FI94339B - Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi - Google Patents
Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi Download PDFInfo
- Publication number
- FI94339B FI94339B FI903614A FI903614A FI94339B FI 94339 B FI94339 B FI 94339B FI 903614 A FI903614 A FI 903614A FI 903614 A FI903614 A FI 903614A FI 94339 B FI94339 B FI 94339B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- compound
- pyrrole
- methylethyl
- fluorophenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 42
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 5
- XCIMEFFZGKWCOT-UHFFFAOYSA-N 7-[3-phenyl-4-(phenylcarbamoyl)-2-propan-2-ylpyrrol-1-yl]heptanoic acid Chemical compound C=1N(CCCCCCC(O)=O)C(C(C)C)=C(C=2C=CC=CC=2)C=1C(=O)NC1=CC=CC=C1 XCIMEFFZGKWCOT-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 claims description 2
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- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims 2
- HCPLPXQDAYFYCK-UHFFFAOYSA-N 7-[2-(phenylcarbamoyl)pyrrol-1-yl]heptanoic acid Chemical compound OC(=O)CCCCCCN1C=CC=C1C(=O)NC1=CC=CC=C1 HCPLPXQDAYFYCK-UHFFFAOYSA-N 0.000 claims 1
- 101000870363 Oryctolagus cuniculus Glutathione S-transferase Yc Proteins 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
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- 239000000203 mixture Substances 0.000 description 31
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 150000002596 lactones Chemical class 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
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- 238000004458 analytical method Methods 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical class CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 4
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 239000007858 starting material Substances 0.000 description 3
- KOTYNWBVGZFLLM-JWXFUTCRSA-N (2r,3r,4s,5s)-5-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CN[C@@](C)(O)[C@@H](O)[C@H](O)[C@H](O)CO KOTYNWBVGZFLLM-JWXFUTCRSA-N 0.000 description 2
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- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
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- 125000004326 2H-pyran-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])(*)O1 0.000 description 1
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- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960000816 magnesium hydroxide Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
94339
Menetelmä farmaseuttisesti käyttökelpoisen [R-(R*,R*)]-2-(4-f luorifenyyli) -/3,S-dihydroksi-5- (l-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
Trans-(±)-5-(4-fluorifenyyli)-2-(l-metyylietyyli)-N,4-di-fenyyli-l-[2-tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yy-li)etyyli]-lH-pyrroli-3-karboksamideja on esitetty US-pa-tentissa n:o 4,681,893 yhdisteinä, joita voidaan käyttää kolesteroli-biosynteesin inhibiittoreina. Siinä esitetyt yhdisteet käsittävät yleisesti 4-hydroksipyran-2-oneja ja niistä muodostettuja vastaavia avatun renkaan omaavia happoja.
Nyt on odottamatta todettu, että trans-5-(4-fluorifenyyli ) -2 - ( 1-metyy1ietyy1i)-N,4-difenyyli-1-(2-tetrahydro-4-hydr oks i- 6-okso-2H-pyran-2 -yy 1 i) etyyli ] - lij-pyrrol i-3 -kar-boksamidin avatun renkaan omaavan hapon R-muodon enantio-meeri, s.o. [R-(R*,R*) ]-2-(4-f luorifenyyli)-/3, δ-dihydrok-si-5-(l-metyylietyyli)-3-fenyyli-4-[(fenyyliamino)karbonyyli ]-lfi-pyrroli-l-heptaanihappo saa aikaan kolesterolin biosynteesin yllättävän inhibiition.
On tunnettua, että 3-hydroksi-3-metyyliglutaryyli-koent-: syymi A (HMG-CoA) esiintyy 3R-stereoisomeerinä. Lisäksi, kuten Stokker et ai. ovat osoittaneet 5-substituoitujen 3.5- dihydroksipentaanihappojen ryhmän tutkimuksessa artikkelissa "3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3.5- Dihydroxypentanoic acids and Their Lactone Derivati- * ves" julkaisussa J. Med. Chem. 1985, 28, 347 - 358, olen naisesti koko biologinen aktiivisuus kuuluu positiivisesti kiertävän (E)-6-[2-(2,4-dikloorifenyyli)etenyyli]-3,4,5,6-tetrahydro-4-hydroksi-2H-pyranonin trans-diastereomeereil-le. Edelleen HMG-CoA-reduktaasin inhibiitioon tarvitaan ilmeisesti /3-hydroksi-5-laktoni-osan absoluuttista konfiguraatiota, joka osa on yhteinen kaavan (la) 2 Q A τ 7 Q 7 ‘τ o O 7 / HO—ί o h3c' mukaiselle mevinoliinille ja kaavan (lb) W°
H0-< o H
mukaiselle kompaktiinille. Lynch et ai. ovat esittäneet tämän 4R,6R-konfiguraationa artikkelissa "Synthesis of an HMG-CoA Reductase Inhibitor; A Diastereoselective Aldol Approach" julkaisussa Tetrahedron Letters, Vol. 28, No.
13, s. 1385 - 1388 (1987).
Kuitenkaan alan ammattihenkilö ei voi ennakoida tämän keksinnön odottamatonta ja yllättävää kolesteroli-biosyntee-. sin inhibiitiota näiden julkaisujen perusteella.
Siten tämä keksintö saa aikaan yhdisteitä, jotka koostuvat [R-(R*,R*) ]-2-(4-fluorifenyyli) -/3,5-dihydroksi-5-((1-me-tyylietyyli)-3-fenyyli-4-[(fenyyliamino)karbonyyli]-1H-pyrroli-l-heptaanihaposta (kaavan I mukainen yhdiste) ja sen farmaseuttisesti hyväksyttävistä suoloista. Heptaani- 3 94339 hapon laktonimuoto on (2R-trans)5-(4-fluorifenyyli)-2-(1-metyy1ietyy1i)-N,4-d i fenyy1i-1[2-(tetrahydro-4-hydroks i- 6-okso-2H-pyran-2-yyli)etyyli]lH-pyrroli-3-karboksamidi (kaavan II mukainen yhdiste).
Tämän keksinnön mukaisesti valmistetuista yhdisteistä voidaan valmistaa myös farmaseuttinen koostumus, jota voidaan käyttää hypokolesteroleemisenä aineena ja joka käsittää hypokolesteroleemisesti vaikuttavan määrän [R-(R*,R*)]-2-(4-f luorifenyyli) -/9, δ—dihydroksi-5- (1-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappoa tai sen farmaseuttisesti hyväksyttäviä suoloja ja farmaseuttisesti hyväksyttävää kantoainetta. Edelleen tämän keksinnön mukaisesti valmistettuja yhdisteitä voidaan käyttää menetelmässä hyperkolesterolemiaa sairastavien nisäkkäiden, mukaanlukien ihmisen hoitamiseksi, missä menetelmässä tällaiselle nisäkkäälle annetaan yllä selitetyn farmaseuttisen koostumuksen annostusmuoto.
Tämä keksintö koskee siten menetelmää kaavan I mukaisten yhdisteiden valmistamiseksi, kuten oheisissa vaatimuksissa on esitetty.
Farmaseuttisesti hyväksyttäviä suoloja ovat sellaiset, jotka on tavallisesti muodostettu liuottamalla vapaa happo tai laktoni, etenkin laktoni vesipitoiseen tai vesipitoiseen alkoholiliuottimeen tai muihin sopiviin liuottimiin sopivan emäksen kanssa ja eristämällä suola haihduttamalla liuos tai saattamalla vapaa happo tai laktoni, etenkin laktoni ja emäs reagoimaan orgaanisessa liuottimessa, jos-sa suola erottuu suoraan tai se voidaan saada konsentroimalla liuos.
Käytännössä suolamuodon käyttö merkitsee happo- tai lakto-nimuodon käyttöä. Keksinnön puitteissa sopivia farmaseut- . tisesti hyväksyttäviä suoloja ovat sellaiset, jotka on « ί 4 94339 muodostettu emäksistä, kuten natriumhydroksidista, kalium-hydroksidista, litiumhydroksidista, kalsiumhydroksidista, l-deoksi-2-(metyyliamino)-D-glusitolista, magnesiumhydroksidista, sinkkihydroksidistä, aluminiumhydroksidistä, rauta(II)- tai rauta(III)-hydroksidista, ammoniumhydroksi-dista tai orgaanisista amiineista, kuten N-metyyliglu-kamiinista, koliinista, arginiinista tai vastaavasta. Litium-, kalsium-, magnesium-, aluminium- ja rauta(II)- ja rauta(III)-suolat valmistetaan edullisesti natrium- tai kaliumsuolasta lisäämällä sopivaa reagenssia natrium- tai kaliumsuolan liuokseen, s.o. kalsiumkloridin lisäys kaavan I mukaisen yhdisteen natrium- tai kaliumsuolan liuokseen tuottaa sen kalsiumsuolan.
Vapaa happo voidaan valmistaa hydrolysoimalla kaavan II mukainen laktonimuoto tai ohjaamalla suola kationinvaihto-hartsin (H+-hartsin) läpi ja haihduttamalla vesi.
Tämän keksinnön edullisin suoritusmuoto on [R-(R*,R*)]-2-(4-f luorifenyyli) -0,6-dihydroksi-5- (1-me tyyli etyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappo-hemikalsiumsuola.
Tavallisesti yhdisteet I ja II voidaan valmistaa (1) erot-: tamalla rasemaatti, joka on valmistettu US-patentissa n:o 4,681,893 esitettyjen menetelmien mukaisesti, joka patentti on tässä viitejulkaisuna, tai (2) syntetisoimalla haluttu kiraalinen muoto lähtöaineista, jotka ovat tunnettuja tai valmistetaan helposti käyttämällä tunnettuja menetelmiä vastaavia menetelmiä.
• ·
Etenkin rasemaatin erotus voidaan suorittaa kaaviossa 1 (jossa Ph on fenyyli) esitetyllä tavalla seuraavasti: 5 94339
Kaavio 1 r
I O
p ? XX? H
[ N^s'^r'RV'^' N^Ph
Phs^J I I Phfflipv H I
\ I V ( CH>
PhHN a 0 / ^ r
q \\ 4 H2N'-|'''I>h vaihe A
f 013 F
R I
trans-rasemaatti
O
OH OH 0 V['k Nvl^ph
PhHN^>>V H^T
T \ f CH)
0 R
Vaihe B
1) Erotus
2) NaOH
3) Kuumennus palautusjäähdyttäen tolueenissa HO ν./'Ύ'0 ΗΟ'θ/^γ ° X^O ίγ° 'T0UO. ''Op
Ph CONHPh ph COKHPh [R(R«R*1]isomeeri (S (R*R*) ) isomeeri
NaOH J Na0H
COjNa COjNa V-OH /-08 S-OB V-0»
Ph^^CONHPh P hCOKHPh 6 94339
Kaavion 1 "trans-rasemaatti" tarkoittaa seuraavien ΗΟ,,,^Ο
Ph CONHPh Ph CONHPh [R(R1R1)]isomeeri [S (R1R1)]isomeeri yhdisteiden seosta.
Kaavion I vaiheen 1 ja 2 olosuhteet ovat yleisesti, kuten on esitetty esimerkeissä 6 ja 7.
