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WO2000071131A1 - Mimetiques hexacycliques de g-csf - Google Patents

Mimetiques hexacycliques de g-csf Download PDF

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Publication number
WO2000071131A1
WO2000071131A1 PCT/US2000/014857 US0014857W WO0071131A1 WO 2000071131 A1 WO2000071131 A1 WO 2000071131A1 US 0014857 W US0014857 W US 0014857W WO 0071131 A1 WO0071131 A1 WO 0071131A1
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substituted
compound
cycloalkyl
alkyl
pharmaceutically acceptable
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Inventor
Kevin J. Duffy
Juan I. Luengo
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to AU72534/00A priority Critical patent/AU7253400A/en
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • G-CSF Granulocyte colony-stimulating factor
  • G-CSF has pleiotropic effects on mature neutrophils, enhancing their survival and stimulating functional activation, including induction of neutrophil alkaline phosphatase (Sato. N. et al., J. Cell. Phvsiol. (1988) 37:272) and high affinity IgA F c receptors (Weisbart, R. H., et al., Nature (Lond.) (1988) 332:647), priming for respiratory burst (Nathan, C. F. Blood (1989) 73:301) and increased chemotaxis (Wang, J.M., Blood (1988) 72: 1456).
  • G-CSF effects have also been observed on hematopoietic cells that are not committed to the granulocyte lineage, for example, stimulation of the proliferation on monocytic differentiation in vitro of some myeloid leukemic cells (Geissler, K., J. Immunol. (1989) 143:140) and the proliferation in vitro of some multipotential hematopoietic precursors (Ferrero, D., Blood (1989) 73:402).
  • G-CSF is beneficial as an adjuvant in chemotherapy and in bone marrow transplantation (Morstyn, G., et al., Trends Pharmacol. Sci. JO, ( 1989) 154- 159). G-CSF activity is also associated with mobilization of hematopoietic stem cells from the marrow to the peripheral blood. (See review article, Good Review article Haylock et al., Blood 89:2233-2258, 1997). It would be desirable to provide compounds which allow for the treatment of neutropenia to enhance leukocyte production by acting as a G-CSF mimetics. As disclosed herein it has unexpectedly been discovered that certain hexacyclic compounds are effective as G-CSF mimetics.
  • This invention relates to compounds of Formula (1):
  • R ! and R ⁇ are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRHR 12, NR ⁇ R ⁇ , aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C ⁇ aryl, alkoxy, acyloxy, substituted Cg-Ci2 ar yf trifluoro methyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O) n R 13 , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyl
  • R 1 1 is hydrogen or alkyl, n is 0-2,
  • R !2 i hydrogen or alkyl
  • Rl3 is hydrogen, cycloalkyl, Cg-C ⁇ aryl ' substituted cycloalkyl, substituted C6-Ci2 ar yh alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORl 1, -S(O) n Rl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ⁇ -C ⁇ aryl, substituted Cg-Cj 2 a ryl and protected -OH, where R* 1, n, and R 12 are as described above;
  • R 3 , R 4 , R 5 and R 6 are independently hydrogen, C(O)NRl !R 1 , Np! 1R12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C ⁇ aryl- alkoxy, acyloxy, substituted C6-Ci2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O) n R!3, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C ⁇ -C ⁇ aryl, substituted Cg-C ⁇ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O) n Rl3, aryloxy, nitro.
  • the present invention also relates to the discovery that the compounds of Formula (I) are active as G-CSF mimetics.
  • the invention also is a method for treating neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
  • the invention is also a method for treating bacterial and fungal infections in mammals, including humans, which comprises administering to a subject in need thereof an effective amount of a presently invented G-CSF mimetics compound.
  • novel processes useful in preparing the presently invented G-CSF mimetics compounds include pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.
  • G-CSF mimetics compounds with further active ingredients.
  • DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention that act as G-CSF mimetics have the following Formula (1):
  • R ! and R ⁇ are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRl 1 R12, NRI 1R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ⁇ -C ⁇ aryl.
  • Rl2 is hydrogen or alkyl
  • RI 3 is hydrogen, cycloalkyl, ⁇ - ⁇ a ⁇ l, substituted cycloalkyl, substituted 6 ⁇ i2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORl 1, -S(O) n Rl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, substituted Cg-Ci2 ar yl an d protected -OH, where RI 1, n, and Rl2 are as described above; R 3 , R 4 , R 5 and R 6 are independently hydrogen, C(O)NR R 1 2 , NRI 1R 2, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C6-Ci2 ar yl ' lk°x
  • Fromula I compounds are those in which aryl is: C5-Ci2 a ryl, optionally containing one or two heteroatoms and optionally substituted with one or more substituents selected from the group consisting of: -OCg-C ⁇ aryl, -(CH2) m OH, Cg-C ⁇ aryl, C ⁇ -C4alkyl,-OC ⁇ -C4alkyl, amino, nitro, cyano, methoxycarbonyl, N-acylamino, trifluoromethyl, C3.
  • cycloalkyl halogen, -(CH2) p COOH, -S(O) n Rl 2 and protected -OH, where m is 0- 4, p is 0-3, n is 0-2 and Rl2 is hydrogen or Ci _4alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • R and R 2 are independently phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl or quinolyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, Cj-salkyl, trifluoromethyl, methoxycarbonyl, C3_7cycloalkyl and -O-C 1-4 alkyl;
