WO1997017985A1 - Composes hematoregulateurs - Google Patents

Composes hematoregulateurs Download PDF

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Publication number
WO1997017985A1
WO1997017985A1 PCT/US1996/018245 US9618245W WO9717985A1 WO 1997017985 A1 WO1997017985 A1 WO 1997017985A1 US 9618245 W US9618245 W US 9618245W WO 9717985 A1 WO9717985 A1 WO 9717985A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
lys
compound
bis
optionally
Prior art date
Application number
PCT/US1996/018245
Other languages
English (en)
Inventor
Pradip Kumar Bhatnagar
Peter Martin Fischer
Original Assignee
Smithkline Beecham Corporation
Nycomed Imaging As
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 Imaging As filed Critical Smithkline Beecham Corporation
Priority to EP96940437A priority Critical patent/EP0874638A4/fr
Priority to JP9519060A priority patent/JP2000500461A/ja
Publication of WO1997017985A1 publication Critical patent/WO1997017985A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel compounds which have hemoregulatory activities and can be used to stimulate haematopoiesis and for the treatment of viral, fungal and bacterial infectious diseases.
  • the haematopoietic 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: 1 192-1194) of at least nine different cell lineages (erythrocytes, platelets, eosinophils, basophils, neutrophils, monocytes/macrophages, osteoclastes and lymphocytes) (Metcalf D. The Molecular Control of Blood Cells, 1988; Harvard University Press, Cambridge, MA). The stem cells are also ultimately responsible for regenerating the bone marrow following treatment with cytotoxic agents or following bone marrow transplantation.
  • 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).
  • the control of haematopoiesis involves the interplay of a variety of cytokines and growth factors during various stages of the haematopoietic cascade, including early pluripotent stem cells and mature circulating effector cells.
  • G-CSF granulocyte colony stimulating factor
  • GM-CSF granulocyte- macrophage stimulating factor
  • M-CSF macrophage-colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • G-CSF granulocyte- macrophage stimulating factor
  • M-CSF macrophage-colony stimulating factor
  • interleukines which have overlapping, additive and synergistic actions which play major roles in host defence. Mechanistically, this is accomplished by enhancing the production of granulocytes and macrophages, as well as by the activation of effector cell functions (Moore MAS. Haematopoietic growth factor interactions: in vitro and in vivo preclinical evaluation. Cancer Surveys 1990; 9:7-80).
  • These co-ordinated activities support optimal host defences which are necessary for fighting bacterial, viral and fungal infections.
  • G-, GM- and/or M-CSF may reduce the duration of neutropenia, accelerate myeloid recovery and reduce neutropenia-associated infections and other infectious complications in patients with malignancies who are receiving cytotoxic chemotherapy or in high infectious-risk patients following bone marrow transplantation (Steward WP. Granulocyte and granulocyte-macrophage colony stimulating factors, Lancet 1993; 342: 153-157 and Munn DH, Cheung NKV. Preclinical and clinical studies of macrophage colony- stimulating factor. Semin Oncol 1992; 19:395-407).
  • This invention comprises compounds, hereinafter represented as Formula (I), which have hemoregulatory activities and can be used to stimulate haematopoiesis 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 diseases, particularly Candida, Herpes and hepatitis in both immunosuppressed and "normal" subjects.
  • This invention is also a pharmaceutical composition, which comprises a compound of Formula (I) 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).
  • This invention also constitutes a method for preventing and treating viral, fungal and bacterial infections including sepsis, 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).
  • Aj and A2 independently from each other are Z-(CH2)p-(NR ⁇ )q-, wherein
  • Z is a 4 - 10 membered mono- or bicyclic heterocyclic 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 C ⁇ _4alkyl, F, Cl, Br, I, C ⁇ .4 alkoxy,
  • R 1 , R 2 , R 3 , R 4 and R 1 1 independently hydrogen, C 1 . 4 alkylC(O)R 13 , Ci _4alkyl or R 1 , R 2 , R 3 , R 4 and R 1 ! are benzyl which is optionally substituted by one or two Cj ⁇ alkyl, Cj ⁇ alkoxy, F, Cl, I, Br, OH, or N(R 12 )2; p is an integer from 0 to 4; q, n and m are independently zero or one;
  • R5 and R6 are independently hydrogen, C ⁇ _4-alkyl, C ⁇ _4-alkyl-OH, C 1 . 4 -alkyl-OCH 3 , C 1 . 4 -alkylaryl-OH, C ⁇ _ 4 -alkylaryl-OCH3 or C 1 . 4 -alkyl-COOH;
  • Di and D2 are Ci .g-alkyl
  • R , R8, 9 and R10 ⁇ g independently hydrogen or Ci .4-alkyl;
  • R ⁇ 2 is independently hydrogen, Cj-C4-alkyl or benzyl;
  • R 13 is independently -OR 12 , -N(R 12 )2, - SR 12 ;
  • Z in the above Formula (I) denotes an optionally substituted pyrrolyl, isopyrrolyl, pyrazolyl, isoimidazolyl, triazolyl, iosxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, piperazinyl, triazinyl, morpholinyl, indolyl, indoleninyl,
  • SUBST1TUTE SHEET (RULE 26) isobenzazolyl, pyrindinyl, ioindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyridopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, indolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, piperidyl, tetrazolyl, quinuclidinyl, azetidinyl, or purinyl.