Kiraalinen synteesi on esitetty kaaviossa 2 (jossa Ph on fenyyli) seuraavasti: · 7 94339
Kaavio 2 F Γ Ί JL Μσ*4
v _ , 1. THF-80—90eC
Ο Θθ·' Ph', Q _lhr
ηΎ ? ♦ 2-lc0H
T"" N^ Ph
PhNHC'^1^ L J
0 /V (2)
F F
(^j) 1.1 eq NaOMe
I OH 0 ph -1-“ ον. I »H
PhN<A ^ X JL JL OH MeOH -10‘C Ph>A COjMe
' 1 Ph /^V
PhNHOC I Ph PhNHOC I
(3 J (4) 73% <3) 78%
F
0 JL
X^OBu1 8 eq O 1. B (Et)3 , NaBH4 - I °H 0 ——~~~ "
Ph^J | | t 2. H202 -30--4 0®C ^χ^*\χ^ν^Οθ2Βυ 5hrs JUs*/
PhNHOC I
(5) 78%
F
F 1 ; 6 V Λ
Ph. T f f . 2. Toi. -H20*| Ph^A ^11 V\ ^\xAv^*\^C02But -- Γ N o o A=v PhNHOC''^!
PhNHOC Ίί ^ (7, 57% (6,83% [«]"-♦ 18.07 (CHC1,) 94339 δ
Kaavion 2 olosuhteet ovat yleisesti, kuten on esitetty esimerkeissä 1-5.
Alan ammattihenkilö tunnistaa kaavioiden 1 ja 2 muunnelmia, jotka ovat sopivia tämän keksinnön mukaisten yhdisteiden valmistamiseksi.
Tämän keksinnön mukaisesti valmistetut yhdisteet ja etenkin kaavan I mukainen yhdiste inhiboivat kolesterolin biosynteesin, kuten on havaittu CSI-seulonta-analyysissä, joka on esitetty US-patentissa n:o 4,681,893, joka on tässä samoin viitteenä. Yhdisteen I, sen enantiomeerin yhdisteen II, ja näiden kahden yhdisteen rasemaatin CSI-arvot ovat seuraavat:
Yhdiste Ic50 (μ™00!!3/!) [R-(R*,R*)]-isomeeri 0,0044 [S-(R*,R*)]-isomeeri 0,44 rasemaatti 0,045
Farmaseuttiset koostumukset, jotka sisältävät keksinnön mukaisesti valmistettuja yhdisteitä, valmistetaan US-patentissa n:o 4,681,893 esitetyllä tavalla, joka patentti on siten jälleen tässä viitteenä.
» Tämän keksinnön mukaisesti valmistettuja yhdisteitä voidaan käyttää hypolipideemisinä tai hypokolesteroleemisinä aineina. Farmaseuttisessa menetelmässä käytettäviä tämän keksinnön mukaisesti valmistettuja yhdisteitä annetaan po-i tilaalle 10 - 500 mg/päivä, jolloin n. 70 kg painavan nor maalin täysikasvuisen annostuksena on 0,14 - 7,1 mg/kg päivää kohden. Annostukset voivat olla edullisesti 0,5 - 1,0 mg/kg/päivä.
Annostus annetaan edullisesti yksikköannostusmuodossa.
Oraalisesti tai parenteraalisesti käytettävä yksikköannos- li 9 94339 tusmuoto voi olla 10 - 500 mg, edullisesti 20 - 100 mg erityisen antomuodon ja aktiivisen aineen tehon mukaisesti. Koostumukset voivat haluttaessa sisältää myös muita aktiivisia terapeuttisia aineita. Alan ammattihenkilö osaa määrittää optimaaliset annostukset erityistä tilannetta varten.
Kaavan I ja II mukaiset yhdisteet ja niiden farmaseuttisesti hyväksyttävät suolat ovat yleensä samanarvoisia aktiivisuuden suhteen, kuten tässä on esitetty.
Seuraavat esimerkit havainnollistavat erityisiä menetelmiä tämän keksinnön mukaisten yhdisteiden valmistamiseksi.
Näitä esimerkkejä ei tule kuitenkaan pitää keksinnön piiriä rajoittavina.
Esimerkki l 285 ml 2,2 M n-butyylilitiumia (heksaanissa) lisätään ti-poittain 92 ml:aan di-isopropyyliamiinia 300 ml:ssa THF:ää -50 - -60eC:ssa 1000 ml:n yksikaulaisessa pullossa tiputus-suppilon kautta ja typpiatmosfäärissä. Hyvin sekoitetun keltaisen liuoksen annetaan lämmetä n. -20°C:seen. sitten se kanyloidaan suspensioon, jossa on 99 g S(+)-2-asetoksi- 1,1,2-trifenyylietanolia 500 ml:ssa absoluuttista THF:ää ja joka on 2 l:n 3-kaulaisessa pullossa ja pidetään -70eC: ssa. Lisäyksen päätyttyä reaktioseoksen annetaan lämmetä -10°C:seen 2 tunnin kuluessa. Tällä välin valmistetaan suspensio, jossa on 0,63 moolia MgBr2:ta, lisäämällä tipoit-tain 564 ml (0,63 moolia) bromia suspensioon, jossa on 15,3 g magnesiumia (0,63 moolia) 500 ml:ssa THF:ää ja joka on 3 l:n pullossa, joka on varustettu palautusjäähdytti-mellä ja ylhäällä olevalla sekoittimella. Kun tämä on päättynyt, MgBr2-suspensio jäähdytetään -78°C:seen ja enolaat-tiliuos (tummanruskea) kanyloidaan suspensioon 30 minuutin : kuluessa. Sekoittamista jatketaan 60 minuutin ajan -78°C:ssa.
94339 10 k
Sitten lisätään 150 g 5-(4-fluorifenyyli)-2-(l-metyyli-etyyli)-1-(3-oksopropyyli)-N,4-difenyyli-lH~pyrroli-3-kar-boksamidia 800 ml:ssa absoluuttista THF:ää tipoittain 30 minuutin kuluessa. Sitten sekoitetaan 90 minuutin ajan -78°C:ssa, sitten reaktio sammutetaan 200 ml:11a AcOH:ta -78°C:ssa. Tämä poistetaan jäähdytyshauteeseen, lisätään 500 ml H20:ta ja seos konsentroidaan tyhjössä 40 -50°C:ssa. Kellertävään lietteeseen lisätään 500 ml EtOAc:n ja heptaanin l:l-seosta ja sitten suodatetaan. Suodos pestään perusteellisesti 0,5 N HClrllä, sitten useita kertoja H20:lla ja lopuksi EtOAc/heptaanilla (3:1), joka oli jäähdytetty kuivajäällä -20°C:seen. Vaaleanruskea kiteinen tuote (esimerkki IA) kuivatetaan tyhjöuunissa 40°C:ssa.
Saanto on 194 g.
Tuote IA kiteytetään uudelleen EtOAc:stä -10°C:ssa, jolloin saadaan 100 g tuotetta IB ja sitten kiteytetään uudelleen asetoni/pentaanista, jolloin saadaan 90 g tuotetta 1C. Emäliuos yhdistetään raa'an aineen pesusta ja kiteytetään uudelleen EtOAc/heksaanista. Tuotteen IB (33 g) HPLC: R,S-isomeerin suhde S,S-isomeeriin 97,4:2,17. Tuotteen 1C (28,5 g) HPLC: 95,7:3,7. Yhdistetty IB ja 1C kiteytetään uudelleen CHCl3:n ja MeOH:n 10:1-seoksesta, jolloin saadaan tuote 1F, jonka saanto on 48,7 g valkoista kidettä.
I ·
Ensimmäisen vesipesun emäliuos kiteytetään (EtOAc/heptaa-ni), jolloin saadaan 21,4 g tuotetta ID: HPLC: 71,56:25,52.
; Tuotteiden IB ja 1C emäliuos yhdistetään ja kiteytetään uudelleen CHCl3:n, MeOH:n ja heptaanin seoksesta, jolloin saadaan 55,7 g tuotteen 1G valkoisia kiteitä.
ID kiteytetään uudelleen CHCl3/MeOH:sta, jolloin saadaan tuote 1H.
94339 11
Kaikki emäliuos yhdistetään, sitten konsentroidaan ja jäännös liuotetaan kuumaan CHCl3:n ja MeOH:n 10:l-seok-seen, laitetaan piihappogeelipylväälle ja eluoidaan EtOAc:n ja heksaanin 40:60-seoksella. Aine kiteytyy pylväällä ja piihappogeeli uutetaan CHCl3/MeOH:11a ja konsentroidaan. Jäännöksen uudelleenkiteytys CHCl3/heptaanis-ta (3:1) tuottaa 33,7 g tuotetta 11.
Tuotteen 11 emäliuos kiteytetään uudelleen, jolloin saadaan 18,7 g tuotetta 1K.
Tuotteen 1K emäliuos kiteytetään, jolloin saadaan 6,3 g tuotetta IL.
II, 1K, IL yhdistetään ja kiteytetään uudelleen CHCl3/hep-taanista, jolloin saadaan 48 g.
Tuotteiden li, 1K ja IL yhdistetty emäliuos konsentroidaan, jolloin saadaan 31 g tuotetta IM.
Tuote 1F omaa seuraavat arvot:
Analyysi: 1F, sp. 229 - 230°C: laskettu: C 77,84, H 6,02, N 3,56 saatu: C 77,14, H 6,45, N 3,13.
Nämä arvot ovat yhtäpitäviä kaavan 1 4 i 12 94339
F
p
Ph OH 1
Ph. 1 I Λ. .OH
Ίγ" >co2 X
Ν «Ph ^=5/ Ph
PhNHCO I
kanssa.
Esimerkki 2 162 g (0,206 M) esimerkin l yhdistettyjä tuotteita IF, 1G, 1H ja IL suspendoidaan 800 ml:aan metanolin ja THF:n 5:3-seosta. Jäähdytetään 0°C:seen ja lisätään 11,7 g:aan nat-riummetoksidia. Seosta sekoitetaan, kunnes kaikki on liuennut, sitten se laitetaan pakastimeen yön ajaksi.
Reaktioseoksen annetaan lämmetä huoneen lämpötilaan, reaktio sammutetaan 15 ml:11a HOAc:tä, sitten seos konsentroidaan tyhjössä 40eC:ssa, jolloin saadaan odotettu tuote seuraavasti:
F
O
| OH
.C02Me : 0 L** ^ v
PhNHC1^] Tämä tuote lisätään 500 ml:aan H20:ta ja uutetaan kahdesti EtOAc:llä (300 ml). Yhdistetyt uutteet pestään kylläste-... tyllä NaHC03:lla, suolaliuoksella, kuivatetaan vedettömän 94339 13 magnesiumsulfaatin päällä, suodatetaan ja liuotin haihdutetaan. Jäännös kromatografoidaan piihappogeelillä käyttämällä eluenttina EtOAcrn ja heptaanin l:4-seosta, jolloin saadaan 109 g väritöntä öljyä, joka kiteytetään uudelleen Et20/heptaanista, jolloin saadaan 73,9 g:n ensimmäinen erä valkoisia kiteitä ja 8,2 g:n toinen erä valkoisia kiteitä. Kiteet omaavat seuraavat arvot: sp. 125 - 126°C, [a]D20 = 4,23® (1,17 M, CH3OH).
Analyysi: laskettu: C 72,76, H 6,30, N 5,30 saatu: C 72,51, H 6,23, N 5,06.
Nämä arvot ovat yhtäpitäviä kaavan
F
O
I OH
Ph N C02Me
PhNHCO*I
kanssa.
