WO2001087877A1 - Nouveaux composés thiophénamide - Google Patents

Nouveaux composés thiophénamide Download PDF

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Publication number
WO2001087877A1
WO2001087877A1 PCT/JP2001/004097 JP0104097W WO0187877A1 WO 2001087877 A1 WO2001087877 A1 WO 2001087877A1 JP 0104097 W JP0104097 W JP 0104097W WO 0187877 A1 WO0187877 A1 WO 0187877A1
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WIPO (PCT)
Prior art keywords
group
compound
pyrd
stereoisomer
substituent
Prior art date
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PCT/JP2001/004097
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English (en)
Japanese (ja)
Inventor
Masakazu Fujita
Hideyuki Sato
Tetsuya Hirayama
Yoshikazu Kawahara
Original Assignee
Nikken Chemicals Co., Ltd.
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 Nikken Chemicals Co., Ltd. filed Critical Nikken Chemicals Co., Ltd.
Priority to AU2001258760A priority Critical patent/AU2001258760A1/en
Publication of WO2001087877A1 publication Critical patent/WO2001087877A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a thiophenamide compound having an unsubstituted amino group, and more particularly to a thiophenamide compound having an unsubstituted amino group having an inhibitory effect on TNF (tumor dying factor) production.
  • TNF tumor death factor
  • TNF- ⁇ production regulation mechanism for example, persistent and excessive production, could cause various diseases and cause exacerbations, such as causing tissue damage. Preventing or impairing the overproduction or action of is potentially a useful therapeutic for a number of inflammatory, infectious, immune or malignant diseases.
  • Japanese Patent Application Laid-Open No. 10-95070 describes a thiophene compound having an inhibitory effect on cytokine production. Have been. However, there is no description suggesting a thiophenamide compound having an unsubstituted amino group as in the present invention.
  • thiophene compounds those having anti-inflammatory and analgesic effects are described in Japanese Patent Application Laid-Open No. Hei 6-51019, and those having anti-inflammatory properties are described in Japanese Patent Application Laid-Open No. Hei 10-316673. Each of them has an anti-allergic effect, but a description suggesting an inhibitory effect on TNF- ⁇ production. ⁇ is missing. Disclosure of the invention
  • An object of the present invention is to provide a drug that inhibits TNF- ⁇ production, and is considered to be a disease in which TNF-1 is involved, such as allergy, bronchial asthma, septic shock, inflammatory bowel disease, organ inflammation, and bone.
  • TNF-1 a disease in which TNF-1 is involved
  • allergies such as allergy, bronchial asthma, septic shock, inflammatory bowel disease, organ inflammation, and bone.
  • septic shock such as allergy, bronchial asthma, septic shock, inflammatory bowel disease, organ inflammation, and bone.
  • inflammatory bowel disease such as allergy, bronchial asthma, septic shock, inflammatory bowel disease, organ inflammation, and bone.
  • Behcet's disease rheumatoid arthritis, osteoarthritis, etc.
  • Behcet's disease diabetes
  • psoriasis Crohn's disease
  • ulcerative colitis inflammatory lung disease
  • thrombosis AIDS, etc. It is in.
  • the present invention provides a compound represented by the general formula (I):
  • I 1 , R 2 , R 3 and R 4 each independently represent a hydrogen atom, a hydroxyl group, an aryl group, a lower alkyl group which may have a substituent, or a substituent. It indicates ⁇ re Ichiru group, and R 1 and R 2,: R 3 may be bonded to each other to form a cyclic structure with R 4 or R 1 and R 2 force or R 3 and R 4, is A r 1 represents a nitrogen-containing heteroaryl group which may have a substituent; A r 2 represents an aryl group which may have a substituent; Or a cycloalkyl group which may have a substituent; m is an integer of 0 to 7, n and p are 0 or 1, q is an integer of 0 to 7, and r is 0 or 1.
  • a novel thiophenamide compound having an unsubstituted amino group, a stereoisomer thereof, or a pharmacologically acceptable salt thereof comprising a thiophenamide compound represented by the above general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the medicament of the present invention is particularly useful for the prevention and treatment of inflammatory diseases involving TNF-hi.