  • R 3 , R 4 , R5 and R ⁇ are independently hydrogen, -OCg-C ⁇ ryh Cg-C ⁇ ryl, C1-C4 alkyl, -OCj-C4alkyl, amino, nitro, cyano, N-acylamino, C3-7cycloalkyl, halogen, -S(O) n Rl2 or protected -OH, where m is 0-4, p is 0-3, n is 0-2 and Rl2 is hydrogen or C 1-4 alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • RI and R 2 are independently phenyl, furyl, thienyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, Cj_5alkyl, trifluoromethyl, methoxycarbonyl, C3_6cycloalkyl and -O-Cj. 3 alkyl;
  • R 3 , R 4 , R and R ⁇ are independently hydrogen, halogen, C ⁇ alkyl, C3-. cycloalkyl or -O-Cj ⁇ alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • RI and R 2 are independently phenyl, furyl or pyridyl all of which are unsubstituted or substituted with a substituent selected from the group consisting of: halogen, C ⁇ _ 5alkyl, trifluoromethyl, methoxycarbonyl and -O-Cj-3alkyl; and
  • R 3 , R 4 , R5 and R ⁇ are independently hydrogen, trifluoromethyl, methoxycarbonyl, halogen or C ⁇ alkyl; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.
  • protected hydroxy or “protected -OH” as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art as described in “Protective Groups In Organic Synthesis” by Theodora W. Greene, Wiley-Interscience, 1981, New York.
  • C5-C12 aryl as use d herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic C5-C12 optionally containing one or two heteroatoms.
  • C6-C 2 aryl as used herein, unless otherwise defined, is meant phenyl, naphthyl, 3,4-methylenedioxyphenyI, pyridyl, or biphenyl.
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH2) g C(O)ORl 1, -S(O) n R 2, nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R 1 1 is hydrogen or alkyl, n is 0-2, and Rl2 is hydrogen or alkyl.
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12.
  • cycloalkyl and substituted cycloalkyl substituents as used herein include: cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.
  • acyloxy as used herein is meant -OC(O)alkyl where alkyl is as described herein.
  • Examples of acyloxy substituents as used herein include: - OC(O)CH 3 , -OC(O)CH(CH 3 ) 2 and -OC(O)(CH 2 )3CH 3 .
  • N-acylamino as used herein is meant -N(H)C(O)alkyl, where alkyl is as described herein.
  • Examples of N-acylamino substituents as used herein include: -N(H)C(O)CH 3 , -N(H)C(O)CH(CH 3 ) 2 and -N(H)C(O)(CH 2 )3CH 3 .
  • aryloxy as used herein is meant -OCg-C ⁇ l where Cg- Ci2 a ryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N- acylamino, hydroxy, -(CH2) g C(O)ORl 1, -S(O) n Rl2, nitro, cyano, halogen and protected -OH, where g is 0-6, Rl 1 is hydrogen or alkyl, n is 0-2 and Rl2 is hydrogen or alkyl.
  • substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
  • heteroatom oxygen, nitrogen or sulfur.
  • halogen as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.
  • alkyl and derivatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C1 -C12 carbon atoms.
  • treating and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy.
  • mobilizing peripheral blood stem cells as used herein is meant the mobilization of hematopoietic stem cells from the marrow to the peripheral blood.
  • esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • co-administering and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a G-CSF mimetic compound, as described herein, and a further active ingredient or ingredients, such as antibacterial agents, antifungal agents as well as agents known to treat neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production.
  • a G-CSF mimetic compound as described herein
  • a further active ingredient or ingredients such as antibacterial agents, antifungal agents as well as agents known to treat neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compounds may be administered orally.
  • novel compounds of Formula (I) are prepared as shown in Scheme I below provided that the R ⁇ X and Y substituents do not include any such substituents that render inoperative the Scheme I process.
  • the compounds of Foumula (2) are prepared by methods analogous to the Schemes and Examples used to prepare the Formula (I) compounds in International Application PCT/US97/08864, Published on November 27, 1997 as WO 97/44033.
  • the reagents used herein are commercially available or are readily made by those skilled in the art from commercially available materials.
  • Rl, R 2 , R3, R4 R5 a nd R ⁇ and X are as described in Formula (I) above, are reacted with phosgene or thiophosgene or an appropriate phosgene or thiophosgene equivalent such as bistrichloromethyl carbonate, disuccinidimoyl carbonate, carbonyl diimidazole or thiocarbonyl diimidazole in an appropriate solvent, preferably pyridine or 1 ,2-dichloroethane, to afford hexacyclic compounds of Foumula (1),
  • the pharmaceutically active compounds of the present invention are active as G-CSF mimetics they exhibit therapeutic utility in treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production.
  • the compounds of present invention are tested for potency as G- CSF mimetics in a CFU-G assay, an example of which is described in King AG, Talmadge J., Badger AM, Pelus LM. Regulation of colony stimulating activity production from bone marrow stromal cells by the hematoregulatory peptide, HP-5. Exp. Hematol. 20:223-228. 1992.
  • the pharmaceutically active compounds within the scope of this invention are useful as G-CSF mimetics in mammals, including humans, in need thereof.