Esimerkki 3 77 ml di-isopropyyliamiinia liuotetaan 250 ml:aan THF:ää 2000 ml:n kolmikaulaisessa pullossa, joka on varustettu ·♦ lämpömittarilla ja tiputussuppilolla. Reaktioseos pidetään typpiatmosfäärissä. Seos jäähdytetään -42°C:seen ja lisätään tipoittain 20 minuutin kuluessa 200 ml:aan 2,2 H n-butyylilitiumia (heksaanissa) ja sekoitetaan 20 minuutin ajan ja sitten lisätään tipoittain 62 ml t-butyyliasetaat-tia, joka on liuotettu 200 ml:aan THF:ää (n. 30 minuutin v kuluessa). Tätä seosta sekoitetaan 30 minuutin ajan i 14 94339 -40°C:ssa, sitten lisätään 140 ml 2,2 M n-butyylilitiumia 20 minuutin kuluessa. Lisäyksen päätyttyä 81 g esimerkin 2 tuotetta 500 ml:ssa THF:ää lisätään mahdollisimman nopeasti antamatta lämpötilan nousta yli -40°C:een. Sekoittamista jatketaan 4 tunnin ajan -70°C:ssa. Reaktio sammutetaan sitten 69 ml:11a jääetikkaa ja sitten seoksen annetaan lämmetä huoneen lämpötilaan. Seos konsentroidaan tyhjössä ja jäännös otetaan EtOAc:hen, pestään perusteellisesti vedellä, sitten kyllästetyllä NH4Cl:llä, NaHC03:lla (kyllästetty) ja lopuksi suolaliuoksella. Orgaaninen kerros kuivatetaan vedettömän MgS04:n päällä, suodatetaan ja liuotin haihdutetaan. Reaktion NMR on yhtäpitävä lähtöaineen + tuotteen n. yhtä suurina määrinä + TLC:n perusviivalla olevan pienen ainemäärän kanssa. TLC:n perusviivan aine erotetaan lähtöaineesta ja tuote uutetaan happo/emäs-uu-tolla. Orgaaninen faasi kuivatetaan ja konsentroidaan tyhjössä, jolloin saadaan 73 g tuotetta. NMR ja TLC ovat yhtäpitäviä kaavan
F
p I OH o 0
PhNHCO'^] kanssa.
Esimerkki 4 - · · 73 g esimerkin 3 raakatuotetta liuotetaan 500 ml:aan absoluuttista THF:ää ja sitten lisätään 120 ml trietyyliboraa-nia ja tämän jälkeen 0,7 g t-butyylikarboksyylihappoa.
Seosta sekoitetaan kuivassa atmosfäärissä 10 minuutin ... ajan, jäähdytetään -78°C: seen ja lisätään 70 ml metanolia 94339 15 ja sitten 4,5 g natriumboorihydridiä. Seosta sekoitetaan jälleen -78°C:ssa 6 tunnin ajan. Sitten se kaadetaan hitaasti jään, 30%:isen H202:n ja H20:n 4:1:1-seokseen. Tätä seosta sekoitetaan yön yli ja sitten sen annetaan lämmetä huoneen lämpötilaan.
CHCl3:a (400 ml) lisätään ja seos jaetaan. Vesikerros uutetaan jälleen CHCl3:lla. Orgaaniset uutteet yhdistetään ja pestään perusteellisesti H20:lla, kunnes ei voida havaita enää yhtään peroksidia. Orgaaninen kerros kuivatetaan MgS04:n päällä, suodatetaan ja liuotin haihdutetaan.
Jäännös käsitellään pikakromatografiällä (flash chromatography) piihappogeelillä käyttämällä eluenttina EtOAc:n ja heksaanin l:3-seosta, jolloin saadaan 51 g tuotetta.
Tuote liuotetaan THF:n ja MeOH:n seokseen ja lisätään 100 ml:aan NaOH:ta ja sitten sekoitetaan 4 tunnin ajan huoneen lämpötilassa. Liuos konsentroidaan huoneen lämpötilassa orgaanisen liuottimen poistamiseksi, lisätään 100 ml:aan H20:ta ja uutetaan Et02:lla kahdesti. Vesikerros tehdään happamaksi 1 N Helillä ja uutetaan EtOAc:llä 3 kertaa. Yhdistetyt orgaaniset kerrokset pestään H20:lla. Orgaaninen kerros kuivatetaan vedettömällä MgS04:llä, suodatetaan ja liuotin haihdutetaan. Jäännös otetaan 2 l:aan tolueenia ja kuumennetaan palautusjäähdyttäen käyttämällä Dean-Stark-loukkua 10 minuutin ajan.
Reaktioseoksen annetaan jäähtyä huoneen lämpötilaan yön :· aikana. Kuumennetaan uudelleen palautusjäähdyttäen 10 mi nuutin ajan ja sitten annetaan jäähtyä 24 tunnin kuluessa.
Yllä esitetty toimenpide toistetaan. Reaktioseos jätetään huoneen lämpötilaan seuraavien 10 päivän ajaksi, sitten se konsentroidaan, jolloin saadaan 51 g väritöntä vaahtoa.
16 94339 Tämä tuote liuotetaan minimimäärään CHCl3:a ja kromatogra-foidaan piihappogeelillä eluoimalla EtOAc:n ja heptaanin 50:50-seoksella, jolloin saadaan 23 g puhdasta ainetta.
Kromatografia piihappogeelillä CHCl3/2-propanolissa (98,5:1,5) tuottaa 13,2 g tuotetta.
Laskettu: C 73,31, H 6,15, N 5,18.
Esimerkki 5 2R-trans-5-(4-fluorifenyyli)-2-(l-metyylietyyli)-fi,4-di-f enyyli-l-[ 2 - (tetrahydr o-4 -hydroksi-6-okso-2H-pyran-2-yy-li)etyyli]-lH-pyrroli-3-karboksamidin valmistus
Esimerkin 4 tuote kiteytetään uudelleen EtOAc/heksaanista.
Fraktio 1 tuottaa 8,20 g yhdistettä 4A. Emäliuos tuottaa 4,60 g yhdistettä 4B. Yhdisteen 4B HPLC osoittaa tuotteen olevan 100%:isesti [R-(R*,R*)]-isomeeri. 4A kiteytetään uudelleen, jolloin saadaan 4,81 g yhdistettä 4C. 4B kroma-tografoidaan piihappogeelillä CHCl3/2-propanolissa, jolloin saadaan 4,18 g yhdisteen 4D väritöntä vaahtoa, jonka [a]D23 = 24,53° (0,53 % CHCl3:ssa). 4C kiteytetään uudelleen ja yhdisteen 4C emäliuos tuottaa 2,0 g. HPLC osoit- .·, taa, että se on 100%:isesti R-trans-isomeeri, 2R-trans- • « 5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroks i-6-okso-2H-pyran-2-yy1i)etyyli]-lH-pyrroli-3-karboksamidi.
Esimerkki 6 : Diastereomeeristen a-metyylibentsyyliamidien valmistus
Rasemaatin, trans-(±)-5-(4-fluorifenyyli)-2-(l-metyyli-etyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboksamidin (30 g, 55,5 ml), liuosta (R)-(+)-a-metyylibentsyyliamiinissa (575 ... ml, 4,45 moolia, 98 % Aldrich) sekoitetaan yön ajan huo neen lämpötilassa.
94339 17
Saatu liuos laimennetaan sitten eetterillä (2 1) ja pestään perusteellisesti 2 M Helillä (4 x 500 ml), vedellä (2 x 500 ml) ja suolaliuoksella (2 x 500 ml). Orgaaninen uute kuivatetaan sitten MgS04:n päällä, suodatetaan ja konsentroidaan tyhjössä, jolloin saadaan 28,2 g diastereomeerisiä a-metyylibentsyyliamideja valkoisena kiintoaineena, sp.
174,0 - 177°C. α-metyylibentsyyliamidit erotetaan liuottamalla 1,5 g seosta 1,5 ml:aan CHCl3:n, CH3OH:n ja NH4OH:n 98:1,9:0,1-seosta (1000 mg/ml) ja injektoimalla prepara-tiivisen HPLC-pylvään päälle (piihappogeeli, 300 mm x 41,4 mm I.D.) kaasunpitäväliä ruiskulla ja eluoimalla yllä esitetyllä liuotinseoksella. Fraktiot kerätään UV-monitoril-la. Diastereomeeri 1 eluoituu 41 minuutissa. Diastereomee-ri 2 eluoituu 49 minuutissa. Keskifraktiot kerätään. Tämä toimenpide toistetaan 3 kertaa ja samanlaiset fraktiot yhdistetään ja konsentroidaan. Jokaisen tutkiminen analyyttisellä HPLC:llä osoittaa, että diastereomeeri 1 on 99,84%:sesti puhdas ja diastereomeeri 2 on 96,53%:sesti puhdas. Kumpikin isomeeri otetaan erikseen seuraaviin esimerkkeihin.
Esimerkki 7 2R-trans-5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-dife-nyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)-etyyli)-ΙΗ-pyrro1i-3-karboksamid in valmistus
Esimerkin 6 diastereomeerin 1, [3R-[3R*(R*),5R*]]-2-(4-fluorifenyyli) -[0], [5]-dihydroksi-5- (1-metyylietyyli) -3-fenyyli-4-[(fenyyliamino)karbonyyli]-N-(1-fenyylietyyli)-lH-pyrroli-l-heptaaniamidin (hydroksikeskukset ovat molemmat R) (1 g, 1,5 mmoolia) etanoliseen liuokseen (50 M) lisätään 1 N NaOHita (3,0 ml, 3 mmoolia). Saatua liuosta kuumennetaan palautusjäähdyttäen 48 tunnin ajan.
Liuos jäähdytetään huoneen lämpötilaan ja konsentroidaan \ tyhjössä. Jäännös suspendoidaan uudelleen veteen ja teh- 18 94339 dään varovasti happamaksi 6 N HCl:llä. Saatu hapan liuos uutetaan etyyliasetaatilla. Orgaaninen uute pestään vedellä, suolaliuoksella, kuivatetaan MgS04:n päällä, suodatetaan ja konsentroidaan tyhjössä. Tämä jäännös liuotetaan uudelleen tolueeniin (100 ml) ja sitä kuumennetaan palautus jäähdyttäen 3 tunnin ajan poistamalla vesi atseotroop-pisesti. Tämä jäähdytetään huoneen lämpötilaan ja konsentroidaan tyhjössä, jolloin saadaan 1,2 g keltaista puoli-kiinteää ainetta. Pikakromatografia piihappogeelillä eluoimalla 40%:isella EtOAc/heksaanilla tuottaa 0,42 g valkoista kiintoainetta, joka sisältää edelleen epäpuhtauksia. Tämä kromatografoidaan uudelleen, jolloin saadaan 0,1 g olennaisesti puhdasta R,R-enantiomeeriä, 2R-trans- 5-(4-fluorifenyyli)-2-(1-metyylietyyli)-N,4-difenyyli-l-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboksamidia valkoisena vaahtona. HPLC osoittaa, että tämä aine on 94,6%:isesti kemiallisesti puhdasta, [a]D23: 0,51 % CHCl3:ssa = 25,5°. Piikki huoneen lämpötilassa = 53,46 minuuttia on kokeellisesti osoitettu tuntemattomaksi diastereomeeriksi, joka johtuu 2 %:sta (S)-(-)-α-metyylibentsyyliamiinia, joka on läsnä Aldrichin a-metyylibentsyyliamiinissa.
\ Esimerkki 8 2S-trans-5- (4-f luorif enyyli) -2- (1-metyylietyyli) -Ji, 4-dif e-nyyli-1-[2-(tetrahydro-4-hydroksi-6-okso-2H-pyran-2-yyli)-etyyli]-l|i-pyrroli-3-karboksamidin valmistus (esimerkissä 5 valmistetun yhdisteen S,S-enantiomeeri ;: Suoritettaessa esimerkissä 7 selitetty menetelmä diaste- reomeerillä 2 saadaan 0,6 g vaahtomaista kiintoainetta, joka pikakromatografoidaan piihappogeelillä. Eluointi 50%:isella EtOAc/heksaanilla tuottaa 0,46 g olennaisesti puhdasta S,S-enantiomeeriä, 2S-trans-5-(4-fluorifenyyli)-2 - (1 -metyy 1 ietyy li) -Ji, 4-dif enyy li-1-[ 2-(t etr ahydr o-4 -hyd-roksi-6-okso-2H-pyran-2-yyli)etyyli]-lH-pyrroli-3-karboks- tl 9 4339 19 amidia valkoisena vaahtona. HPLC osoittaa, että tämä aine on 97,83%:isesti kemiallisesti puhdasta. [a]D23 = 0,51 % CHCl3;ssa = -24,8°.
