WO1998033791A1 - Dihydropyrimidone derivatives as npy antagonists - Google Patents
Dihydropyrimidone derivatives as npy antagonists Download PDFInfo
- Publication number
- WO1998033791A1 WO1998033791A1 PCT/US1998/001429 US9801429W WO9833791A1 WO 1998033791 A1 WO1998033791 A1 WO 1998033791A1 US 9801429 W US9801429 W US 9801429W WO 9833791 A1 WO9833791 A1 WO 9833791A1
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- 0 CC(N1)=C(*)C(c2cccc(NC(NCCCN3CCC(*)CC3)=O)c2)N(*)C1=O Chemical compound CC(N1)=C(*)C(c2cccc(NC(NCCCN3CCC(*)CC3)=O)c2)N(*)C1=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention provides novel heterocyclic carbon compounds comprising 4-phenyl-1 ,4-dihydropyrimidinones with a piperidinyl containing moiety attached to the 3-position of the 4-phenyl ring. These compounds act as NPY antagonists.
- Neuropeptide Y is a 36 amino acid peptide first isolated in
- the peptide is a member of a larger peptide family which also includes peptide YY (PYY), pancreatic peptide (PP), and the non-mammalian fish pancreatic peptide Y (PY).
- Neuropeptide Y is very highly conserved in a variety of animal, reptile and fish species. It is found in many central and peripheral sympathetic neurons and is the most abundant peptide observed in the mammalian brain. In the brain, NPY is found most abundantly in limbic regions. The peptide has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and the regulation of coronary tone.
- Myo-inositol-1 ,2,6-triphosphate (5) was reported to be a potent but non- competitive antagonist to NPY-induced contractions in guinea pig basilar artery [L. Edvinsson, M. Adamsson and I. Jansen, Neuropeptides. (1990) 17, 99-105].
- the benextramine-like bisguanidines 6a and 6b were reported to displace ⁇ -NPY in rat brain (IC50, 19 and 18.4 ⁇ M) and to display functional antagonism in rat femoral artery [M.B. Doughty, C. Chaurasia and K. Li, J. Med. Chem.. (1993) 36, 272-79; M.B.
- a compound of formula (4) has been disclosed in JO 4049-237-A and claimed to be an inhibitor of Phospholipase A2.
- the present invention comprises the compounds of Formula I,
- C ⁇ alkyl indicates that the alkyl group contains from one to three carbon atoms, such as methyl, ethyl, propyl and isopropyl.
- Preferred compounds of the instant invention are Formula I compounds wherein R is -C0 2 R and R 1 is methyl. Most preferred compounds are those wherein R 2 is selected from substituted phenyl, particularly with methoxy substituents.
- the compounds of the present invention can exist as optical isomers and both the racemic mixtures of these isomers as well as the individual optical isomers themselves are within the scope of the present invention.
- the racemic mixtures can be separated into their individual isomers through well known techniques such as the separation of the diastereomeric salts formed with optically active acids, followed by conversion back to the optically active bases.
- the present invention also pertains to the pharmaceutically acceptable non-toxic salts of these basic compounds.
- Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, dichloroacetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, enanthic acid, and the like.
- organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, dichloroacetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, enanthic acid
- the Formula I compounds can also be quaternized by standard techniques to yield quaternary piperidinium salt products of Formula I. Quaternization would be expected to maximize the peripheral effects of Formula I compounds and minimize brain penetration.
- the compounds of the present invention may be prepared by various procedures such as those illustrated herein in the examples, in the reaction schemes and variations thereof which would be evident to those skilled in the art.
- the various compounds of Formula I may advantageously be prepared from the dihydropyrimidinone intermediates Va, Vb and Vc as illustrated in Reaction Schemes 2 and 3.
- the various dihydropyrimidinone intermediates are generally prepared from the Knoevenagel adduct of Formula II as illustrated in Reaction Scheme 1.
- the reaction of the intermediate of Formula II with O-methylisourea produced a mixture of methoxypyrimidine isomers of Formulas III and IV.
- the methoxypyrimidine isomer of Formula III may selectively be crystallized from the mixture of isomers by the method described herein.
- the resulting filtrate that contains a residual mixture of isomers of Formulas III and IV may readily be hydrolyzed under acidic conditions in aqueous tetrahydrofuran to provide the 2-oxopyrimidine intermediate of Formula Va.
- the intermediates of Formulas Vb and Vc are advantageously prepared from the single methoxypyrimidine compound of Formula III by alkylation and acylation reactions, respectively.
- the acylation of the compound of Formula III with a lower alkyl ester of chloroformate in the presence of about one equivalent of a base such as pyridine, lutidine, triethylamine and the like in an inert organic solvent then followed by acid hydrolysis of the methoxy group afforded the intermediate of Formula Vc.
