WO1997017963A1 - Composes hematoregulateurs - Google Patents

Composes hematoregulateurs Download PDF

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Publication number
WO1997017963A1
WO1997017963A1 PCT/US1996/018053 US9618053W WO9717963A1 WO 1997017963 A1 WO1997017963 A1 WO 1997017963A1 US 9618053 W US9618053 W US 9618053W WO 9717963 A1 WO9717963 A1 WO 9717963A1
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WO
WIPO (PCT)
Prior art keywords
bis
formula
compound
picolinoyl
hydrogen
Prior art date
Application number
PCT/US1996/018053
Other languages
English (en)
Inventor
Pradip Kumar Bhatnagar
Dirk Andries Heerding
Michael Hartmann
Johann Hiebl
Peter Kremminger
Franz Rovenszky
Original Assignee
Smithkline Beecham Corporation
Nycomed Austria Gmbh
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 Smithkline Beecham Corporation, Nycomed Austria Gmbh filed Critical Smithkline Beecham Corporation
Priority to JP9518974A priority Critical patent/JP2000500455A/ja
Priority to EP96941338A priority patent/EP0865279A4/fr
Publication of WO1997017963A1 publication Critical patent/WO1997017963A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • 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
    • A61P31/10—Antimycotics
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to novel compounds which have hemoregulatory activities and can be used to stimulate hematopoiesis and for the treatment of viral, fungal and bacterial infectious diseases.
  • the hematopoietic system is a life-long cell renewal process whereby a defined stem cell population gives rise to a larger population of mature, differentiated blood cells (Dexter TM. Stem cells in normal growth and disease. Br Med J 1987; 195: 1 192-1 194) of at least nine different cell lineages (erythrocytes, platelets, eosinophils, basophils, neutrophils, monocytes/macrophages, osteoclasts, and lymphocytes) (Metcalf D. The Molecular Control of Blood Cells. 1988; Harvard University Press, Cambridge, MA). Stem cells are also ultimately responsible for regenerating bone marrow following treatment with cytotoxic agents or following bone marrow transplantation.
  • Dexter TM differentiated blood cells
  • the risk of infection is directly related to the degree of myelosuppression as measured by the severity and duration of neutropenia (Brody GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationship between circulating leukocytes and infections with acute leukemia. Ann In Med 1965; 64:328-334).
  • hematopoiesis involves the interplay of a variety of cytokines and growth factors during various stages of the hematopoietic cascade, including
  • SUBSTITUT ⁇ SHEET (RULE 26) molecules include granulocyte colony stimulating factor (G-CSF), granulocyte - macrophage stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), and a variety of interleukins which have overlapping, additive and synergistic actions which play major roles in host defense Mechanistically, this is accomplished by enhancing the production of granulocytes and macrophages, as well as by the activation of effector cell functions (Moore MAS Hemopoietic growth factor interactions in vitro and in vivo preclinical evaluation. Cancer Surveys 1990, 9 7-80) These coordinated activities support optimal host defences which are necessary for fighting bacterial, viral and fungal infections
  • Synthetic peptides have been reported to induce the synthesis and release of hematopoietic mediators, including m-CSF from bone marrow stromal elements see U S Patent Application 08/001,905.
  • SUBST1TUTE SHEET (RULE 26) reactions i.e. in bone marrow transplant surgery. They may also be used to promote more rapid regeneration of bone marrow after cytostatic chemotherapy and radiation therapy for neoplastic and viral diseases. They may be of particular value where patients have serious infections due to a lack of immune response following bone marrow failure. They are also useful in the treatment and prevention of viral, fungal and bacterial disease.
  • This invention comprises compounds, hereinafter represented as Formula (I), which have hemoregulatory activities and can be used to stimulate hematopoiesis and in the prevention and treatment of bacterial, viral and fungal diseases.
  • These compounds are useful in the restoration of leukocytes in patients with lowered cell counts resulting from a variety of clinical situations, such as surgical induced myelosuppression, AIDS, ARDS, congenital myelodysplacis, bone marrow and organ transplants; in the protection of patients with leukopenia from infection; in the treatment of severely burned patients and in the amelioration of the myelosuppression observed with some cell-cycle specific antiviral agents and in the treatment of infections in patients who have had bone marrow transplants, especially those with graft versus host disease, in the treatment of tuberculosis and in the treatment of fevers of unknown origin in humans and animals.
  • the compounds are also useful in the treatment and prevention of viral, fungal and bacterial infectious diseases, particularly Candida, He ⁇ es and hepatitis in both immunosuppressed and "normal" subjects. They are useful in the treatment of sepsis caused by gram negative and gram positive organisms.
  • This invention is also a pharmaceutical composition, which comprises a compound of Formula (II) and a pharmaceutically acceptable carrier.
  • This invention further constitutes a method for stimulating the myelopoietic system of an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of Formula (I) or Formula (II).
