WO2002004474A1 - Compose d"adenosine et compositions pharmaceutiques contenant ce compose - Google Patents

Compose d"adenosine et compositions pharmaceutiques contenant ce compose Download PDF

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Publication number
WO2002004474A1
WO2002004474A1 PCT/EP2000/006958 EP0006958W WO0204474A1 WO 2002004474 A1 WO2002004474 A1 WO 2002004474A1 EP 0006958 W EP0006958 W EP 0006958W WO 0204474 A1 WO0204474 A1 WO 0204474A1
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WO
WIPO (PCT)
Prior art keywords
tri
compound
methyl
ribosyl
acid
Prior art date
Application number
PCT/EP2000/006958
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English (en)
Inventor
Camille-Georges Wermuth
André Mann
Angèle Schoenfelder
Susumu Kanaya
Original Assignee
Nikken Chemicals Co. Ltd.
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Filing date
Publication date
Application filed by Nikken Chemicals Co. Ltd. filed Critical Nikken Chemicals Co. Ltd.
Priority to EP00945940A priority Critical patent/EP1303528A1/fr
Priority to JP2002509337A priority patent/JP2004502780A/ja
Priority to PCT/EP2000/006958 priority patent/WO2002004474A1/fr
Priority to CA002416199A priority patent/CA2416199A1/fr
Publication of WO2002004474A1 publication Critical patent/WO2002004474A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel adenosine compound.
  • the compounds according to the present invention are effective for the treatment or alleviation of hyperlipemia, diabetes, hypertension, arrhythmia, cardiac infarction, rena failure, epilepsy, mental disorders, obesity, etc. and useful also as an anti- inflammatory and analgesic.
  • the object of the present invention is to provide a novel anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic drug.
  • the present inventors engaged in various studies to found novel adenosine compounds useful as pharmaceuticals and, as a result, found that an ether compound obtained by condensing all of the three hydroxyl groups of the ribosyl portion of an adenosine compound with alkyl groups, a different structure from the compounds described in the above publications, has a superior action against hyperlipemia, anti-inflammatory action, and action in lowering glucose, whereby the present invention was completed.
  • an adenosine compound having the formula ( I ) :
  • R represents a straight or branched lower (e.g., a C 1 - C 5 straight or a C 3 - C 5 branched) alkyl group and R 1 represents a C 2 to C 6 lower alkylamino group or a substituent having the formula (II), (III), or (IV):
  • R 2 independently represent a hydrogen group or lower alkyl group
  • X represents N-R 3 , 0 or CH 2
  • R 3 represents a hydrogen atom, lower alkyl group, or benzyl group
  • n represents an integer of 1 to 6 or an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof suitable for use as an anti-hyperlipemia, anti-inflammatory, antidiabetic or analgesic agent.
  • the preferable compounds include those having the formula (I), wherein R is a C 3 to C 5 alkyl group, in particular a propyl or pentyl group, or those having the formula (I), where R 1 is a carbamoyl alkylamino group or butylamino group. Further, more preferable compounds of the present invention are those satisfying a plurality of the conditions of the substituents given above.
  • the adenosine compounds having the formula (I) of the present invention may be pharmaceutically acceptable salts thereof as well.
  • the compounds of the present invention may form in some cases hydrates.
  • the adenosine compounds according to the present invention may be prepared by a conventional method. Typical methods among these will be explained below.
  • the compounds of the present invention may be synthesized in accordance with the following reaction formulae :
  • HMDS represents hexamethyldisilazane and TMSOTf represents trimethylsilyl triflate and R and R 1 have the same meanings as those of formula ( I) .
  • the desired compound having the formula (I) can be obtained by reacting 6- chloropurine and the corresponding ribose derivative, followed by reacting with the corresponding amino compound.
  • inosine is used as the starting substance, the three reactions of acetylation, chlorination, and then deacetylation are carried out to obtain the chlorinated compound of purine. Then, the resultant compound was benzylated and alkylated and further debenzylated and again chlorinated to obtain a purine compound chlorinated at the 6-position followed by reacting with the corresponding amino compound to produce the desired compound having the formula (I).
  • the amino compound used for introducing R 1 can be easily produced from amino acid by the following process:
  • the ribose compound can be produced by the following process:
  • the present compound When used as an anti- hyperlipemia, anti-inflammatory, antidiabetic, or analgesic agent, it may be administered to the patients by a suitable method of administration such as an oral or nonoral method.
  • a suitable method of administration such as an oral or nonoral method.
  • oral administration for example, tablets, granules, capsules, pills, powders, syrups, etc.
  • nonoral administration for example, injections, inhalants, suppositories, liquids, etc. may be mentioned.
  • these compositions for administration of medicines they may be prepared by ordinary methods using the present compounds or the pharmaceutically acceptable salts thereof etc.
  • an excipient such as lactose, glucose, corn starch, or sucrose, a disintegrant such as carboxylmethyl cellulose calcium or hydroxypropyl cellulose, a lubricant such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hardened oil, a binding agent such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gelatin, and arabia gum, a hu ectant such as glycerol or ethylene glycol, and, optionally or if necessary, a surfactant, flavoring agent, etc. are used to prepare the desired administration preparation.
  • an excipient such as lactose, glucose, corn starch, or sucrose
  • a disintegrant such as carboxylmethyl cellulose calcium or hydroxypropyl cellulose
  • a lubricant such as calcium stearate, magnesium stearate, talc, polyethylene glycol, and hardened oil
  • a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, and tragacanth gum is used and, if necessary, a solution adjuvant, buffer agents, preservative, flavor, coloring agent, etc. may be used .