Esimerkki 9
Kaavan II mukaisen kemiallisen laktonin hydrolyysi
Huoneen lämpötilassa olevaan laktonin liuokseen THF:ssä lisätään natriumhydroksidin liuos vedessä. Seosta sekoitetaan 2 tunnin ajan. HPLC: 99,65 (tuote); 0,34 (lähtölak-toni). Seos laimennetaan 3 1:11a vettä, uutetaan etyyliasetaatilla (2x11) ja tehdään happamaksi pH-arvoon 4 lisäämällä 37 ml 5N kloorivetyhappoa. Vesipitoinen kerros uutetaan 2 x 1,5 l:n annoksilla etyyliasetaattia. Yhdistetyt etyyliasetaattiuutteet pestään 2x1 1:11a vettä, suolaliuosta ja kuivatetaan, jolloin saadaan etyyliasetaatti-liuoksen suodattamisen jälkeen vapaa happo. Tätä liuosta käytetään suoraan N-metyyliglukamiini-suolan fraktiossa.
Suolaliuos-vedestä saadut etyyliasetaattiuutteet konsentroidaan, jolloin saadaan 15,5 g kellertävää kiintoainetta.
Esimerkki 10
Kalsiumsuola natriumsuolasta ja/tai laktonista
Liuotetaan 1 mooli laktonia (540,6 g) 5 Iraan MeOH:ta ja liukenemisen jälkeen lisätään 1 1 H20:ta. Sekoittaen lisätään yksi ekvivalentti NaOH:ta ja seurataan HPLC:llä, kunnes jäljelle jää 2 % tai vähemmän laktonia ja diolihapon metyyliesteriä (ei voida käyttää NaOH:n ylimäärää, koska Ca(OH)2 muodostaa CaCl2:n addition). Lisätään NaOH:ta kaustisena (51,3 ml, 98 ekv.) tai pelletteinä (39,1 g, 0,98 ekv.).
Yllä oleva menetelmä voidaan osoittaa seuraavasti: 94 339 0 20 ‘
Ph p .90 eq. NaOH
0' ,NS -► H Ph MeOH, H20 5 : 1 m.w.= 540.6 g
OH OH O
EtOAc, heksaani /—v h?°— F~H@^ty<
Ph,c.
O .N, H Ph
Hydrolyysin päätyttyä lisätään 10 1 H20:ta ja sitten pestään vähintään 2 kertaa EtOAc:n ja heksaanin l:l-seoksel-la. Jokainen pesu sisältää 10 1 sekä EtOAc:tä että heksaa-nia. Jos natriumsuola on puhdas, lisätään 15 1 MeOH:ta.
Jos se on epäpuhdas ja/tai se sisältää väriä, lisätään 100 g G-60-hiiltä, sekoitetaan 2 tunnin ajan ja suodatetaan Supercelin läpi. Pestään 15 1:11a MeOH:ta. Suoritetaan paino/tilav.-%-määritys reaktioseoksessa HPLC:llä suolan tarkan määrän määrittämiseksi liuoksessa.
«
Liuotetaan 1 ekvivalentti tai pieni ylimäärä CaCl2*2H20:ta (73,5 g) 20 l:aan H20:ta. Kuumennetaan sekä reaktioseos että CaCl2-liuos 60°C:seen. Lisätään hitaasti sekoittaen voimakkaasti CaCl2-liuosta. Lisäyksen päätyttyä jäähdyte-: tään hitaasti 15°C:seen ja suodatetaan. Pestään suodatus- kakku 5 1:11a H20:ta. Kuivatetaan 50°C:ssa tyhjöuunissa.
Voidaan kiteyttää uudelleen liuottamalla 4 l:aan EtOAc:tä (50°C), suodattamalla Supercelin läpi, pesemällä 1 1:11a EtOAc:tä, sitten lisäämällä 3 1 heksaania 50°C:iseen . liuokseen.
94339 21
Yllä selitetty menetelmä voidaan esittää seuraavasti: oh oh o / \ JL JL Jk / OH OH O \ F~\0) C ) C 1/2 eq.CaCli ' 2H20 /f_/qV__/N\_/ ° ^
Ph °,C'K' H’° \ I
\ €KX* / ·.«.· S80.6 g \ / ' m.w.- 1155.4 g ' 2
Esimerkki 11
Kaavan I mukaisen vapaan hapon etyyliasetaattiliuoksen käsittely N-metyyliglukamiinilla
Kaavan I mukaisen vapaan hapon liuokseen (0,106 M) etyyliasetaatissa (3 1) lisätään voimakkaasti sekoittaen huoneen lämpötilassa liuos, jossa on N-metyyliglukamiinia (20,3 g, 0,106 M) veden ja asetonin l:l-seoksessa (120 ml, 120 ml). Sekoittamista jatketaan 16 tunnin ajan ja sitten samea liuos konsentroidaan tyhjössä (- 250 sp.). Lisätään to-lueenia (11) ja seos konsentroidaan valkoiseksi kiintoaineeksi (- 100 g). Kiintoaine liuotetaan 1670 ml:aan aseto-nia ja suodatetaan kolmikaulaiseen pulloon, joka on varustettu mekaanisella sekoittimella ja termostaatti-säätöi-sellä lämpömittarilla. Pullo ja suodatin pestään 115 ml:11a veden ja asetonin l:l-seosta ja kirkas liuos jäähdytetään hitaasti. Näin saadaan sakka, joka liuotetaan uu- : delleen kuumentamalla takaisin 65°C:seen. Lisätään edel- « leen 20 ml vettä ja pestään, jolloin saadaan kiteinen tuote, joka eristetään suodattamalla. Kiintoaineet pestään 1200 ml:lla CH3Cl:ää ja tyhjökuivatetaan 255°C:ssa, jolloin saadaan valkoinen kiintoaine. Tämän aineen analyysi osoittaa, että se sisältää 4 % amiinia samoin kuin 0,4 % “ jäämäasetonia ja 0,67 % vettä. Analyyttiset tulokset ovat seuraavat: 22 94339 sulamispiste: 105 - 155°C (hajaantuen) laskettu analyysi: C 63,73, H 6,95, N 5,57, F2 9,53 saatu analyysi: C 62,10, H 6,89, N 5,34, F2 C 61,92, H 7,02, N 5,38, F2 H20 = 0,47 % (KF) HPLC: MeOH, H20, THF (40, 550, 250)
Econosil: C18, 5 μ, 25 cm 256 nm: 1,0 ml/min.
6-81 min.: 98,76 %
Opt. ret.: [<x]*b = -10,33° (c = 1,00, MeOH) jäämäliuottimet: CH2CH = 0,26 % titraatiot: HC104 (0,1 N) = 203,8 %
BuNOH (0,1 N) = 98,5 %
Muita suoloja, jotka valmistetaan vastaavalla tavalla kuin esimerkeissä 10 ja 11, voivat olla kaliumsuola, hemimagne-siumsuola, hemisinkkisuola tai kaavan I mukaisen yhdisteen l-deoksi-2-(metyyliamino)-D-glusitolikompleksi.
I!
Claims (5)
1. Menetelmä farmaseuttisesti käyttökelpoisen [R-(R*,R*)]~ 2-(4-f luorifenyyli) -/3,5-dihydroksi-5- (1-me tyyli e tyyli) -3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyrroli-l-heptaa-nihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi, tunnettu siitä, että A, 1) käsitellään kaavan F [6) HO XX ro il \ o mukainen trans-rasemaatti kaavan + h2nXp*« /r : ( ch, R mukaisella yhdisteellä, yhdisteiden valmistamiseksi, joiden kaava on 94339 F ph^J^ OH OH o I N'^^'^^Rv'v^'''rvv^''^n Pb PhHN\^w *χΓ Il \ f OHj ° .x^ R + F Φ _. ] OH OH O ΡΗ^Α II phHN H^T » \ f C»3 O R 2. käsitellään yhdisteitä vahvalla emäksellä, 3. palautuskeitetään vaiheen 2 tuote, ja 4. käsitellään vaiheen 3 erotettua tuotetta jolloin saadaan [R-(R*,R*)]-2-(4-fluorifenyyli)-β,5-dihydroksi-5-(1-metyy-lietyyli)-3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyr-roli-l-heptaanihappo ja sen farmaseuttisesti hyväksyttävät suolat, tai B, 1) käsitellään kaavan • · II 94339 F 0} Ph O PhNHC'^'W •I I O I mukainen yhdiste kaavan (2) ..Mg1' ® O Ph \ P'Ph L Ph mukaisella yhdisteellä, minkä jälkeen käsitellään etikkaha-polla kaavan (3) F 0} OH O Ph fh^y***\ Τ’ Π JL· , Ph PhNHOC 1 mukaisen yhdisteen saamiseksi, 2. käsitellään vaiheen 1) kaavan (3) mukainen yhdiste pienellä ylimäärällä natriummetoksidia kaavan (4) 94339 F φ Ph i °H n'^^s^x^vv-^COjMc PhNHOC'''^5^/ (4) mukaisen yhdisteen saamiseksi, 3. käsitellään vaiheen 2 kaavan (4) mukainen yhdiste suurella ylimäärällä o- kaavan (5) F φ I OH o C02Bu' PhNHOC''^V (5) mukaisen yhdisteen valmistamiseksi, ja 4. käsitellään vaiheen 3 kaavan (5) mukainen yhdiste trietyyliboraanilla ja sen jälkeen natriumboorihydridillä metanolissa, minkä jälkeen lisätään vetyperoksidia jolloin : saadaan [R-(R1,R1) ]-2-(4-fluorifenyyli)-/3,5-dihydroksi-5- * · « (1-metyylietyyli)-3-fenyyli-4-[(fenyyliamino)-karbonyyli]-lH-pyrroli-l-heptaanihappo ja sen farmaseuttisesti hyväksyttävät suolat.
2. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-.· t u siitä, että valmistetaan yhdiste, joka on [R(R1,R1)]~ li 94339 2- (4-f luorifenyyli) -/3,5-dihydroksi-5- ((1-metyylietyyli) -3-fenyyli-4-[ (fenyyliamino)karbonyyli]-lH-pyrroli-l-heptaa-nihappo.
3. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen mononatriumsuola.
4. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen hemikalsiumsuola siten että heptaanihappo tai sen suola saatetaan reagoimaan kalsiurosuolan muodostavan aineen kanssa.