  • a pharmaceutical composition of the present invention preferably comprises a thiophenamide compound represented by the above general formula (I), which is an active ingredient, a stereoisomer thereof or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.
  • a TNF-hi production inhibitor comprising, as an active ingredient, a thiophenamide compound represented by the above general formula (I), a stereoisomer thereof, or a pharmacologically acceptable salt thereof;
  • a method for preventing, treating or treating an inflammatory disease associated with TNF- ⁇ the method comprising administering an effective amount of a salt to a mammal including humans.
  • a method comprising administering a prophylactically and / or therapeutically effective amount of a represented thiophenamide compound, a stereoisomer thereof or a pharmacologically acceptable salt thereof to a mammal, including a human, is provided.
  • a "group” is a hydroxyl group; an alkoxy group such as methoxy, ethoxy, or isopropyloxy; an amino group; an alkylamino group such as methylamino, ethylamino, or dimethylamino; a mercapto group; A halogen atom such as an atom, a chlorine atom, a bromine atom, or an iodine atom; an aryl group such as phenyl, 4-fluorophenyl, or 4-hydroxyphenyl.
  • the “substituent” of the aryl group which may have a substituent in I 1 , R 2 , R 3 and R 4 is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; Atom; cyano group; nitro group; hydroxyl group; alkoxy group such as methoxy, ethoxy, or isopropoxy; amino group; alkylamino group such as methylamino, ethylamino, or dimethylamino; mercapto group; methylthio, ethylthio, or propylthio; And the like.
  • General formula (I) may Ariru group which may have a substituent in Teroari Lumpur groups Contact Yopi A r 2 to which may nitrogenous have a substituent for A r 1 in, or a substituent
  • the type, substitution position, and number of the “substituent” of the cycloalkyl group which may be possessed are not particularly limited, but, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a nitro group A hydroxyl group; a cyano group; a rubamoyl group; a lower alkyl group such as methinole, ethyl, or isopropyl; Alkyl groups; aryl groups such as phenyl, pyrrolyl, imidazolyl, pyrimidyl, or pyridazyl; amino groups; methylamido , Also Is an alkylamino
  • Particularly preferred groups for A r 1 are 4-pyridyl, 4-pyridazyl, 4-pyrimidinole and the like.
  • the “aryl group” of the aryl group which may have a substituent at Ar 2 in the general formula (I) includes a phenyl group, a naphthyl group, a biphenyl group and the like. And preferably a phenyl group.
  • the cycloalkyl group include a c 3 to c 3 consequent opening alkyl cyclohexyl such as cyclopropyl, consequent opening pentyl, or cyclohexane, preferably a key Sill group cyclopentyl, or cyclohexylene.
  • Preferred groups for Ar 2 include fluorophenyl, difluorophenyl, chlorophenol, dichlorophenol, methinoresnorelephoninolephen, methinolesnorrebininophenyl and methinorechioff.
  • m represents an integer of 0 to 7, preferably represents an integer of 0 to 6, and particularly preferably represents an integer of 0 to 2.
  • q represents an integer of 0 to 7, preferably represents an integer of 0 to 3, and particularly preferably represents 0 or 1.
  • preferred specific examples of the compound represented by the general formula (I) include the compounds shown in Tables 1 and 2 below, and pharmacologically acceptable salts or hydrates thereof.
  • Particularly preferred compounds include Compound Nos. 1-11, 112, 1-19, 1-26, 1-146, 1-53, 1-170, 1-134, 1-185, 2-5, 2- 1 1, 2
  • the thiophene compound of the present invention can be produced by a known method. For example, it can be produced by applying or applying the method described in the following reaction step formulas (1) to (6) or the method described in Examples. Reaction process formula (1):
  • a base is present in compound (2-1) or (2-1,). Lower, like malononitrile etc.
  • the compound (I-1) can be produced by reacting activated nitrile with sulfur. The reaction proceeds at 20-150 ° C, preferably 20-80, for 3 hours to 3 days, usually 3 to 8 hours.