  • This invention also constitutes a method for preventing and treating viral, fungal and bacterial infections in immunosuppressed and normal animals, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of Formula (I) or Formula (II).
  • Rj is independently quinolinyl, 2-pyridinyl, isoquinolinyl, 2-pyrrolidonyl, pyrrolidinyl or N-methyl-2-imidazolyl;
  • R2 is independently hydrogen, Cj_4CO2H or Cj ⁇ alkyl
  • R3 is hydrogen or Cj .4 alkyl
  • n is an integer from 3 to 8; is 1 to 4; and s is 1 to 4; provided that the compound is not: N,N'-bis(picolinoyl)- 1 ,3- diaminopropane N, N';
  • the invention is also a pharmaceutical composition, which comprises a compound of Formula (II):
  • Rj is independently a 4 - 10 membered mono- or bicyclic heterocydic ring system containing up to four heteroatoms N, O, S in the ring in which at least one heteroatom is N, and wherein the ring is substituted or unsubstituted by one or two Cj_4 alkyl, F, Cl, Br, I, C1.4 alkoxy, (CH 2 )rnR5> oxo ' oxime, hydroxy, N(R4) 2 , acylamino or aminoacyl groups, 8, 9, 10 membered monocyclic ring systems being excluded;
  • R is independently hydrogen, C ⁇ .4 alkyl C(O)R5, C ⁇ alkyl or R 2 is benzyl which is optionally substituted by one or two C ⁇ aikyl, C1.4a.koxy, F, Cl, I, Br, OH, or N(R 4 ) 2 ;
  • R3 is hydrogen or C 1.4 alkyl
  • R4 is independently hydrogen, Cj ⁇ alkyl, or benzyl
  • R5 is independently OR4, N(R4) 2 or SR4;
  • the invention is also a method of stimulating myelopoiesis in an animal, including humans, in need thereof, by administering an effective amount of a compound of Formula II.
  • C _4 alkyl groups may be straight or branched.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All these compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Rl in the above Formula (II) denotes an optionally substituted pyrrolyl, isopyrrolyl, pyrazolyl, isoimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, piperazinyl, triazinyl, morpholinyl, indolyl, indoleninyl, isobenzazolyl, pyrindinyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridinyl, tetrahydroquinolinyl,
  • Preferred compounds of Formula (I) are:
  • the preferred compounds of Formula (II) include N, N'-bis (picolinoyl)-l,3-diaminopropane.
  • Appropriate diamines are bis-acylated with appropriate heterocydic acids (such as I in Scheme 1) using an activating agent (such as EDC) in a suitable polar aprotic solvent (such as pyridine)
  • an activating agent such as EDC
  • a suitable polar aprotic solvent such as pyridine
  • Appropriate diamines are bis-protected using conventional amine protecting groups (such as t-butoxycarbonyl) 2 in Scheme 2 is then bis-N- alkylated by treatment with a strong base (such as sodium hydride) in an aprotic solvent (such as THF) followed by an alkylating agent (such as methyl iodide) Removal of the protecting group of 3. in Scheme 2 under standard acidic conditions (such as 4N HCl/dioxane) followed by acylation of the resulting amine with suitable acids (such as 4 in Scheme 2) using an activating agent (such as EDC) in a suitable solvent (such as pyndine) furnishes the bis-N-alkylated product 5 in Scheme 2
  • a strong base such as sodium hydride
  • an aprotic solvent such as THF
  • an alkylating agent such as methyl iodide
  • Appropriate diamines (such as 2 in Scheme 3) are bis-acylated with appropriate heterocydic acids (such as 1 in Scheme 3) using an activating agent (such as EDC) in a suitable polar aprotic solvent (such as pyridine) to give 3 in Scheme 3.
  • an activating agent such as EDC
  • a suitable polar aprotic solvent such as pyridine
  • the CBZ group is then removed using hydrogen and an appropriate catalyst (such as 10% Pd/C) in a suitable solvent (such as methanol), giving 4 in Scheme 3.
  • Appropriate diamines are bis-protected using conventional amine protecting groups (such as t-butoxycarbonyl).
  • 2 in Scheme 4 is then bis-N- alkylated by treatment with a strong base (such as sodium hydride) in an aprotic solvent (such as THF) followed by an alkylating agent (such as methyl iodide).
  • a strong base such as sodium hydride
  • an aprotic solvent such as THF
  • an alkylating agent such as methyl iodide
  • amines (such as 1 in Scheme 5) are protected using conventional amine protecting groups (such as t-butoxycarbonyl).
  • Compound 2 in Scheme 5 is then alkylated by treatment with a strong base (such as sodium hydride) in a polar aprotic solvent (such as THF) followed by an alkylating agent (such as methyl iodide).
  • a strong base such as sodium hydride
  • a polar aprotic solvent such as THF
  • an alkylating agent such as methyl iodide
  • Removal of the nitrogen protecting group of 3_ in Scheme 5 under standard acidic conditions such as 4N HCl/dioxane
  • acylation of the resulting amine with a suitable acid such as 4 in Scheme 5
  • a suitable solvent such as pyridine
  • a suitably protected diamine such as I in Scheme 6, prepared as shown in Scheme 2 is treated with a strong base (such as sodium hydride) in the presence of an alkenyl halide (such as allyl bromide) in a polar aprotic solvent (such as a mixture of DMF and THF).
  • a strong base such as sodium hydride
  • an alkenyl halide such as allyl bromide
  • a polar aprotic solvent such as a mixture of DMF and THF.
  • the bis-olefin, 2 in Scheme 6 is oxidatively cleaved with an oxidizing agent (such as ozone in NaOMe/MeOH) giving the bis-ester 3_ in Scheme 6.
  • a suitably protected aminothiol (such as 1 in Scheme 7) is treated with a strong base (such as sodium hydride) in the presence of a halo-ester (such as methyl bromoacetate) in a polar aprotic solvent (such as DMF)