5. Patenttivaatimuksen 1 mukainen menetelmä, tunnet-t u siitä, että valmistetaan patenttivaatimuksen 2 mukaisen yhdisteen N-metyyliglukamiinisuola. 1 94339
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US38418789A | 1989-07-21 | 1989-07-21 | |
US38418789 | 1989-07-21 |
Publications (3)
Publication Number | Publication Date |
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FI903614A0 FI903614A0 (fi) | 1990-07-18 |
FI94339B true FI94339B (fi) | 1995-05-15 |
FI94339C FI94339C (fi) | 1995-08-25 |
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Application Number | Title | Priority Date | Filing Date |
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FI903614A FI94339C (fi) | 1989-07-21 | 1990-07-18 | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
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US (2) | US5273995A (fi) |
EP (2) | EP0409281B1 (fi) |
JP (6) | JP3506336B2 (fi) |
KR (1) | KR0167101B1 (fi) |
AT (2) | ATE270274T1 (fi) |
AU (1) | AU628198B2 (fi) |
CA (1) | CA2021546C (fi) |
CY (1) | CY2357B1 (fi) |
DE (3) | DE1061073T1 (fi) |
DK (2) | DK1061073T3 (fi) |
ES (2) | ES2167306T3 (fi) |
FI (1) | FI94339C (fi) |
GE (1) | GEP20043167B (fi) |
GR (1) | GR20010300002T1 (fi) |
IE (1) | IE902659A1 (fi) |
NO (1) | NO174709C (fi) |
NZ (1) | NZ234576A (fi) |
PT (1) | PT94778B (fi) |
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Families Citing this family (546)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU621874B2 (en) * | 1988-02-22 | 1992-03-26 | Warner-Lambert Company | Improved process for trans-6-(2-(substituted-pyrrol-1-yl) alkyl)pyran-2-one inhibitors of cholesterol synthesis |
US5003080A (en) * | 1988-02-22 | 1991-03-26 | Warner-Lambert Company | Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis |
FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
JP3528186B2 (ja) * | 1991-06-24 | 2004-05-17 | 日産化学工業株式会社 | 光学活性キノリンメバロン酸のジアステレオマー塩 |
JP2502605Y2 (ja) * | 1992-02-14 | 1996-06-26 | 株式会社大日パレット製作所 | 部品、素材類の取り出し装置 |
CA2150372C (en) * | 1993-01-19 | 2002-08-20 | Nancy L. Mills | Stable oral ci-981 formulation and process of preparing same |
US5298627A (en) * | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
US5385929A (en) * | 1994-05-04 | 1995-01-31 | Warner-Lambert Company | [(Hydroxyphenylamino) carbonyl] pyrroles |
US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
US6268392B1 (en) | 1994-09-13 | 2001-07-31 | G. D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors |
JP3210552B2 (ja) * | 1995-06-07 | 2001-09-17 | ダイワ精工株式会社 | 魚釣用両軸受型リ−ル |
RU2158607C2 (ru) * | 1995-07-03 | 2000-11-10 | Санкио Компани Лимитед | Лечение артериосклероза и ксантомы |
HRP960313B1 (en) * | 1995-07-17 | 2002-08-31 | Warner Lambert Co | Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1) |
HRP960312B1 (en) * | 1995-07-17 | 2001-10-31 | Warner Lambert Co | NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS /R-(R*, R*)/-2-(4-FLUOROPHENYL)-"beta", "delta"-DIHYDROXY-5-PHENYL-4-/(PHENYLAMINO)CARBONYL/-1H-PYRROLE -1-HEPTANOIC ACID CALCIUM SALT (2 : 1) |
EE03606B1 (et) * | 1995-07-17 | 2002-02-15 | Warner-Lambert Company | Kristalliline [R-(R*,R*)]-2-(4-fluorofenüül)-beeta, delta-dihüdroksü-5-(1-metüületüül)-3-fenüül-4-[(fenüülamino)karbonüül]-1H-pürrool-1-hept aanhappehemikaltsiumsool (atorvastatiin) |
CN1217656C (zh) * | 1995-11-02 | 2005-09-07 | 沃尼尔·朗伯公司 | 用于调节脂浓度的方法和药物组合物 |
US6087511A (en) * | 1996-07-16 | 2000-07-11 | Warner-Lambert Company | Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1) |
DE19714343A1 (de) | 1997-04-08 | 1998-10-15 | Bayer Ag | Chromatographische Enantiomerentrennung von Lactonen |
GT199800127A (es) * | 1997-08-29 | 2000-02-01 | Combinaciones terapeuticas. | |
GT199800126A (es) * | 1997-08-29 | 2000-01-29 | Terapia de combinacion. | |
US6177121B1 (en) | 1997-09-29 | 2001-01-23 | Purdue Research Foundation | Composition and method for producing low cholesterol eggs |
US6147109A (en) * | 1997-10-14 | 2000-11-14 | The General Hospital Corporation | Upregulation of Type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors |
US6083497A (en) | 1997-11-05 | 2000-07-04 | Geltex Pharmaceuticals, Inc. | Method for treating hypercholesterolemia with unsubstituted polydiallylamine polymers |
US20080275104A1 (en) * | 1997-11-25 | 2008-11-06 | Musc Foundation For Research Development | Methods of treating juvenile type 1 diabetes mellitus |
US20060141036A1 (en) * | 1997-12-12 | 2006-06-29 | Andrx Labs Llc | HMG-CoA reductase inhibitor extended release formulation |
ATE360608T1 (de) * | 1997-12-19 | 2007-05-15 | Pfizer Ireland Pharmaceuticals | Verfahren zur herstellung von 1,3-diolen |
US7223428B2 (en) * | 1998-01-09 | 2007-05-29 | Mars Incorporated | Method of embossing chocolate products |
US6180597B1 (en) | 1998-03-19 | 2001-01-30 | Brigham And Women's Hospital, Inc. | Upregulation of Type III endothelial cell nitric oxide synthase by rho GTPase function inhibitors |
US20030078211A1 (en) * | 1998-06-24 | 2003-04-24 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
EP1088333A4 (en) | 1998-06-24 | 2005-08-10 | Merck & Co Inc | METHOD AND COMPOSITIONS FOR CONNECTING OSTEOPROSIS |
US6423751B1 (en) | 1998-07-14 | 2002-07-23 | The Brigham And Women's Hospital, Inc. | Upregulation of type III endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization |
AU767154B2 (en) | 1998-11-20 | 2003-10-30 | Skyepharma Canada Inc. | Dispersible phospholipid stabilized microparticles |
SI20109A (sl) * | 1998-12-16 | 2000-06-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Stabilna farmacevtska formulacija |
PL348609A1 (en) | 1998-12-23 | 2002-06-03 | Searle Llc | Combinations of ileal bile acid transport inhibitors and bile acid sequestring agents for cardiovascular indications |
US6462091B1 (en) | 1998-12-23 | 2002-10-08 | G.D. Searle & Co. | Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications |
US6489366B1 (en) | 1998-12-23 | 2002-12-03 | G. D. Searle, Llc | Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications |
DK1140189T3 (da) | 1998-12-23 | 2003-09-15 | Searle Llc | Kombinationer af ileal galdesyre-transportinhibitorer og fibrinsyrederivater til cardiovaskulære indikationer |
EA005815B1 (ru) | 1998-12-23 | 2005-06-30 | Джи.Ди.Сирл Ллс | Комбинация ингибиторов транспорта желчных кислот в подвздошной кишке и ингибиторов белка, переносящего эфиры холестерина, для сердечно-сосудистых показаний |
ES2203239T3 (es) | 1998-12-23 | 2004-04-01 | G.D. Searle Llc | Combinaciones de inhibidores de la proteina de transferencia de ester de colesterilo y de agentes secuestrantes de acidos biliares para indicaciones cardiovasculares. |
CA2356157C (en) | 1998-12-23 | 2008-04-01 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications |
JP2002539108A (ja) * | 1999-03-08 | 2002-11-19 | メルク エンド カムパニー インコーポレーテッド | 結晶質水和ジヒドロキシオープンアシッドシンバスタチンカルシウム塩 |
US6569461B1 (en) * | 1999-03-08 | 2003-05-27 | Merck & Co., Inc. | Dihydroxy open-acid and salts of HMG-CoA reductase inhibitors |
IN191236B (fi) * | 1999-05-25 | 2003-10-11 | Ranbaxy Lab Ltd | |
HN2000000050A (es) | 1999-05-27 | 2001-02-02 | Pfizer Prod Inc | Sal mutua de amlodipino y atorvastatina |
JP2003500487A (ja) | 1999-05-27 | 2003-01-07 | ファイザー・プロダクツ・インク | アムロジピンおよびアトルバスタチンの共通プロドラッグ |
SE9903028D0 (sv) * | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
KR20020040795A (ko) * | 1999-08-30 | 2002-05-30 | 로버트 흐라이탁, 미쉘 베스트 | 심혈관 사고 예방용 레닌-안지오텐신 시스템 억제제의 용도 |
US6646133B1 (en) | 2000-10-17 | 2003-11-11 | Egis Gyogyszergyar Rt. | Process for the preparation of amorphous atorvastatin calcium |
US20040063969A1 (en) * | 1999-10-18 | 2004-04-01 | Egis Gyogyszergyar Rt. | Process for the preparation of amorphous atorvastatin calcium |
HU226640B1 (en) * | 1999-10-18 | 2009-05-28 | Egis Gyogyszergyar Nyilvanosan | Process for producing amorphous atorvastatin calcium salt |
US20020107173A1 (en) * | 1999-11-04 | 2002-08-08 | Lawrence Friedhoff | Method of treating amyloid beta precursor disorders |
AU780624B2 (en) * | 1999-11-04 | 2005-04-07 | Andrx Corporation | Method of treating amyloid beta precursor disorders |
EP2206497A1 (en) * | 1999-11-17 | 2010-07-14 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
US7411075B1 (en) | 2000-11-16 | 2008-08-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
SI20425A (sl) | 1999-12-10 | 2001-06-30 | LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. | Priprava amorfnega atorvastatina |
CA2391357C (en) * | 1999-12-17 | 2009-01-06 | Warner Lambert Research And Development Ireland Limited | A process for producing crystalline atorvastatin calcium |
DE60024133T2 (de) | 1999-12-17 | 2006-08-03 | Pfizer Science And Technology Ireland Ltd., Dun Laoghaire | Herstellungsverfahren auf industrieller basis von atorvastatin trihydrat hemi-kalziumsalz in kristalliner form |
ES2328446T5 (es) | 2000-02-04 | 2014-02-27 | Children's Hospital Research Foundation | Uso de lipasa ácida lisosomal para tratar la aterosclerosis y enfermedades asociadas |
US20040092574A1 (en) * | 2000-02-07 | 2004-05-13 | Bisgaier Charles Larry | Statin-Lp(a) inhibitor combinations |
EP1275388A4 (en) * | 2000-02-10 | 2003-11-26 | Takeda Chemical Industries Ltd | TNF ALPHA INHIBITORS |
GB0003305D0 (en) | 2000-02-15 | 2000-04-05 | Zeneca Ltd | Pyrimidine derivatives |
AU2001240115A1 (en) | 2000-03-10 | 2001-09-24 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
USRE44578E1 (en) | 2000-04-10 | 2013-11-05 | Teva Pharmaceutical Industries, Ltd. | Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids |
CA2406574C (en) | 2000-04-10 | 2006-12-05 | Teva Pharmaceutical Industries, Ltd. | Stable pharmaceutical compositions containing 7-substituted-3,5-dihydroxyheptanoic acids or 7-substituted-3,5-dihydroxyheptenoic acids |
US8586094B2 (en) | 2000-09-20 | 2013-11-19 | Jagotec Ag | Coated tablets |