  • Possible substituents for Z are C ⁇ .4-alkyl, O-Cj.4-alkyl, C ⁇ _4-alkyl-O-C ⁇ _ 4-alkyl, oxo, oxime, O-C ⁇ _4-alkyloxime, hydroxy, amino, N-C ⁇ _4-alkylamino, N,N-di-C ⁇ _4-alkylamino, CO, C ⁇ _ 4 -aIkyl-CO and (C 1 . -alkyl) 2 -NC(O)-.
  • R 5 and R 6 denote hydrogen, Cj.4-alkyl, C ⁇ -alkyl-OH, C ⁇ _4-alkyl-OCH3, C1.4- alkyl-(phenyl-OH), C ⁇ . 4 -alkyl-(phenyl-OCH 3 ) and C ⁇ _ 4 -alkyl-(phenyl-COOH).
  • Preferred compounds are those wherein Z is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridyl, pyridazinyl, quinolinyl, tetrahydroquinolinyl, azetidinyl, or pyrrolidinyl.
  • More preferred compounds are those wherein Z is optionally substituted 2-pyridinyl, 2-pyrimidinyl, 2-pyrazinyl, 2-pyrrolidon-5-yl, 2-pyridyl, 3-pyridyl, or pyrrolidinyl.
  • 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 the compounds and diastereomers are contemplated to be within the scope of the present invention.
  • Especially preferred compounds are:
  • suitable amino-protecting groups e.g. t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.
  • R ⁇ and R ⁇ contain hydroxyl or carboxyl groups, these are protected in the form of ethers or esters, chosen in such a way as to permit selective removal of the amino protecting group PG without regenerating the hydroxyl or carboxyl functions.
  • a suitable combination of protecting groups would be when PG corresponds to benzyloxycarbonyl and the amino side chain hydroxyl or carboxyl is blocked in the form of a t-butyl ether or ester.
  • Diketopiperazine diamines of structure (IV) can be prepared by cyclisation of the corresponding dipeptidyl precursors of structure (VIII), in which the definitions are as in formulae (I), (II) and (III). Additionally, PG in structure (VIII) stands for suitable amino-protecting groups.
  • Cyclisation through intramolecular ester amminolysis may be acid- or base- catalysed or may be induced simply by heating a solution of compounds of structure (VIII) in some inert solvent.
  • the ester portion E in structure (VIII) may correspond e.g. to methyl, ethyl, benzyl, N-hydroxysuccinimidyl, etc.
  • compounds of structural formula (IV) are thus obtained, which in cases where R ⁇ and R ⁇ are hydrogen may be converted to the imino ether compounds of structure (V) e.g. through the action of trialkyl oxonium tetrafluoroborates.
  • compositions comprising as active ingredient one or more compounds of Formula (I) 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 peptides 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 as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • a sustained release material such as 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 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.
  • Organ specific carrier systems may also be used.
  • compositions of the peptides 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, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • a pulverized powder of the peptides 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 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 0.05-50 mg, for example 0.05-5 mg of the compound of Formula (I) or of the salt thereof.
  • a method of stimulation of myelopoiesis which comprises administering an effective amount of a pharmaceutical composition as hereinbefore defined to a subject. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
  • the murine bone marrow derived from stromal cell line C6.4 is grown in 12 well pates 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 supernatants are collected 18 hours later. Supernatants are fractionated with a Centricon-30 molecular weight cut-off membrane. C6.4 cell hematopoietic synergistic factor (HSF) activity is measured in a murine CFU-C assay. 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 supernatants 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 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% CO2) 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% CO2).
  • 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. Examples
  • Example 1 Preparation of ⁇ , ⁇ '-bis(picolinoyl-seryl)-[cyc/ ⁇ -(D-Lys-L-Lys)]
  • the resulting cyc/ ⁇ -[D-Lys-L-Lys] was suspended in DMF (25 mL) and added to a pre-activated (5 min) solution of Z-Se ⁇ Bu ⁇ -OH (153 mg, 0.4 mmol), PyBOP (208 mg, 0.4 mmol), HOBt (54 mg, 0.4 mmol) and NMM (0.13 mL, 1.2 mmol) in DMF (5 mL). The mixture was stirred for 2 h. The resulting clear solution was evaporated and treated with 5 % aq NaHCO3. The precipitated oil was extracted into CH2C12- The extract was washed successively with 10 % aq citric acid and 2 M aq NaCl.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne de nouveaux composés de la formule générale (I), présentant des activités hématorégulatrices et pouvant être utilisés pour stimuler l'hématopoïèse et dans le traitement de maladies infectieuses virales, fongiques et bactériennes.
PCT/US1996/018245 1995-11-13 1996-11-12 Composes hematoregulateurs WO1997017985A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96940437A EP0874638A4 (fr) 1995-11-13 1996-11-12 Composes hematoregulateurs
JP9519060A JP2000500461A (ja) 1995-11-13 1996-11-12 血液調節化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US647495P 1995-11-13 1995-11-13
US60/006,474 1995-11-13