  • the unit of administration in terms of the compound of the present invention, is, per adult in the case of oral administration, 1 to 1000 mg, preferably 30 to 600 mg, per day and, in the case of nonoral administration, 0.1 to 100 mg, preferably 0.5 to 30 mg per day.
  • the desired therapeutic effect can be expected by administration one to three times a day.
  • 6-chloropurine (0.32 g) in hexamethyldisilazane (10 ml) was refluxed under a nitrogen atmosphere for 2 hours, then the mixture was evaporated in vacuo. The residue thus obtained was dissolved in acetonitrile (17 ml).
  • 2 , 3 ,5-Tri-O-isobutyl-l-O-methyl-D-ribofuranose (0.68 g) in acetonitrile (4 ml) solution was added thereto, and the solution was cooled to -30 °C, then trimethylsilyl triflate (0.4 ml) in acetonitrile (4 ml) solution was added and the solution stirred under a nitrogen atmosphere at room temperature overnight.
  • the desired compound was prepared by a similar method to Example 1, except for using 2 , 3 ,5-tri-O-pentyl- 1-O-methyl-D-ribofuranose (0.48 g), instead of 2,3,5-tri- O-isobutyl-1-O-methyl-D-ribofuranose (Yield 19%). Melting point: 87 °C
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminovaleric acid amide (0.35 g), instead of ⁇ -aminobutyric acid (GABA) amide, and using 2 , 3 , 5-tri-O-pentyl-l-O-methyl-D- ribofuranose, instead of 2 , 3 , 5-tri-O-isobutyl-l-O-methyl- D-ribofuranose (Yield 19%).
  • GABA ⁇ -aminobutyric acid
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminopropionic acid amide, instead of ⁇ -aminobutyric acid (GABA) amide, and using 2, 3,5-tri-O-propyl-l-O-methyl-D-ribofuranose instead of 2 ,3 , 5-tri-O-isobutyl-l-O-methyl-D-ribofuranose (Yield 18%) .
  • GABA ⁇ -aminobutyric acid
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminovaleric acid amide, instead of ⁇ -aminobutyric acid (GABA) amide and using 2,3, 5-tri-O-propyl-l-O-methyl-D-ribofuranose instead of 2 ,3 , 5-tri-O-isobutyl-l-O-methyl-D-ribofuranose (Yield 14%).
  • GABA ⁇ -aminobutyric acid
  • Compound 8 N-6- ( 5-carbamoylpentyl ) -9- ( 2 ', 3 ', 5 ' -tri- O-propyl- ⁇ -D-ribosyl ) adenine
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminocaproic acid amide, instead of ⁇ -aminobutyric acid (GABA) amide, and using 2,3, 5-tri-0-propyl-l-0-methyl-D-ribofuranose, instead of 2 ,3 , 5-tri-O-isobutyl-l-O-methyl-D-ribofuranose (Yield 14%).
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminocaproic acid amide, instead of ⁇ -aminobutyric acid (GABA) amide, and using 2,3, 5-tri-O-pentyl-l-O-methyl-D-ribofuranose, instead of 2 , 3 , 5-tri-O-isobutyl-l-O-methyl-D-ribofuranose (Yield 17%).
  • GABA ⁇ -aminobutyric acid
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminobutyric acid N-methyl amide, instead of ⁇ -aminobutyric acid (GABA) amide, and using 2 , 3 , 5-tri-O-propyl-l-O-methyl-D- ribofuranose, instead of 2 , 3 , 5-tri-O-isobutyl-l-O-methyl- D-ribofuranose (Yield 18%).
  • GABA ⁇ -aminobutyric acid
  • the desired compound was prepared by a similar method to Example 1, except for using ⁇ -aminobutyric acid
  • N,N-dimethyl amide instead of ⁇ -aminobutyric acid (GABA) amide, and using 2 , 3 , 5-tri-O-pentyl-l-O-methyl-D- ribofuranose, instead of 2 , 3 ,5-tri-O-isobutyl-l-O-methyl- D-ribofuranose (Yield 17%).
  • GABA ⁇ -aminobutyric acid
  • the 6-chloro-9- ( 2 ' , 3 ' , 5 ' -tri-O-acetyl- ⁇ -D- ribofuranosyl )purine (3.6 g) obtained at (2) was dissolved in methanol (72 ml). Ammonia gas was saturated and the resultant mixture was stirred for 6 hours. The reaction solution was concentrated to dryness, then the residue was crystallized from acetone/ether to obtain 6- chloropurine riboside (2.2 g) .
  • the desired compound was prepared by a similar method to Example 12, except for using ⁇ -aminobutyric acid morpholinamide, instead of the N-methyl- ⁇ - aminobutyric acid amide.
  • the desired compound was prepared by a similar method to Example 12, except for using ⁇ -aminobutyric acid piperizinamide , instead of the N-methyl- ⁇ - aminobutyric acid amide.
  • the desired compound was prepared by a similar method to Example 12, except for using ⁇ -aminobutyric acid 4-benzylpiperizinamide, instead of the N-methyl- ⁇ - aminobutyric acid amide. Melting point: 145°C (2-HCl « 2H 2 0)
  • Example 17 Compound 17: 6- ( 4-carbamoylpiperadino) -9- ( 2 ' , 3 ' , 5 ' - tri-O-propyl- ⁇ -D-ribosyl )purine
  • the desired compound was prepared by a similar method to Example 12, except for using isonipecotic acid amide, instead of the N-methyl- ⁇ -aminobutyric acid amide. Melting point: 104 °C (1H 2 0)
  • Magnesium stearate 10 g The present compound, lactose, and corn starch were mixed until becoming homogeneous, then a 5 W/V% ethanol hydroxypropyl cellulose solution was added and the mixture mixed, then granulated. The granules were passed through a 16 mesh sieve for grading, then tableted by an ordinary method to obtain tablets having a weight of 130 mg per tablet, a diameter of 7 mm, and a medicine content of 25 mg.
  • Test Example 1 (Pharmacological Test in Normal Rats) Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in 1% sodium CMC solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. Two hours after the administration, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L- ⁇ - glycerophosphate oxidase method and the concentration of glucose in the serum was measured by glucose oxidase method.
  • test compound in lowering the triglycerides was shown in Table 1 as a rate of suppression (%) against the solvent treated rats, while the action in lowering the glucose was shown in Table 2 as a rate of suppression (%) against the solvent treated rats.
  • Test Example 2 (Pharmacological Test of Hvpertriglyceridemia Model)
  • Test compounds Male Sprague-Dawley rats (Charles river, Japan) aged 6 weeks were used in this Experiment. Test compounds were suspended in 1% CMC Na solution, and were given orally to rats fasted for 18 hours at the ratio of 1 mg/mL/100 g body weight. 20 minutes after the administration of Test compounds, 400 mg/kg body weight of Triton WR-1339 (Sigma) was injected to the tail vein. Two hours after the injection of the Triton WR-1339, blood was collected from abdominal aorta under ether anesthesia, and the concentration of triglycerides in the serum was measured by the L- ⁇ -glycerophosphate oxidase method.
  • the present compounds have action in improving hyperlipemia accompanying hypertriglyceridemia or diabetes etc., have a low toxicity, and exhibit effects in both oral and nonoral administration and, therefore, are useful as medical drugs for human use.