- the compounds of Formula I were prepared from the intermediates of Formulas Va, Vb and Vc as outlined by the process in Reaction Scheme 2 or the alternate process as outlined in Scheme 3.
- the nitrophenyl intermediates of Formulas Va, Vb and Vc were subjected to catalytic hyrdrogenation in an acetic acid solvent to produce the aminophenyl intermediates of Formulas Via, VIb and Vic which were then coupled with the activated carboxylate intermediate of Formula VII to produce the corresponding dihydropyrimidinone compounds of Formula la, lb and lc.
- the intermediate of Formula VII can readily be prepared by methods described in the literature and preferably by the method described herein.
- the compounds of this invention demonstrate binding affinity at NPY Yi receptors. This pharmacologic activity is assayed in SK-N-MC (human neuroblastoma) cell membranes using iodine-125-labeled I- PYY as a radioligand.
- the compounds of this invention had good binding affinities as evidenced by IC50 values being about 1 ⁇ M or less at NPY Yi receptors.
- Preferred compounds have IC50 values less than 100 nM.
- the compounds of this invention possess much weaker affinities for c ⁇ adrenergic receptors and Ca ++ channels.
- Pharmacologically, these compounds act as selective NPY antagonists at NPY Y t receptor sites.
- the compounds of Formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.
- the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.
- physiological disorder associated with an excess of neuropeptide Y encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amont of neuropeptide Y present in the locale.
- disorders or diseases pertaining to the heart, blood vessels or the renal system such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
- Cerebral diseases and diseases related to the central nervous system such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
- abnormal drink and food intake disorders such as obesity, anorexia, bulemia, and metabolic disorders
- respiratory diseases such as asthma and conditions related to asthma and bronchoconstriction
- NPY neuropeptide Y
- hypertension eating disorders
- depression/anxiety NPY contributes to certain symptoms in these disorders: hypertension, eating disorders, and depression/anxiety [C. Wahlestedt and D.J. Reis, Annual Rev. Pharmacol. Toxicol.. (1993) 32, 309-52; p. 331]; as well as circadian rhythms.
- Compounds of this invention are expected to be useful in treating these disorders as well as sleep disturbance and diabetes.
- Another aspect of the invention concerns a process for reducing food intake in an obese mammal or a mammal with an eating disorder.
- the process comprises systemic administration to such a mammal of an anorexiant-effective dose of a Formula I compound or a pharmaceutically acceptable acid addition salt and/or hydrate thereof.
- an effective dose given parenterally could be expected to be in a range of about 0.05 to 1 mg/kg body weight and if given orally would be expected to be in the range of about 1 to 20 mg/kg body weight.
- the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness.
- the compounds of the instant invention will be administered in the same manner as for available anorexiant drugs such as Diethylpropion, Mazindol, or Phentermine and the daily oral dose would comprise from about 70 to about 1400 mg, preferably 500 to 1000 mg administered from 1 to 3 times a day. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.
- systemic administration refers to oral, buccal, transdermal, rectal, and parenteral (i.e. intramuscular, intravenous, and subcutaneous) routes.
- parenteral i.e. intramuscular, intravenous, and subcutaneous
- a compound of the present invention is administered orally, which is the preferred route, a larger quantity of reactive agent is required to produce the same effect as a smaller quantity given parenterally.
- the instant compounds can be administered to treat hypertension, depression, diabetes and anxiety disorders.
- compositions comprised of an effective anorectic amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
- Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, e.g. from 95 to 0.5% of at least one compound of the present invention in combination with the pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, filler, and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable.
- Such pharmaceutical compositions are preferably in dosage unit forms; i.e., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response.
- the dosage units can contain 1 , 2, 3, 4, or more single doses, or, alternatively, one-half, one-third, or one-fourth of a single dose.
- a single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to the pre-determined dosage regimen usually a whole, half, third, or quarter of the daily dosage administered once, twice, three, or four times a day.
- Other therapeutic agents can also be present.
- Pharmaceutical compositions which provide from about 50 to 1000 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, transdermal patches, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions.
- Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate).
- binding agents e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinylpyrrolidone
- fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine
- lubricants e.g. magnesium stearate, talc
- Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are generally employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.
- parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.
- Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1 % to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propyleneglycol, and polyethelene glycols or mixtures thereof.
- the polyethyleneglycols consist of a mixture of non-volatile, usually liquid, polyethyleneglycols which are soluble in both water and organic liquids and which have molecular weights from about 200 to 1500. Description of the Specific Embodiments
- the nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts ( ⁇ ) expressed in parts per million (ppm) versus tetramethylsilane.(TMS) as reference standard.
- the relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule.
