattern, S.-M. Mong, J. CLeary Bartus, R. K. Johnson, and W. D. Kingsbury /. Med. Chem., 1989, 32, 715.
  • the red residue was covered witii 0.5 mL methylene chloride, and a few drops each of triethylamine and methanol were added to convert it to a golden solution that was chromatographed on silica gel using 3% methanol in methylene chloride as elution solvent.
  • the yellow solid obtained was recrystallized from methanol to give yellow crystals of the title compound as a hydrate, mp 226.5-228.5°C.
  • a parenteral pharmaceutical composition of this invention suitable for administration by injection 100 mg of a water soluble salt of a compound of Formula I is mixed with 10 ml of 0.9% sterile saline, and d e mixture is incorporated into a dosage unit form suitable for administration by injection.
  • an oral pharmaceutical composition of this invention 100 mg of a compound of Formula I is mixed with 750 mg of lactose, and the mixture is incorporated into an oral dosage unit form, such as a hard gelatin capsule, which is suitable for oral administration.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de traitement d'infections virales consistant à utiliser des composés antiviraux de furoindolizino[1,2-b]quinolinones substituées, des composés antiviraux de furoindolizino[1,2-b]quinolinones substituées, ainsi que leurs compositions pharmaceutiques.
PCT/US1993/001027 1992-02-21 1993-02-05 FURO[3',4':6,7]INDOLIZINO[1,2-b]QUINOLINONES SUBSTITUEES WO1993016698A1 (fr)

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US83982392A 1992-02-21 1992-02-21
US07/839,823 1992-02-21

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994025030A1 (fr) * 1993-05-03 1994-11-10 Smithkline Beecham Corporation DIOXOLO[4,5-g]FURO[3',4':6,7]INDOLOZINO[1,2-b]QUINOLINONES SUBSTITUEES
WO1997016454A1 (fr) * 1995-11-02 1997-05-09 Glaxo Wellcome Inc. Procede pour preparer des derives de camptothecine
US5837673A (en) * 1995-08-02 1998-11-17 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
US5840898A (en) * 1994-05-03 1998-11-24 Glaxo Wellcome, Inc. Method of removing heavy metal contaminants from organic compounds
US5843693A (en) * 1989-08-16 1998-12-01 Chiron Corporation Assay method for screening for inhibitors of proTNF conversion
US5932732A (en) * 1996-10-30 1999-08-03 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US5998378A (en) * 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US6586222B1 (en) 1989-08-16 2003-07-01 Chiron Corporation Recombinant PR-3 and compositions thereof
US6599706B1 (en) 1994-03-07 2003-07-29 Chiron Corporation Recombinant PR-3 and assays employing the same
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR

Citations (1)

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US4981968A (en) * 1987-03-31 1991-01-01 Research Triangle Institute Synthesis of camptothecin and analogs thereof

Patent Citations (1)

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US4981968A (en) * 1987-03-31 1991-01-01 Research Triangle Institute Synthesis of camptothecin and analogs thereof

Non-Patent Citations (3)

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Title
CHEMICAL ABSTRACT, Vol. 77, (1977), Entry 70781u, HORWITZ et al., "Camptothecin Mechanism of Inhibition of Adenovirus Formation". *
JOUR. MED. CHEM., 1986, WALL et al., "Plant Antitumor Agents 22' Bolation of II Hydroxycamptothecin from Camptoheca Acuminata Deane: Total Synthesis and Biological Activity", Vol. 29, pages 1553-5. *
JOUR. MED. CHEM., 1989, HERTZBERG et al., "Modification of the Hydroxyring of Camptothecin: Inhibition of Mammalian Topoisomerase I and Biological Activity", Vol. 32, pages 715-20. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843693A (en) * 1989-08-16 1998-12-01 Chiron Corporation Assay method for screening for inhibitors of proTNF conversion
US5998378A (en) * 1989-08-16 1999-12-07 Chiron Corporation Compositions for the inhibition of TNF hormone formation and uses thereof
US6586222B1 (en) 1989-08-16 2003-07-01 Chiron Corporation Recombinant PR-3 and compositions thereof
WO1994025030A1 (fr) * 1993-05-03 1994-11-10 Smithkline Beecham Corporation DIOXOLO[4,5-g]FURO[3',4':6,7]INDOLOZINO[1,2-b]QUINOLINONES SUBSTITUEES
US6599706B1 (en) 1994-03-07 2003-07-29 Chiron Corporation Recombinant PR-3 and assays employing the same
US5840898A (en) * 1994-05-03 1998-11-24 Glaxo Wellcome, Inc. Method of removing heavy metal contaminants from organic compounds
US5837673A (en) * 1995-08-02 1998-11-17 Tanabe Seiyaku Co., Ltd. Camptothecin derivatives
US6284891B1 (en) 1995-11-02 2001-09-04 Gilead Sciences, Inc. Method for preparing camptothecin derivatives
WO1997016454A1 (fr) * 1995-11-02 1997-05-09 Glaxo Wellcome Inc. Procede pour preparer des derives de camptothecine
US6143891A (en) * 1995-11-02 2000-11-07 Glaxo Wellcome Inc. Method for preparing camptothecin derivatives
US5932732A (en) * 1996-10-30 1999-08-03 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6277992B1 (en) 1996-10-30 2001-08-21 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6388078B1 (en) 1996-10-30 2002-05-14 Tanabe Seiyaku Company, Limited S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6114529A (en) * 1996-10-30 2000-09-05 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6015901A (en) * 1996-10-30 2000-01-18 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6716983B2 (en) 1996-10-30 2004-04-06 Tanabe Seiyaku Co., Ltd. S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US7060832B2 (en) 1996-10-30 2006-06-13 Tanabe Seiyaku Co., Ltd. Nitrogen-containing fused heterocyclic carboxylic acids having an absolute configuration of “R”
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US6821982B2 (en) 1996-11-01 2004-11-23 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US7998986B2 (en) 2001-12-21 2011-08-16 Exelixis Patent Company Llc Modulators of LXR
US8013001B2 (en) 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR

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