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  • Obesity (AREA)
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  • Urology & Nephrology (AREA)
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Abstract

L"invention concerne un composé d"adénosine représenté par la formule (I) dans laquelle R représente un groupe alkyle inférieur linéaire ou ramifié, et R1 représente un groupe alkylamino inférieur C¿2? à C6 ou un substituant représenté par les formules (II), (III) ou (IV) dans lesquelles R?2¿ représente indépendamment un groupe hydrogène ou un groupe alkyle inférieur, X représente N-R3, O ou CH¿2, R?3 représente un atome d"hydrogène, un groupe alkyle inférieur ou un groupe benzyle et n représente un nombre entier compris entre 1 et 6. L"invention concerne également un sel pharmaceutiquement acceptable ou un hydrate de ce composé, ainsi qu"une composition pharmaceutique contenant ce composé. Ce composé présente une action anti-hyperlipidémie, antiallergique, anti-diabète ou analgésique.
PCT/EP2000/006958 2000-07-12 2000-07-12 Compose d"adenosine et compositions pharmaceutiques contenant ce compose WO2002004474A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00945940A EP1303528A1 (fr) 2000-07-12 2000-07-12 Compose d'adenosine et compositions pharmaceutiques contenant ce compose
JP2002509337A JP2004502780A (ja) 2000-07-12 2000-07-12 アデノシン化合物及びそれを含む医薬組成物
PCT/EP2000/006958 WO2002004474A1 (fr) 2000-07-12 2000-07-12 Compose d"adenosine et compositions pharmaceutiques contenant ce compose
CA002416199A CA2416199A1 (fr) 2000-07-12 2000-07-12 Compose d'adenosine et compositions pharmaceutiques contenant ce compose