- the nature of the shifts as to multiplicity is reported as broad singlet (br s), singlet (s), multiplet (m), doublet (d), triplet (t) doublet of doublets (dd), quartet (q) or pentuplet (p).
- Abbreviations employed are DMSO-d6, (deuterodimethylsulf oxide), CDCI3 (deuterochloroform), and are otherwise conventional.
- the infrared (IR) spectral descriptions include only absorption wave numbers (cm "1 ) having functional group identification value.
- the IR determinations were generally employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.
- the title compound was prepared from the compound of Example 5 and the intermediate of Formula VII by the method described in Example 3.
- the solvent was removed in vacuo from the reaction mixture, and the residue partitioned between CH2CI2 and H2O.
- the organic extract was dried over Na2S04, the solvent removed in vacuo. and the residue subjected to flash chromatography (Si ⁇ 2: MeOH/CH2Cl2).
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU59639/98A AU733883B2 (en) | 1997-02-04 | 1998-01-26 | Dihydropyrimidone derivatives as NPY antagonists |
JP53298398A JP2002514199A (en) | 1997-02-04 | 1998-01-26 | Dihydropyrimidone derivatives as NPY antagonists |
CA002277965A CA2277965A1 (en) | 1997-02-04 | 1998-01-26 | Dihydropyrimidone derivatives as npy antagonists |
EP98902841A EP0986553A4 (en) | 1997-02-04 | 1998-01-26 | Dihydropyrimidone derivatives as npy antagonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3718397P | 1997-02-04 | 1997-02-04 | |
US60/037,183 | 1997-02-04 | ||
US5089397P | 1997-06-26 | 1997-06-26 | |
US60/050,893 | 1997-06-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998033791A1 true WO1998033791A1 (en) | 1998-08-06 |
Family
ID=26713884
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/001429 WO1998033791A1 (en) | 1997-02-04 | 1998-01-26 | Dihydropyrimidone derivatives as npy antagonists |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0986553A4 (en) |
JP (1) | JP2002514199A (en) |
AU (1) | AU733883B2 (en) |
CA (1) | CA2277965A1 (en) |
WO (1) | WO1998033791A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6127414A (en) * | 1997-09-23 | 2000-10-03 | Astra Aktiebolag | NPY antagonists |
US6201165B1 (en) | 1997-10-16 | 2001-03-13 | Board Of Regents, University Of Texas System | Transgenic animal models for cardiac hypertrophy and methods of use thereof |
EP1299362A1 (en) * | 2000-07-05 | 2003-04-09 | Synaptic Pharmaceutical Corporation | Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof |
US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
WO2007101213A2 (en) * | 2006-02-28 | 2007-09-07 | Kalypsys, Inc. | Novel 2-oxo-1,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidazolidine-2,4-diones useful as inducible nitric oxide synthase inhibitors |
US7485653B2 (en) | 2003-11-03 | 2009-02-03 | Gilead Sciences, Inc. | 1,4-dihydropyridine compounds, pharmaceutical compositions, and methods for the treatment of cardiovascular disease |
EP2434017A2 (en) | 2006-08-01 | 2012-03-28 | Board of Regents of the University of Texas System | Identification of a micro-RNA that activates expression of beta-myosin heavy chain |
CN103193715A (en) * | 2013-03-28 | 2013-07-10 | 浙江大学 | Preparation method of 5,6-dihydropyrimidone derivative |
US9539427B2 (en) | 2010-11-08 | 2017-01-10 | The Johns Hopkins University | Methods for improving heart function |
US9856232B1 (en) | 2017-06-20 | 2018-01-02 | King Saud University | Dihydropyrimidinone derivatives |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4609494A (en) * | 1985-02-21 | 1986-09-02 | Merck & Co., Inc. | 5-acetyl-3,4,5,6-tetrahydro-4-oxo-2,6-methano-2H-1,3,5-benzothiazocine(benzodiazocine)-11-carboxylates useful as calcium channel blockers |
JPS6287574A (en) * | 1985-10-14 | 1987-04-22 | Suntory Ltd | Novel n-substituted 3,4-dihydropyrimidin-2-one derivative, production thereof and remedy for circulatory disease containing same |
US4675321A (en) * | 1986-02-07 | 1987-06-23 | Merck & Co., Inc. | Substituted pyrimidines useful as calcium channel blockers |
US4684656A (en) * | 1986-03-14 | 1987-08-04 | E. R. Squibb & Sons, Inc. | 1,2,3,4-tetrahydro-6-substituted-4-aryl-3-(substituted sulfonyl)-2-thioxo(or oxo)-5-pyrimidinecarboxylic acids and esters and method of using them to lower blood pressure |