  • an organic base such as triethylamine, morpholine and piperazine is desirable.
  • Compound (1-1) can also be produced by the following method.
  • the compound (I-11) is subjected to decarboxylation, deesterification, etc. by a hydrolysis reaction or a reduction reaction. And compound (1-2) can be produced.
  • This reaction is carried out using acids such as hydrochloric acid, hydrobromic acid, formic acid, and trifluoroacetic acid, or inorganic salts such as sodium hydrogencarbonate, sodium carbonate, and sodium hydroxide, sodium hydride, and alkali metal hydrides desorbed from hydrogenation power.
  • acids such as hydrochloric acid, hydrobromic acid, formic acid, and trifluoroacetic acid
  • inorganic salts such as sodium hydrogencarbonate, sodium carbonate, and sodium hydroxide, sodium hydride, and alkali metal hydrides desorbed from hydrogenation power.
  • organic salts such as triethylamine, pyridine and piperazine at 20 to 200 ° C for 30 minutes to 1 day.
  • R 6 represents a protecting group such as pendinoleoxycanolepodinole, t-butoxycarbinole, or 9-fluorenylmethoxycarbonyl.
  • R 6 represents a protecting group such as pendinoleoxycanolepodinole, t-butoxycarbinole, or 9-fluorenylmethoxycarbonyl.
  • the reactive derivative of the compound (I-3) includes, for example, acid anhydride, mixed acid anhydride (eg, methyl carbonate, ethyl carbonate, etc.), acid halide (acid chloride, etc.), imidazolide, etc. Is mentioned.
  • a mixed acid anhydride e.g, methyl carbonate, ethyl carbonate, etc.
  • the compound (1-3) is reacted with a carbonic acid carbonate (for example, methyl methyl carbonate and ethyl ethyl carbonate) in the presence of a base, and then the compound (1-2) is reacted.
  • This reaction proceeds at 130 to 100 ° C, preferably at 0 to 60 for 0.5 to 24 hours, usually 1 to 2 hours.
  • organic bases such as triethylamine, piperidine and N-methylmorpholine, and alkali metal bases such as sodium hydrogencarbonate and sodium carbonate are desirable.
  • an acid halide is used in the presence of a base, the reaction proceeds at 130 to 100 ° C, preferably at 0 to 40 ° C, for 0.5 to 24 hours, usually 0.5 to 2 hours. .
  • each reaction in the reaction scheme is performed by a known method.
  • Each reaction in the present specification is performed in an atmosphere of a dry inert gas (nitrogen gas, argon gas, or the like) or without a solvent, or as a solvent or a solvent such as toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, dioxane, or the like.
  • a solvent that does not participate in the reaction such as N, N-dimethylformamide, dimethylsulfoxide, pyridine, quinoline, methanol, ethanol, and acetic acid.
  • the reaction product can be used as a free salt or as a salt thereof by conventional purification means, for example, extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc. It can be isolated and purified. Purification may be performed for each reaction, or may be performed after several reactions.
  • the reagents and starting materials used in the method for producing the compound of the present invention can be easily produced by known methods.
  • the compound according to the present invention when used as the above-mentioned medicament, it can be administered in the form of a pharmaceutical composition usually together with additives for pharmaceutical preparation by an appropriate administration method, either oral or parenteral.
  • an appropriate administration method either oral or parenteral.
  • examples of the form of the pharmaceutical composition for oral administration include tablets, granules, capsules, pills, powders, and syrups.
  • Examples of the form of the pharmaceutical composition for parenteral administration include injection Preparations, inhalants, suppositories, liquid preparations and the like.
  • these pharmaceutical compositions When these pharmaceutical compositions are formulated, they can be prepared according to a conventional method using the compound of the present invention or a salt thereof.
  • excipients such as lactose, glucose, corn starch, sucrose, etc.
  • disintegrants such as carboxymethylcellulose calcium, hydroxypropyl oral cellulose, calcium stearate, magnesium stearate, etc.