  • a strong base such as sodium hydride
  • a halo-ester such as methyl bromoacetate
  • a polar aprotic solvent such as DMF
  • the bis-olefin 2 in Scheme 8 is oxidatively cleaved with an oxidizing agent (such as ozone in NaOMe/MeOH) giving the bis-ester 3_ in Scheme 8.
  • an oxidizing agent such as ozone in NaOMe/MeOH
  • Removal of the terminal diamino-protecting groups in 3 in Scheme 8 under standard acidic conditions (such as 4N HCl/dioxane) is followed by acylation of the resulting amine with suitable aromatic acids (such as picolinic acid) using an activating agent (such as EDC) in a suitable solvent (such as pyridine).
  • the central amino-protecting group is cleaved under standard reductive conditions (such as H 2 in MeOH) in the presence of a suitable catalyst (such as 10 % Pd/C) to give the amino ester 4 in Scheme 8.
  • a suitable catalyst such as 10 % Pd/C
  • the methyl esters are saponified under basis aqueous conditions (such as IN NaOH) giving the product 5 in Scheme 8.
  • compositions comprising as active ingredient one or more compounds of Formula (II) as herein before defined or physiologically compatible salts thereof, in association with a pharmaceutical carrier or excipient.
  • the compositions according to the invention may be presented for example, in a form suitable for oral, nasal, parenteral or rectal administration.
  • the term "pharmaceutical” includes veterinary applications of the invention. These compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such a glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • a sustained release material such as a glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • Capsules containing one or several active ingredients may be produced, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatin capsules.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. Organ specific carrier systems may also be used.
  • compositions of the compounds of this invention, or derivatives thereof may be formulated as solutions of lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration and contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols
  • the pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch.
  • Nasal sprays may be formulated similarly in aqueous solution and packed into spray containers either with an aerosol propellant or provided with means for manual compression.
  • Dosage units containing the compounds of this invention preferably contain .05-50 mg, for example .05-5 mg of the compound of Formula (I) and (II) or salt thereof.
  • a method of stimulation of myelopoiesis which comprises administering an effective amount of a pharmaceutical composition of Formula (II) as hereinbefore defined to a subject.
  • the murine bone marrow derived stromal cell line, C6 4 is grown in 12 well plates in RPMI 1640 with 10% FBS Upon reaching confluence, the C6 4 cells are washed and the media exchanged with fresh RPMI 1640 without FBS Confluent cell layers of murine C6 4 cells are treated with compound Cell-free supematants are collected 18 hours later Supematants are fractionated with a Cent ⁇ con-30 molecular weight cut-off membrane C6 4 cell hematopoietic synergistic factor (HSF) activity is measured in a murine CFU-C assay
  • Bone marrow cells are obtained from C57B 1/6 female mice and suspended in RPMI 1640 with 10% FBS Bone marrow cells (7 5E+4 cells/mL) are cultured with sub optimal levels of CFU plus dilutions of test C6 4 cell 30K-E supematants from above in a standard murine soft agar CFU-C assay Cell aggregates >50 cells are counted as colonies The number of agar colonies counted is proportional to the amount of HSF present within the C6 4 bone marrow stromal line supernatant
  • mice Female C57B 1 mice are administered test compound IP or PO daily for 8 days
  • Resident peritoneal exudate cells (PEC) utilized ex vivo from treated or untreated mice are harvested with cold calcium and magnesium-free DPBS supplemented with heparin and antibiotics within 2-4 hours following the last injection
  • Adherent PEM populations are prepared by incubating standardized PEC suspensions in microtiter dishes for 2 hours at 37 °C (5% CO 2 ) and removing nonadherent cells by washing the wells with warm buffer.
  • SOD superoxide dismutase-inhibitable
  • PMA phorbol myristate acetate
  • nmoles of cytochrome c reduced/well is calculated from spectrophotometric readings (550 nm) taken following a 1 hour incubation at 37 °C (5% CO 2 ).
  • the amount of SOD-inhibitable cytochrome c reduced is determined by the inclusion of wells containing SOD (200 U/well). Baseline superoxide release is determined in the absence of stimuli. Experimental data are expressed as a percentage of the control group.
  • Step 1 Blend ingredients No. 1 , No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its converion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a
  • Step 4 The wet granules are then dried in an oven at
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I or II in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Pyridine Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouveaux composés dotés d'une activité hématorégulatrice et que l'on peut utiliser pour stimuler l'hématopoïèse ainsi que pour traiter des maladies infectieuses virales, mycosiques et bactériennes.
PCT/US1996/018053 1995-11-13 1996-11-12 Composes hematoregulateurs WO1997017963A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9518974A JP2000500455A (ja) 1995-11-13 1996-11-12 血液調節化合物
EP96941338A EP0865279A4 (fr) 1995-11-13 1996-11-12 Composes hematoregulateurs