US6534540B2 (en) | 2000-10-06 | 2003-03-18 | George Kindness | Combination and method of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor |
US20030162829A1 (en) * | 2000-10-06 | 2003-08-28 | George Kindness | Combination of treatment of cancer utilizing a COX-2 inhibitor and a 3-hydroxy-3-methylglutaryl-coenzyme-a (HMG-CoA) reductase inhibitor |
CA2424060A1 (en) * | 2000-10-12 | 2003-03-31 | Nissan Chemical Industries, Ltd. | Preventives and remedies for complications of diabetes |
CA2426632C (en) | 2000-11-03 | 2008-08-05 | Teva Pharmaceutical Industries, Ltd. | Atorvastatin hemi-calcium form vii |
US6737430B2 (en) | 2000-11-09 | 2004-05-18 | Pfizer, Inc. | Mutual prodrug of amlodipine and atorvastatin |
GB0027410D0 (en) * | 2000-11-09 | 2000-12-27 | Pfizer Ltd | Mutual prodrug of amlodipine and atorvastatin |
CA2427255A1 (en) * | 2000-11-16 | 2002-06-06 | Teva Pharmaceutical Industries Ltd. | Hydrolysis of [r(r*,r*)]-2-(4-fluorophenyl)-.beta.,.delta. -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid esters with calcium hydroxide |
US7501450B2 (en) * | 2000-11-30 | 2009-03-10 | Teva Pharaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
IL156055A0 (en) * | 2000-11-30 | 2003-12-23 | Teva Pharma | Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms |
LT5196B (lt) | 2000-11-30 | 2005-02-25 | Teva Pharmaceutical Industries Ltd. | Naujos atorvastatino pusiau kalcio kristalinės formos ir jų gavimo būdai, taip pat ir nauji kitų formų gavimo būdai |
CA2626317A1 (en) * | 2000-12-27 | 2002-07-04 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of atorvastatin |
US6476235B2 (en) * | 2001-01-09 | 2002-11-05 | Warner-Lambert Company | Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide |
EP1734034A3 (en) | 2001-01-09 | 2007-01-03 | Warner-Lambert Company LLC | Carboxylic acid salts of beta-alanine esters or -amides |
WO2002057229A1 (en) | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
SI20814A (sl) * | 2001-01-23 | 2002-08-31 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Priprava amorfnega atorvastatina |
SI20848A (sl) * | 2001-03-14 | 2002-10-31 | Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. | Farmacevtska formulacija, ki vsebuje atorvastatin kalcij |
US6645946B1 (en) | 2001-03-27 | 2003-11-11 | Pro-Pharmaceuticals, Inc. | Delivery of a therapeutic agent in a formulation for reduced toxicity |
ES2258141T3 (es) | 2001-04-11 | 2006-08-16 | Bristol-Myers Squibb Company | Complejos de aminoacidos de glucosidos c-arilo para el tratamiento de la diabetes y procedimiento. |
IN190564B (fi) * | 2001-04-11 | 2003-08-09 | Cadila Heathcare Ltd | |
CN1509180A (zh) * | 2001-04-18 | 2004-06-30 | ԭ���ø� | 用脂肪族聚胺治疗综合症x的方法 |
RS100003A (en) | 2001-06-29 | 2007-02-05 | Warner-Lambert Company, | Crystalline forms of /r-(r*,r*)-2-(4- fluorphenyl)-beta,delta -dihydroxy-5(1- methylethyl)-phenyl-4-/phenylamino) carbonyl/-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
JP2004533482A (ja) * | 2001-07-06 | 2004-11-04 | テバ ファーマシューティカル インダストリーズ リミティド | 6−シアノ−syn−3,5−ジヒドロキシ・ヘキサン酸誘導体による7−アミノ−syn−3,5−ジヒドロキシ・ヘプタン酸誘導体の製法 |
US20040092565A1 (en) * | 2001-07-25 | 2004-05-13 | George Kindness | Composition and method of sustaining chemotherapeutic effect while reducing dose of chemotherapeutic agent using cox-2 inhibitor and statin |
US7074818B2 (en) * | 2001-07-30 | 2006-07-11 | Dr. Reddy's Laboratories Limited | Crystalline forms VI and VII of Atorvastatin calcium |
PE20030324A1 (es) * | 2001-07-31 | 2003-04-03 | Warner Lambert Co | Composiciones farmaceuticas de amlodipina y atorvastatina |
KR20040026705A (ko) * | 2001-08-16 | 2004-03-31 | 테바 파마슈티컬 인더스트리즈 리미티드 | 스타틴의 칼슘 염 형태의 제조 방법 |
WO2005033078A1 (en) * | 2003-10-07 | 2005-04-14 | Biocon Limited | Process for the production of atorvastatin calcium |
KR20010099097A (ko) * | 2001-08-29 | 2001-11-09 | 강태구 | 베개와 베개용 높이조절패드의 제조방법. |
CA2456095C (en) * | 2001-08-31 | 2010-05-11 | Morepen Laboratories Ltd. | An improved process for the preparation of amorphous atorvastatin calcium salt (2:1) |
GB0121436D0 (en) * | 2001-09-04 | 2001-10-24 | Pfizer Ltd | Biomodulated multiparticulate formulations |
JP2005532982A (ja) * | 2001-09-24 | 2005-11-04 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | 肥満の処置のためのピロール誘導体の製造及び使用 |
US6924311B2 (en) | 2001-10-17 | 2005-08-02 | X-Ceptor Therapeutics, Inc. | Methods for affecting various diseases utilizing LXR compounds |
YU31004A (sh) * | 2001-10-18 | 2006-08-17 | Bristol-Myers Squibb Company | Mimetici humanog glukagonu sličnog peptida-1 i njihova upotreba u lečenju dijabetesa i srodnih stanja |
US7238671B2 (en) * | 2001-10-18 | 2007-07-03 | Bristol-Myers Squibb Company | Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions |
US6806381B2 (en) * | 2001-11-02 | 2004-10-19 | Bristol-Myers Squibb Company | Process for the preparation of aniline-derived thyroid receptor ligands |
CA2464685A1 (en) | 2001-11-02 | 2003-05-15 | G.D. Searle Llc | Novel mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (asbt) and taurocholate uptake |
AU2002348276A1 (en) * | 2001-11-16 | 2003-06-10 | Bristol-Myers Squibb Company | Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein |
CA2412012C (en) * | 2001-11-20 | 2011-08-02 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage |
US20060020137A1 (en) * | 2001-11-29 | 2006-01-26 | Limor Tessler | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
US6831102B2 (en) * | 2001-12-07 | 2004-12-14 | Bristol-Myers Squibb Company | Phenyl naphthol ligands for thyroid hormone receptor |
UA77990C2 (en) * | 2001-12-12 | 2007-02-15 | Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid | |
US7482366B2 (en) | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
ES2421511T3 (es) | 2001-12-21 | 2013-09-03 | X Ceptor Therapeutics Inc | Moduladores de LXR |
US6696473B2 (en) * | 2001-12-21 | 2004-02-24 | X-Ceptor Therapeutics, Inc. | Heterocyclic modulators of nuclear receptors |
MXPA04006255A (es) | 2002-01-17 | 2004-09-27 | Pharmacia Corp | Compuestos novedosos de alquil/aril hidroxi o ceto tiepina como inhibidores del transporte del acido biliar codependiente del sodio apical y la captacion de taurocolato. |
CZ296967B6 (cs) * | 2002-02-01 | 2006-08-16 | Zentiva, A.S. | Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) |
US7122681B2 (en) * | 2002-02-19 | 2006-10-17 | Teva Pharmaceutical Industries, Ltd. | Desolvation process for the production of atorvastatin hemi-calcium essentially free of bound organic solvent |
GB0204129D0 (en) * | 2002-02-21 | 2002-04-10 | Novartis Ag | Process for the manufacture of organic compounds |
EP2316468A1 (en) | 2002-02-22 | 2011-05-04 | Shire LLC | Delivery system and methods for protecting and administering dextroamphetamine |
KR100379075B1 (en) * | 2002-03-07 | 2003-04-08 | Jinis Biopharmaceuticals Co | Method for producing low cholesterol animal food product and food product therefrom |
EP1485343B1 (en) * | 2002-03-18 | 2009-12-23 | Biocon Limited | Amorphous hmg-coa reductase inhibitors of desired particle size |
DE10212492B4 (de) * | 2002-03-21 | 2012-02-02 | Daimler Ag | Kolbenpumpe |
EP1496982A4 (en) * | 2002-04-16 | 2006-07-19 | Merck & Co Inc | SOLID FORMS OF SALTS WITH TYROSINE KINASE EFFECT |
ITMI20020907A1 (it) * | 2002-04-29 | 2003-10-29 | Chemi Spa | Processo di preparazione della forma amorfa del sale di calcio della atorvastatina |
AU2003225305A1 (en) | 2002-05-08 | 2003-11-11 | Bristol-Myers Squibb Company | Pyridine-based thyroid receptor ligands |
WO2003094856A2 (en) | 2002-05-09 | 2003-11-20 | The Brigham And Women's Hospital, Inc. | 1l1rl-1 as a cardiovascular disease marker and therapeutic target |
CN100471047C (zh) * | 2002-05-14 | 2009-03-18 | 西门子公司 | 用于产生发射信号的方法 |
US7057046B2 (en) * | 2002-05-20 | 2006-06-06 | Bristol-Myers Squibb Company | Lactam glycogen phosphorylase inhibitors and method of use |
DE60323835D1 (de) * | 2002-06-13 | 2008-11-13 | Novartis Ag | Calciumsalze von statinen aus indol |
US7078430B2 (en) * | 2002-07-08 | 2006-07-18 | Ranbaxy Laboratories Limited | HMG CoA-reductase inhibitors |
US20060211761A1 (en) * | 2002-07-08 | 2006-09-21 | Yatendra Kumar | Hmg-coa-reductase inhibitors |
US20050182106A1 (en) * | 2002-07-11 | 2005-08-18 | Sankyo Company, Limited | Medicinal composition for mitigating blood lipid or lowering blood homocysteine |
WO2004009093A1 (de) * | 2002-07-23 | 2004-01-29 | Nutrinova Nutrition Specialties & Food Ingredients Gmbh | Cholesterinsenkendes mittel aus ballaststoffen und cholesterinsenkenden stoffen |
WO2004014896A1 (en) * | 2002-08-06 | 2004-02-19 | Warner-Lambert Company Llc | Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy -6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide |
US7407955B2 (en) * | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
AU2002330735A1 (en) * | 2002-09-03 | 2004-03-29 | Morepen Laboratories Limited | Atorvastatin calcium form vi or hydrates thereof |
US20040132728A1 (en) * | 2002-09-17 | 2004-07-08 | Pfizer Inc | Combinations of atorvastatin and alpha1adrenergic receptor antagonists |
US20080293750A1 (en) * | 2002-10-17 | 2008-11-27 | Anna Helgadottir | Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment |
US20060019269A1 (en) * | 2002-10-17 | 2006-01-26 | Decode Genetics, Inc. | Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment |
US6995180B2 (en) * | 2002-10-23 | 2006-02-07 | Bristol Myers Squibb Company | Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods |
CA2503284A1 (en) * | 2002-10-24 | 2004-05-06 | Enos Pharmaceuticals, Inc. | Sustained release l-arginine formulations and methods of manufacture and use |
US7098235B2 (en) | 2002-11-14 | 2006-08-29 | Bristol-Myers Squibb Co. | Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds |
US20040102511A1 (en) * | 2002-11-21 | 2004-05-27 | Jitendra Sattigeri | Substituted pyrrole derivatives |
EP1424324A1 (en) * | 2002-11-28 | 2004-06-02 | Teva Pharmaceutical Industries Limited | Crystalline form F of Atorvastatin hemi-calcium salt |
US20040110241A1 (en) * | 2002-12-06 | 2004-06-10 | Segal Mark S. | Materials and methods for monitoring vascular endothelial function |
EP1585500B8 (en) | 2002-12-20 | 2017-07-26 | Auritec Pharmaceuticals | Coated particles for sustained-release pharmaceutical administration |
BR0317521A (pt) | 2002-12-20 | 2005-11-16 | Pfizer Prod Inc | Formas de dosagem compreendendo um inibidor da cetp e um inibidor da redutase hmg-coa |
US20040132771A1 (en) * | 2002-12-20 | 2004-07-08 | Pfizer Inc | Compositions of choleseteryl ester transfer protein inhibitors and HMG-CoA reductase inhibitors |
DE10261067A1 (de) * | 2002-12-24 | 2004-08-05 | Nutrinova Nutrition Specialties & Food Ingredients Gmbh | Cholesterinsenkendes Mittel, enthaltend eine n-3-Fettsäure |
DE10261061A1 (de) * | 2002-12-24 | 2004-07-15 | Nutrinova Nutrition Specialties & Food Ingredients Gmbh | Diätetisches Lebensmittel zur positiven Beeinflussung der kardiovaskulären Gesundheit |
EP1587783A4 (en) * | 2003-01-24 | 2006-11-08 | Bristol Myers Squibb Co | CYCLOALKYL-CONTAINING ANILID LIGANDS FOR THE THYROID RECEPTOR |
TW200504021A (en) * | 2003-01-24 | 2005-02-01 | Bristol Myers Squibb Co | Substituted anilide ligands for the thyroid receptor |
PT1603553E (pt) * | 2003-03-17 | 2012-02-03 | Japan Tobacco Inc | Composições farmacêuticas de inibidores de cetp |
BRPI0408442A (pt) * | 2003-03-17 | 2006-04-04 | Japan Tobacco Inc | método para aumento da biodisponibilidade oral de s-[2-([[1-(2-etilbutil)ciclohexil]carbonil]amino)fenil]2- metilpropanotioato |
WO2004091626A1 (en) * | 2003-04-07 | 2004-10-28 | Osteoscreen, Inc. | Bone growth stimulation with no/statin and other no modulating combinations |
JP2006523670A (ja) * | 2003-04-14 | 2006-10-19 | ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー | 5−(4−フルオロフェニル)−1−[2−((2r,4r)−4−ヒドロキシ−6−オキソ−テトラヒドロ−ピラン−2−イル)エチル]−2−イソプロピル−4−フェニル−1h−ピロール−3−カルボン酸フェニルアミドの調製方法 |
AU2003901812A0 (en) * | 2003-04-15 | 2003-05-01 | Vital Health Sciences Pty Ltd | Phosphates of secondary alcohols |
US7557143B2 (en) | 2003-04-18 | 2009-07-07 | Bristol-Myers Squibb Company | Thyroid receptor ligands |
US9345671B2 (en) * | 2003-04-28 | 2016-05-24 | Daiichi Sankyo Company, Limited | Adiponectin production enhancer |
CA2524175C (en) * | 2003-04-28 | 2016-06-14 | Sankyo Company Limited | Sugar intake-ability enhancer |
TWI494102B (zh) * | 2003-05-02 | 2015-08-01 | Japan Tobacco Inc | 包含s-〔2(〔〔1-(2-乙基丁基)環己基〕羰基〕胺基)苯基〕2-甲基丙烷硫酯及hmg輔酶a還原酶抑制劑之組合 |
AR041089A1 (es) | 2003-05-15 | 2005-05-04 | Merck & Co Inc | Procedimiento y composiciones farmaceutiicas para tratar aterosclerosis, dislipidemias y afecciones relacionadas |
AU2004247627A1 (en) * | 2003-05-16 | 2004-12-23 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
US20040248972A1 (en) * | 2003-05-16 | 2004-12-09 | Ambit Biosciences Corporation | Compounds and uses thereof |
US20050182125A1 (en) * | 2003-05-16 | 2005-08-18 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
CA2527731A1 (en) * | 2003-05-30 | 2004-12-09 | Ranbaxy Laboratories Limited | Substituted pyrrole derivatives as hmg-coa reductase inhibitors |
EA009646B1 (ru) | 2003-05-30 | 2008-02-28 | Рэнбакси Лабораториз Лтд. | Замещённые производные пиррола и их применение в качестве ингибиторов hmg-coa |
US20040242670A1 (en) * | 2003-06-02 | 2004-12-02 | Sonny Sebastian | Process for preparation of amorphous atorvastatin calcium |
US7790197B2 (en) * | 2003-06-09 | 2010-09-07 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
US7459474B2 (en) * | 2003-06-11 | 2008-12-02 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
US20050271717A1 (en) | 2003-06-12 | 2005-12-08 | Alfred Berchielli | Pharmaceutical compositions of atorvastatin |
US7655692B2 (en) * | 2003-06-12 | 2010-02-02 | Pfizer Inc. | Process for forming amorphous atorvastatin |
US20040253305A1 (en) * | 2003-06-12 | 2004-12-16 | Luner Paul E. | Pharmaceutical compositions of atorvastatin |
EP1643969A2 (en) * | 2003-07-11 | 2006-04-12 | Pro-Pharmaceuticals, Inc. | Compositions and methods for hydrophobic drug delivery |
CA2530163C (en) | 2003-07-25 | 2012-10-02 | Avecia Pharmaceuticals Limited | Process and intermediate compounds useful in the preparation of statins, particularly atorvastatin |
US6995183B2 (en) * | 2003-08-01 | 2006-02-07 | Bristol Myers Squibb Company | Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods |
WO2005014541A1 (en) * | 2003-08-12 | 2005-02-17 | Biocon Limited | Novel antihypercholesterolemic compound |
CA2535359A1 (en) | 2003-08-21 | 2005-03-03 | Merck Frosst Canada Ltd. | Cathepsin cysteine protease inhibitors |
EP1510208A1 (en) * | 2003-08-22 | 2005-03-02 | Fournier Laboratories Ireland Limited | Pharmaceutical composition comprising a combination of metformin and statin |
US20050053664A1 (en) * | 2003-09-08 | 2005-03-10 | Eliezer Zomer | Co-administration of a polysaccharide with a chemotherapeutic agent for the treatment of cancer |
RU2315755C2 (ru) * | 2003-09-17 | 2008-01-27 | Уорнер-Ламберт Компани Ллс | Кристаллические формы [r-(r*,r*)]-2-(4-фторфенил)-бета, дельта-дигидрокси-5-(1-метилэтил)-3-фенил-4-[(фениламино)карбонил]-1н-пиррол-1-гептановой кислоты |
US20050171207A1 (en) * | 2003-09-26 | 2005-08-04 | Myriad Genetics, Incorporated | Method and composition for combination treatment of neurodegenerative disorders |
EP1675619A4 (en) * | 2003-09-29 | 2010-10-06 | Palmetto Pharmaceuticals Llc | EXTENDED RELEASE ARGININE FORMULATIONS, METHODS OF MAKING, AND USES |
WO2005042483A1 (en) * | 2003-11-03 | 2005-05-12 | Biocon Limited | [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl]- 1h-pyrrole-1-heptanoic acid iron salt |
CA2543596A1 (en) * | 2003-11-07 | 2005-05-26 | Jj Pharma, Inc. | Hdl-boosting combination therapy complexes |
US7317109B2 (en) * | 2003-11-12 | 2008-01-08 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
US7767828B2 (en) * | 2003-11-12 | 2010-08-03 | Phenomix Corporation | Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
ES2524916T3 (es) * | 2003-11-12 | 2014-12-15 | Sino-Med International Alliance, Inc. | Compuestos heterocíclicos de ácido borónico |
US7576121B2 (en) * | 2003-11-12 | 2009-08-18 | Phenomix Corporation | Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
WO2005051298A2 (en) | 2003-11-19 | 2005-06-09 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
US8415364B2 (en) * | 2003-11-26 | 2013-04-09 | Duke University | Method of preventing or treating glaucoma |
MXPA06005915A (es) * | 2003-12-05 | 2006-06-27 | Warner Lambert Co | N-alquil pirroles como inhibidores de la hmg-coa reductasa. |
CN1913892A (zh) * | 2003-12-17 | 2007-02-14 | 大日本住友制药株式会社 | 药物组合物及联合药物 |
CA2550373C (en) | 2003-12-23 | 2012-01-31 | Merck & Co., Inc. | Anti-hypercholesterolemic compounds |
US20070161700A1 (en) * | 2004-12-28 | 2007-07-12 | Kowa Company, Ltd. | Inhibitor for the formation of y-secretase complex |
CA2456430A1 (en) * | 2004-01-28 | 2005-07-28 | Brantford Chemicals Inc. | Improved process for the preparation of amorphous atorvastatin calcium |
WO2005073187A1 (en) * | 2004-01-28 | 2005-08-11 | Apotex Pharmachem Inc. | Improved process for the preparation of amorphous atorvastatin calcium |
US20100216863A1 (en) * | 2004-01-30 | 2010-08-26 | Decode Genetics Ehf. | Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment |
US8158362B2 (en) * | 2005-03-30 | 2012-04-17 | Decode Genetics Ehf. | Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype |
EP1563837A1 (en) * | 2004-02-03 | 2005-08-17 | Ferrer Internacional, S.A. | Hypocholesterolemic compositions comprising a statin and an antiflatulent agent |
WO2005079314A2 (en) * | 2004-02-13 | 2005-09-01 | Pro-Pharmaceuticals, Inc. | Compositions and methods used to treat acne and candida |
US7501426B2 (en) * | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
EP1719525B1 (en) * | 2004-02-25 | 2014-12-10 | Kowa Company, Ltd. | Nuclear transfer promoter for cdc42 protein and method of screening the same |
US8309574B2 (en) * | 2004-02-25 | 2012-11-13 | Kowa Company, Ltd. | Nuclear transfer promoter for Rac protein and method of screening the same |
US7262318B2 (en) * | 2004-03-10 | 2007-08-28 | Pfizer, Inc. | Substituted heteroaryl- and phenylsulfamoyl compounds |
CA2460935C (en) * | 2004-03-15 | 2010-05-18 | Brantford Chemicals Inc. | An improved preparation of atorvastatin |
US20060211752A1 (en) | 2004-03-16 | 2006-09-21 | Kohn Leonard D | Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression |
PT1727795E (pt) | 2004-03-17 | 2012-04-11 | Ranbaxy Lab Ltd | Processo para a produção de atorvastatina cálcica na forma amorfa |
ATE414071T1 (de) * | 2004-03-30 | 2008-11-15 | Lupin Ltd | Verbessertes verfahren zur herstellung von 4- hydroxypyran-2-onderivaten |
SI21745A (sl) * | 2004-04-09 | 2005-10-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Polimorfi derivata 1-pirol-1-heptanojske kisline, intermediata za pripravo atorvastatina |
KR100829268B1 (ko) * | 2004-04-16 | 2008-05-13 | 화이자 프로덕츠 인코포레이티드 | 비정질 아토바스타틴 칼슘의 제조 방법 |
JP2007532653A (ja) * | 2004-04-16 | 2007-11-15 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | 新規なイミダゾール類 |
RU2387445C2 (ru) * | 2004-05-03 | 2010-04-27 | ОМЕГА БИО-ФАРМА (Ай.Пи. 3) ЛИМИТЕД | Материалы и способы модуляции метаболизма |
JP2007536373A (ja) * | 2004-05-05 | 2007-12-13 | ファイザー・プロダクツ・インク | アトルバスタチンの塩形態 |
MXPA06013672A (es) * | 2004-05-24 | 2007-02-13 | Warner Lambert Co | Formas salinas del acido [r-(r*, r*)]-2-(4- fluorofenil)-??, d-dihidroxi-5 -(1-metiletil)-3- fenil-4 -[(fenilamino)carbonil] -1h-pirrol -1-heptanoico._. |