Publications (1)

Publication Number Publication Date
WO1997017985A1 true WO1997017985A1 (fr) 1997-05-22

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PCT/US1996/018245 WO1997017985A1 (fr) 1995-11-13 1996-11-12 Composes hematoregulateurs

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EP (1) EP0874638A4 (fr)
JP (1) JP2000500461A (fr)
WO (1) WO1997017985A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0861078A1 (fr) * 1995-11-13 1998-09-02 Smithkline Beecham Corporation Composes hemoregulateurs
WO2001010845A1 (fr) * 1999-08-10 2001-02-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Nouvelles diketo-piperazines
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
WO2013142969A1 (fr) * 2012-03-28 2013-10-03 Jian Ping Gao Uréthanes et urées, et procédés associés

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499081A (en) * 1982-11-26 1985-02-12 Nyegaard & Co A/S Peptide compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL104323A0 (en) * 1992-01-10 1993-05-13 Smithkline Beecham Corp Hemoregulatory peptides
US5352461A (en) * 1992-03-11 1994-10-04 Pharmaceutical Discovery Corporation Self assembling diketopiperazine drug delivery system
US5830867A (en) * 1993-05-24 1998-11-03 Smithkline Beecham Corporation Hemoregulatory peptides for stimulating the myelopoietic system
EP0866700A4 (fr) * 1995-11-13 1999-04-07 Smithkline Beecham Corp Composes hemoregulateurs
US6197793B1 (en) * 1995-11-13 2001-03-06 Smithkline Beecham Corporation Hemoregulatory compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499081A (en) * 1982-11-26 1985-02-12 Nyegaard & Co A/S Peptide compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0874638A4 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0861078A1 (fr) * 1995-11-13 1998-09-02 Smithkline Beecham Corporation Composes hemoregulateurs
EP0861078A4 (fr) * 1995-11-13 1999-03-17 Smithkline Beecham Corp Composes hemoregulateurs
WO2001010845A1 (fr) * 1999-08-10 2001-02-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Nouvelles diketo-piperazines
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US8158622B2 (en) 2003-05-21 2012-04-17 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
US7884112B2 (en) 2004-03-08 2011-02-08 Stuart Edward Bradley Pyrrolopyridine-2-carboxylic acid hydrazides
WO2006059164A2 (fr) 2004-12-02 2006-06-08 Prosidion Limited Amides d'acide pyrrolopyridine-2-carboxylique
WO2013142969A1 (fr) * 2012-03-28 2013-10-03 Jian Ping Gao Uréthanes et urées, et procédés associés

Also Published As

Publication number Publication date
EP0874638A1 (fr) 1998-11-04
JP2000500461A (ja) 2000-01-18
EP0874638A4 (fr) 1999-07-21

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