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US664395P 1995-11-13 1995-11-13
US663895P 1995-11-13 1995-11-13
US1553696P 1996-04-17 1996-04-17
US60/006,638 1996-04-17
US60/015,536 1996-04-17
US60/006,643 1996-04-17

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WO1997017963A1 true WO1997017963A1 (fr) 1997-05-22

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JP (1) JP2000500455A (fr)
WO (1) WO1997017963A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0861080A1 (fr) * 1995-11-13 1998-09-02 Smithkline Beecham Corporation Composes hemoregulateurs
US7018642B2 (en) 2001-04-27 2006-03-28 The Procter & Gamble Company Compounds, compositions, and methods for controlling biofilms
EP2365052A1 (fr) * 2010-03-12 2011-09-14 The Procter & Gamble Company Compositions liquides de détergent comprenant des gélifiants amido à pH réglable et procédés de fabrication
EP2365050A1 (fr) * 2010-03-12 2011-09-14 The Procter & Gamble Company Gélifiant di-amido pour une utilisation dans des compositions de produits de consommation

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See also references of EP0865279A4 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0861080A1 (fr) * 1995-11-13 1998-09-02 Smithkline Beecham Corporation Composes hemoregulateurs
EP0861080A4 (fr) * 1995-11-13 1999-01-20 Smithkline Beecham Corp Composes hemoregulateurs
US7018642B2 (en) 2001-04-27 2006-03-28 The Procter & Gamble Company Compounds, compositions, and methods for controlling biofilms
EP2365052A1 (fr) * 2010-03-12 2011-09-14 The Procter & Gamble Company Compositions liquides de détergent comprenant des gélifiants amido à pH réglable et procédés de fabrication
EP2365050A1 (fr) * 2010-03-12 2011-09-14 The Procter & Gamble Company Gélifiant di-amido pour une utilisation dans des compositions de produits de consommation
WO2011112887A1 (fr) * 2010-03-12 2011-09-15 The Procter & Gamble Company Gélifiant di-amido utilisé dans des compositions de produit de consommation
WO2011112912A1 (fr) * 2010-03-12 2011-09-15 The Procter & Gamble Company Gélifiant d'amidon à ph réglable utilisable dans des compositions de produit de consommation
US8207107B2 (en) 2010-03-12 2012-06-26 The Procter & Gamble Company Di-amido gellant for use in consumer product compositions
US8236748B2 (en) 2010-03-12 2012-08-07 The Procter & Gamble Company pH tuneable amido-gellant for use in consumer product compositions

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EP0865279A1 (fr) 1998-09-23
EP0865279A4 (fr) 1999-03-03
JP2000500455A (ja) 2000-01-18

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