  • the present invention therefor provides a method of treating bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, which comprises administering a compound of Formula (1):
  • Rl and R 2 are independently aryl, where aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms, and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: C(O)NRl 1R 2, NRI 1R 12, aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, trifluoromethyl, methoxycarbonyl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C(O)ORl 1, -S(O) n Rl 3 , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C - Ci2- ⁇ ryl, substituted Cg-C ⁇ aryl, amino, N-acylamino,
  • Rl2 is hydrogen or alkyl
  • Rl 3 is hydrogen, cycloalkyl, ⁇ -C ⁇ ⁇ yl, substituted cycloalkyl, substituted 6" l2 ar yl > a lkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(O)ORH, -S(O) n Rl2, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, "d protected -OH, where Rl 1, n, and R 12 are as described above; R 3 , R 4 , R 5 and R 6 are independently hydrogen, C(O)NRl 1R 12, NRI !
  • R 1 2 aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, Cg-C ⁇ f alkoxy, acyloxy, substituted Cg-C ⁇ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, - C(O)ORl 1, -S(O) n Rl3, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-Ci2aryl, substituted Cg-C ⁇ ryl * a mino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C(O)ORl 1, -S(O) n Rl3, aryloxy, nitro, cyano, halogen and protected - OH, where Rl 1, n, Rl2 and R I are as described above; X is O, S or X
  • the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as G-CSF mimetics.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral.
  • the pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations.
  • Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products.
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg.
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally.
  • parenteral administration examples include topically, rectally, transdermally, by injection and continuously by infusion.
  • Oral dosage units for human administration preferably contain from 0.05 to 3500 mg, preferably 0.1 to 350 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular G-CSF mimetics in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • the method of this invention of inducing G-CSF mimetic activity in mammals, including humans, comprises administering to a subject in need of such activity an effective amount of of a presently invented G-CSF mimetic compound.
  • the invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use as a G-CSF mimetic.
  • the invention also provides for the use of a compound of Formula ( 1 ) in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula ( 1 ) in the manufacture of a medicament for use in enhancing leukocyte production.
  • the invention also provides for the use of a compound of Formula (1) in the manufacture of a medicament for use in treating bacterial and fungal infections.
  • the invention also provides for a pharmaceutical composition for use as a G- CSF mimetic which comprises a compound of Formula (1) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of neutropenia which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in enhancing leukocyte production which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in treating bacterial infections which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in treating fungal infections which comprises a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula (I) into association with the pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, or compounds known to have utility when used in combination with a G-CSF mimetic.
  • active ingredients such as other compounds known to treat bacterial infections, fungal infections, neutropenia, including chemotherapy-induced neutropenia and bone marrow transplantation and in mobilizing peripheral blood stem cells and other conditions with depressed leukocyte production, or compounds known to have utility when used in combination with a G-CSF mimetic.
  • An oral dosage form for administering a presently invented agonist of the G- CSF receptor is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • Example 2 Injectable Parenteral Composition
  • An injectable form for administering a presently invented agonist of the G- CSF receptor is produced by stirring 1.5% by weight of a Compound of Foumula (1) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a presently invented agonist of the G-CSF receptor are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet

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Abstract

La présente invention concerne des mimétiques de G-CSF. Elle concerne aussi des composés hexacycliques choisis, des compositions pharmaceutiques les contenant, ainsi que des procédés d'utilisation des ces composés comme mimétiques de G-CSF. Elle concerne enfin des procédés de préparation de ces composés.
PCT/US2000/014857 1999-05-26 2000-05-24 Mimetiques hexacycliques de g-csf Ceased WO2000071131A1 (fr)

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AU72534/00A AU7253400A (en) 1999-05-26 2000-05-24 Hexacyclic G-CSF mimetics

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061445A1 (fr) * 1998-05-22 1999-12-02 Smithkline Beecham Corporation Mimetiques du g csf
WO1999061446A1 (fr) * 1998-05-22 1999-12-02 Smithkline Beecham Corporation Mimetiques du g csf

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061445A1 (fr) * 1998-05-22 1999-12-02 Smithkline Beecham Corporation Mimetiques du g csf
WO1999061446A1 (fr) * 1998-05-22 1999-12-02 Smithkline Beecham Corporation Mimetiques du g csf

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