IL81800A0 (en) * | 1986-03-14 | 1987-10-20 | Squibb & Sons Inc | 1,2,3,4-tetrahydro-6-substituted-4-aryl(or heterocyclo)-3-((substituted amino)carbonyl)-2-thioxo(or oxo)-5-pyrimidine-carboxylic acids and esters and pharmaceutical compositions containing the same |
US4684655A (en) * | 1986-03-14 | 1987-08-04 | E. R. Squibb & Sons, Inc. | 1,2,3,4-tetrahydro-6-substituted-4-aryl-3-substituted-2-thioxo(or oxo)-5-pyrimidinecarboxylic acids and esters and use thereof to lower blood pressure |
US4738965A (en) * | 1987-02-03 | 1988-04-19 | Institut Organischskogo Sinteza Akademii Nauk Ssr | 2-oxo-4-(2'-difluoromethylthiophenyl)-5-methoxycarbonyl-6-methyl-1,2,3,4-tetrahydropyrimidine |
US4847379A (en) * | 1987-11-30 | 1989-07-11 | E. R. Squibb & Sons, Inc. | 3,6-dihydro-1,5(2H)-pyrimidinecarboxylic acid esters |
CA2004617A1 (en) * | 1988-12-05 | 1990-06-05 | Craig E. Crosson | Therapeutic use of dihydropyrimidones and benzazepine and benzothiazepine derivatives |
-
1998
- 1998-01-26 CA CA002277965A patent/CA2277965A1/en not_active Abandoned
- 1998-01-26 AU AU59639/98A patent/AU733883B2/en not_active Ceased
- 1998-01-26 EP EP98902841A patent/EP0986553A4/en not_active Ceased
- 1998-01-26 WO PCT/US1998/001429 patent/WO1998033791A1/en not_active Application Discontinuation
- 1998-01-26 JP JP53298398A patent/JP2002514199A/en active Pending
Non-Patent Citations (1)
Title |
---|
Chemical Abstracts Service (C A S); 1 January 1900 (1900-01-01), XP002912273, Database accession no. 108-150408 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6127414A (en) * | 1997-09-23 | 2000-10-03 | Astra Aktiebolag | NPY antagonists |
US6201165B1 (en) | 1997-10-16 | 2001-03-13 | Board Of Regents, University Of Texas System | Transgenic animal models for cardiac hypertrophy and methods of use thereof |
US6657104B1 (en) | 1997-10-16 | 2003-12-02 | Texas Systems, University Of The Board Of The Regents | Transgenic mouse model for cardiac hypertrophy and methods of use thereof |
US6673768B1 (en) | 1997-10-16 | 2004-01-06 | Board Of Regents, The University Of Texas System | Transgenic animal models for cardiac hypertrophy and methods of use thereof (treating) |
EP1299362A1 (en) * | 2000-07-05 | 2003-04-09 | Synaptic Pharmaceutical Corporation | Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof |
EP1299362A4 (en) * | 2000-07-05 | 2004-11-03 | Synaptic Pharma Corp | Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof |
US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
US7485653B2 (en) | 2003-11-03 | 2009-02-03 | Gilead Sciences, Inc. | 1,4-dihydropyridine compounds, pharmaceutical compositions, and methods for the treatment of cardiovascular disease |
WO2007101213A2 (en) * | 2006-02-28 | 2007-09-07 | Kalypsys, Inc. | Novel 2-oxo-1,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidazolidine-2,4-diones useful as inducible nitric oxide synthase inhibitors |
WO2007101213A3 (en) * | 2006-02-28 | 2008-02-21 | Kalypsys Inc | Novel 2-oxo-1,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidazolidine-2,4-diones useful as inducible nitric oxide synthase inhibitors |
EP2434017A2 (en) | 2006-08-01 | 2012-03-28 | Board of Regents of the University of Texas System | Identification of a micro-RNA that activates expression of beta-myosin heavy chain |
US9539427B2 (en) | 2010-11-08 | 2017-01-10 | The Johns Hopkins University | Methods for improving heart function |
US10525269B2 (en) | 2010-11-08 | 2020-01-07 | The Johns Hopkins University | Methods for improving heart function |
US11633606B2 (en) | 2010-11-08 | 2023-04-25 | The Johns Hopkins University | Methods for improving heart function |
CN103193715A (en) * | 2013-03-28 | 2013-07-10 | 浙江大学 | Preparation method of 5,6-dihydropyrimidone derivative |
US9856232B1 (en) | 2017-06-20 | 2018-01-02 | King Saud University | Dihydropyrimidinone derivatives |
Also Published As
Publication number | Publication date |
---|---|
JP2002514199A (en) | 2002-05-14 |
AU5963998A (en) | 1998-08-25 |
EP0986553A1 (en) | 2000-03-22 |
EP0986553A4 (en) | 2000-12-27 |
CA2277965A1 (en) | 1998-08-06 |
AU733883B2 (en) | 2001-05-31 |
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