  • Lubricants such as gum, talc, polyethylene glycol, hydrogenated oil, etc.
  • a desired dosage form can be prepared by using a binder, a humectant such as glycerin and ethylene glycol, and, if necessary, a surfactant and a flavoring agent.
  • the present invention will be described more specifically with reference to Production Examples, Examples, Formulation Examples, and Test Examples, but the scope of the present invention is not limited to the following Examples.
  • the 1 H-NMR data indicate a sign using tetramethylsilane (TMS) as an internal standard.
  • N [(9-Fluorenylmethoxyethoxycarbonyl) 1 L—ara-nore] —4 _ (4—fluorophenyl) -5- (4 _pyridinole) 1—2-thiophenamine 4- (4-Fluorophenyl) -5- (4-pyridinole) 1-2-thiophenamine 30
  • N- (9-Phenylolenylmethoxycarbonyl) —L-alanine, 1-hydroxybenzotriazole 51 9 mg
  • To 15 ml of the tetrahydrofuran solution 5 ml of a tetrahydrofuran solution containing 345 mg of 1,3-dicyclohexylcarpoimide was added.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • the target compound was synthesized in the same manner as in Example 1.
  • N_ N-glycinole-L-one-port isyl
  • the compound of the present invention has an excellent TNF-a production inhibitory action.
  • Pharmaceuticals containing the compound of the present invention as an active ingredient, by inhibiting the production of TNF- ⁇ , have a very effective effect on many diseases, particularly inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, allergic diseases, etc. . Therefore, the medicament of the present invention is useful as a new type of preventive and / or therapeutic agent for a disease associated with TNF- ⁇ .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés thiophénamide de formule générale (I) présentant un effet inhibitoire de production de TNF-α, formule dans laquelle R1 à R4 représentent hydrogène, hydroxyle, allyle, un alkyle inférieur éventuellement substitué, ou un aryle éventuellement substitué, ou éventuellement R1 et R2 ou R3 et R4 peuvent être réunis de façon à former un cycle, ou R1 et R2 ou R3 et R4 peuvent représenter ensemble un atome d'oxygène, Ar1 représente un hétéroaryle azoté éventuellement substitué, Ar2 représente un aryle éventuellement substitué ou un cycloalkyle éventuellement substitué, m est un nombre entier compris entre 0 et 7, n et p sont indépendamment l'un de l'autre un nombre entier compris entre 0 et 1, q est un nombre entier compris entre 0 et 7, et r est un nombre entier compris entre 0 et 1.
PCT/JP2001/004097 2000-05-17 2001-05-17 Nouveaux composés thiophénamide WO2001087877A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258760A AU2001258760A1 (en) 2000-05-17 2001-05-17 Novel thiophenamide compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000145680 2000-05-17
JP2000-145680 2000-05-17
JP2001-104917 2001-04-03
JP2001104917A JP2002037784A (ja) 2000-05-17 2001-04-03 新規チオフェンアミド化合物

Publications (1)

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WO2001087877A1 true WO2001087877A1 (fr) 2001-11-22

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AU (1) AU2001258760A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003022838A1 (fr) * 2001-09-05 2003-03-20 Smithkline Beecham Plc Derives furaniques substitues par une pyridine servant d'inhibiteurs de raf kinase
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA06010520A (es) * 2004-03-30 2007-03-26 Chiron Corp Derivados de tiofeno sustituidos como agentes anticancerosos.

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019708A1 (fr) * 1990-06-11 1991-12-26 Fujisawa Pharmaceutical Co., Ltd. Nouveaux derives de thiophene

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019708A1 (fr) * 1990-06-11 1991-12-26 Fujisawa Pharmaceutical Co., Ltd. Nouveaux derives de thiophene

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003022838A1 (fr) * 2001-09-05 2003-03-20 Smithkline Beecham Plc Derives furaniques substitues par une pyridine servant d'inhibiteurs de raf kinase
US7375105B2 (en) 2001-09-05 2008-05-20 Smithkline Beecham P.L.C. Pyridine substituted furan derivatives as Raf kinase inhibitors
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB

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AU2001258760A1 (en) 2001-11-26

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