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Application Number Priority Date Filing Date Title
PCT/EP2000/006958 WO2002004474A1 (fr) 2000-07-12 2000-07-12 Compose d"adenosine et compositions pharmaceutiques contenant ce compose

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JP (1) JP2004502780A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017000125A1 (fr) * 2015-06-29 2017-01-05 Merck Sharp & Dohme Corp. Inhibiteurs puriques de la phosphatidylinositol 3-kinase delta humaine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101712709A (zh) * 2008-10-06 2010-05-26 中国医学科学院药物研究所 三乙酰基-3-羟基苯基腺苷及其调血脂的用途
AU2010295392B2 (en) * 2009-09-21 2015-10-22 Gilead Sciences, Inc. Processes and intermediates for the preparation of 1'-substituted carba-nucleoside analogs

Citations (3)

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Publication number Priority date Publication date Assignee Title
DE1955387A1 (de) * 1969-10-29 1971-05-06 Schering Ag 9-(beta-D-Arabinofuranosyl)-N?-isopentenyladenin
US5322840A (en) * 1990-08-03 1994-06-21 Centre D'etudes Experimentales Et Cliniques De Physiobiologie, De Pharmacologie Et D'eutonologie (Cepbepe) Treatment of hyperlipemia and hypertriglyceridemia
WO1997043300A1 (fr) * 1996-05-14 1997-11-20 Glaxo Group Limited Derives d'adenosine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1955387A1 (de) * 1969-10-29 1971-05-06 Schering Ag 9-(beta-D-Arabinofuranosyl)-N?-isopentenyladenin
US5322840A (en) * 1990-08-03 1994-06-21 Centre D'etudes Experimentales Et Cliniques De Physiobiologie, De Pharmacologie Et D'eutonologie (Cepbepe) Treatment of hyperlipemia and hypertriglyceridemia
WO1997043300A1 (fr) * 1996-05-14 1997-11-20 Glaxo Group Limited Derives d'adenosine

Non-Patent Citations (7)

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Title
BLANK, HEINZ U. ET AL: "Nucleosides. IV. Tritylation and benzylation of adenosine derivatives", JUSTUS LIEBIGS ANN. CHEM. (1970), 742, 34-42, XP002164934 *
HORNDLER, CORNELIA ET AL: "Nucleotides. Part 51. Synthesis and biological activities of (2'-5')adenylate trimer conjugates with 2'-terminal 3'-O-(.omega.-hydroxyalkyl) and 3'-O-(.omega.-carboxyalkyl) spacers", HELV. CHIM. ACTA (1997), 80(3), 767-785, XP002164930 *
K W PANKIEWICZ ET AL: "A Synthesis of 9-(2-Deoxy-2-fluoro-B-D-arabinofuranosyl)adenine and Hypoxanthine", JOURNAL OF ORGANIC CHEMISTRY,AMERICAN CHEMICAL SOCIETY. EASTON,US, vol. 57, 1992, pages 553 - 559, XP002107309, ISSN: 0022-3263 *
MACLEOD, JOHN K. ET AL: "Mass spectrometry of cytokinin metabolites. Per(trimethylsilyl) and permethyl derivatives of glucosides of zeatin and 6-benzylaminopurine", J. ORG. CHEM. (1976), 41(25), 3959-67, XP002164933 *
MANGHOLZ, SISSI E. ET AL: "Glycosylidene Carbenes. Synthesis of N-tosylglycono-1,4-lactone hydrazones as precursors of glycofuranosylidene carbenes", HELV. CHIM. ACTA (1995), 78(4), 1020-35, XP002164931 *
MARTIN, GEORGE C. ET AL: "High-performance liquid chromatographic analysis of permethylated cytokinins", J. CHROMATOGR. (1981), 219(1), 167-70, XP000990543 *
MYLES, ARTHUR ET AL: "Nucleosides. VI. Synthesis of 2'-O-, 3'-O- and 5'-O-benzyladenosine", CHEM. BER. (1972), 105(10), 3327-33, XP002164932 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017000125A1 (fr) * 2015-06-29 2017-01-05 Merck Sharp & Dohme Corp. Inhibiteurs puriques de la phosphatidylinositol 3-kinase delta humaine
US10221178B2 (en) 2015-06-29 2019-03-05 Merck Sharp & Dohme Corp. Purine inhibitors of human phosphatidylinositol 3-kinase delta

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JP2004502780A (ja) 2004-01-29
CA2416199A1 (fr) 2002-01-17

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