AU2005247195A1 (en) * | 2004-05-27 | 2005-12-08 | Dexcel Pharma Technologies Ltd | Localized controlled absorption of statins in the gastrointestinal tract for achieving high blood levels of statins |
UA87854C2 (en) | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
US20050288340A1 (en) * | 2004-06-29 | 2005-12-29 | Pfizer Inc | Substituted heteroaryl- and phenylsulfamoyl compounds |
TW200611704A (en) * | 2004-07-02 | 2006-04-16 | Bristol Myers Squibb Co | Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions |
US7534763B2 (en) | 2004-07-02 | 2009-05-19 | Bristol-Myers Squibb Company | Sustained release GLP-1 receptor modulators |
US7145040B2 (en) * | 2004-07-02 | 2006-12-05 | Bristol-Myers Squibb Co. | Process for the preparation of amino acids useful in the preparation of peptide receptor modulators |
WO2006017292A1 (en) * | 2004-07-12 | 2006-02-16 | Phenomix Corporation | Constrained cyano compounds |
US7572805B2 (en) | 2004-07-14 | 2009-08-11 | Bristol-Myers Squibb Company | Pyrrolo(oxo)isoquinolines as 5HT ligands |
RU2412191C2 (ru) * | 2004-07-16 | 2011-02-20 | Лек Фармасьютиклз Д.Д. | Продукты окислительной деструкции кальций аторвастатина |
MX2007000765A (es) | 2004-07-20 | 2007-03-28 | Warner Lambert Co | Formas cristalinas de sal de calcio del acido (r-(r*, r*))-2- (4-fluorofenil)- beta,gama- dihidroxi-5- (1-metiletil)-3 -fenil-4-((fenilamino) (carbonil)-1ih -pirrol-1- heptanoico (2:1). |
US20110217412A1 (en) * | 2004-07-30 | 2011-09-08 | Jinis Biopharmaceuticals Co. | Cholesterol lowering supplement and low cholesterol egg produced by using the same |
KR100637762B1 (ko) * | 2004-07-30 | 2006-10-23 | 주식회사 지니스 | 저콜레스테롤 란을 생산하기 위한 가금류용 사료첨가제 및 이를 이용한 저콜레스테롤 란의 생산방법 |
US20080286251A1 (en) * | 2004-08-02 | 2008-11-20 | Propharmaceuticals, Inc. | Compositions and Methods for the Enhancement of Chemotherapy with Microbial Cytotoxins |
US20090042979A1 (en) * | 2004-08-06 | 2009-02-12 | Transform Pharmaceuticals Inc. | Novel Statin Pharmaceutical Compositions and Related Methods of Treatment |
MX2007001558A (es) * | 2004-08-06 | 2008-03-13 | Transform Pharmaceuticals Inc | Formulaciones novedosas de fenofibrato y metodos de tratamiento relacionados. |
EP1786414A4 (en) * | 2004-08-06 | 2008-04-09 | Transform Pharmaceuticals Inc | NEW PHARMACEUTICAL STATIN COMPOSITIONS AND RELEVANT TREATMENT PROCEDURES |
WO2006026273A2 (en) * | 2004-08-25 | 2006-03-09 | Merck & Co., Inc. | Method of treating atherosclerosis, dyslipidemias and related conditions |
CA2578721A1 (en) * | 2004-08-26 | 2006-03-02 | Biocon Limited | Process for preparation of 4-fluoro-.alpha.-[2-methyl-1-oxopropyl].gamma.-oxo-n-.beta.-diphenylbenzene butane amide |
CA2578722C (en) | 2004-08-27 | 2010-02-02 | Biocon Limited | Process for atorvastatin calcium amorphous |
US20080033032A1 (en) * | 2004-08-27 | 2008-02-07 | Sandoz A/S | Novel Polymorphs Of The Potassium Salt Of Atorvastatin |
AR051446A1 (es) * | 2004-09-23 | 2007-01-17 | Bristol Myers Squibb Co | Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2) |
MX2007003652A (es) * | 2004-09-28 | 2009-02-16 | Teva Pharma | Proceso para preparar formas de calcio de atorvastatina sustancialmente libre de impurezas. |
EP2927693A1 (en) | 2004-10-06 | 2015-10-07 | The Brigham and Women's Hospital | Relevance of achieved levels of markers of systemic inflammation following treatment |
US7517991B2 (en) * | 2004-10-12 | 2009-04-14 | Bristol-Myers Squibb Company | N-sulfonylpiperidine cannabinoid receptor 1 antagonists |
US20060106230A1 (en) * | 2004-10-18 | 2006-05-18 | Michael Pinchasov | Processes for preparing amorphous atorvastatin hemi-calcium |
CA2585623C (en) | 2004-10-27 | 2012-06-05 | Daiichi Sankyo Company Limited | Ortho-substituted benzene derivatives |
JP2008517992A (ja) * | 2004-10-28 | 2008-05-29 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | アモルファスのアトルバスタチンを形成する方法 |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
WO2006054307A2 (en) * | 2004-11-22 | 2006-05-26 | Dexcel Pharma Technologies Ltd. | Controlled absorption of statins in the intestine |
US20090208539A1 (en) * | 2004-11-22 | 2009-08-20 | Adel Penhasi | Stable atorvastatin formulations |
MX2007005137A (es) * | 2004-11-23 | 2007-06-22 | Warner Lambert Co | Derivados del acido 7-(2h-pyrazol-3-il)-3, 5-dihidroxi-heptanoico como inhibidores de hmg co-a reductasa para el tratamiento de lipidemia. |
JP2008521878A (ja) * | 2004-12-02 | 2008-06-26 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | 非晶質アトルバスタチンの医薬組成物及びその製造のための方法 |
CA2590860C (en) | 2004-12-09 | 2011-05-03 | Merck & Co., Inc. | Estrogen receptor modulators |
US7635699B2 (en) * | 2004-12-29 | 2009-12-22 | Bristol-Myers Squibb Company | Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods |
US7589088B2 (en) * | 2004-12-29 | 2009-09-15 | Bristol-Myers Squibb Company | Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods |
EP1855673A4 (en) * | 2005-01-06 | 2008-03-12 | Merck & Co Inc | COMBINED THERAPY AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
US7314882B2 (en) * | 2005-01-12 | 2008-01-01 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
WO2006076568A2 (en) | 2005-01-12 | 2006-07-20 | Bristol-Myers Squibb Company | Thiazolopyridines as cannabinoid receptor modulators |
WO2006076597A1 (en) * | 2005-01-12 | 2006-07-20 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
WO2006078697A1 (en) * | 2005-01-18 | 2006-07-27 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
EP1848424B1 (en) * | 2005-01-31 | 2017-04-05 | Mylan Laboratories, Inc | Pharmaceutical composition comprising hydroxylated nebivolol |
WO2006086464A2 (en) * | 2005-02-10 | 2006-08-17 | Bristol-Myers Squibb Company | Dihydroquinazolinones as 5ht modulators |
WO2006123358A2 (en) * | 2005-02-22 | 2006-11-23 | Sun Pharmaceutical Industries Limited | Stabilized atorvastatin-containing formulation |
US20070293535A1 (en) * | 2005-02-24 | 2007-12-20 | Kowa Company, Ltd. | Nuclear Transfer Promoter for Ddc42 Protein and Method of Screening the Dame |
CA2498978A1 (en) * | 2005-02-28 | 2006-08-28 | Apotex Pharmachem Inc. | An improved process for the preparation of atorvastatin and intermediates |
CA2499047A1 (en) * | 2005-03-01 | 2006-09-01 | Apotex Pharmachem Inc. | Process for producing atorvastatin hemicalcium |
PL1855674T3 (pl) | 2005-03-02 | 2015-01-30 | Merck Sharp & Dohme | Kompozycja do hamowania katepsyny K |
WO2006103661A2 (en) * | 2005-03-28 | 2006-10-05 | Dexcel Pharma Technologies Ltd. | Controlled absorption of statins in the intestine |
GB2424880A (en) * | 2005-04-06 | 2006-10-11 | Generics | Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase |
JP5523699B2 (ja) * | 2005-04-08 | 2014-06-18 | エギシュ ヂョヂセルヂャール ニルヴァーノサン ミケデ レースヴェーニタールササーグ | 新規な結晶性のアトルバスタチンヘミカルシウム塩の多形相 |
US20060235028A1 (en) | 2005-04-14 | 2006-10-19 | Li James J | Inhibitors of 11-beta hydroxysteroid dehydrogenase type I |
DK1879862T3 (da) * | 2005-05-03 | 2011-05-16 | Ranbaxy Lab Ltd | Magnesiumsalte af HMG-COA reduktaseinhibitorer |
WO2006123182A2 (en) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones for treatment of cancer |
US7521557B2 (en) | 2005-05-20 | 2009-04-21 | Bristol-Myers Squibb Company | Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods |
US7825139B2 (en) * | 2005-05-25 | 2010-11-02 | Forest Laboratories Holdings Limited (BM) | Compounds and methods for selective inhibition of dipeptidyl peptidase-IV |
EP1896074A4 (en) * | 2005-05-25 | 2009-04-22 | Liponex Inc | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OR PREVENTION OF CORONARY ARTERY DISEASE |
AU2006249869A1 (en) * | 2005-05-26 | 2006-11-30 | Bristol-Myers Squibb Company | N-terminally modified GLP-1 receptor modulators |
EP1982711A1 (en) | 2005-05-31 | 2008-10-22 | Mylan Laboratories, Inc | Compositions comprsing nebivolol |
US20060287342A1 (en) * | 2005-06-17 | 2006-12-21 | Mikkilineni Amarendra B | Triazolopyrimidine heterocycles as cannabinoid receptor modulators |
US7629342B2 (en) * | 2005-06-17 | 2009-12-08 | Bristol-Myers Squibb Company | Azabicyclic heterocycles as cannabinoid receptor modulators |
US7317012B2 (en) * | 2005-06-17 | 2008-01-08 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoind-1 receptor modulators |
US7452892B2 (en) * | 2005-06-17 | 2008-11-18 | Bristol-Myers Squibb Company | Triazolopyrimidine cannabinoid receptor 1 antagonists |
US7632837B2 (en) * | 2005-06-17 | 2009-12-15 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
TW200726765A (en) * | 2005-06-17 | 2007-07-16 | Bristol Myers Squibb Co | Triazolopyridine cannabinoid receptor 1 antagonists |
KR101363278B1 (ko) | 2005-06-27 | 2014-02-21 | 엑셀리시스 페이턴트 컴퍼니 엘엘씨 | 이미다졸계 lxr 변조제 |
EP1898922A4 (en) * | 2005-07-04 | 2012-03-14 | Ramu Krishnan | MEDICINE OR IMPROVED PHARMACEUTICAL COMPOUNDS AND PREPARATION THEREOF |
CA2614885C (en) | 2005-07-11 | 2015-03-17 | Pharmena North America Inc. | Methylnicotinamide derivatives and formulations for treatment of lipoprotein abnormalities |
CN101268075A (zh) * | 2005-07-28 | 2008-09-17 | 百时美施贵宝公司 | 作为5-羟色胺受体激动剂和拮抗剂的取代的四氢-1h吡啶并[4,3,b]吲哚 |
DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US7772277B2 (en) * | 2005-08-04 | 2010-08-10 | Transform Pharmaceuticals, Inc. | Formulations comprising fenofibrate and a statin, and related methods of treatment |
US20070032665A1 (en) * | 2005-08-04 | 2007-02-08 | Srinivasulu Gudipati | Preparation of atorvastatin calcium form i |
BRPI0614279A2 (pt) | 2005-08-15 | 2012-11-06 | Arrow Int Ltd | atorvastatina sódica cristalina e amorfa |
CN101268047B (zh) | 2005-08-15 | 2012-11-07 | 箭锋国际有限公司 | 结晶和无定形阿托伐他汀钠 |
US7795436B2 (en) * | 2005-08-24 | 2010-09-14 | Bristol-Myers Squibb Company | Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists |
TW200804345A (en) | 2005-08-30 | 2008-01-16 | Novartis Ag | Substituted benzimidazoles and methods of preparation |
WO2007029216A1 (en) * | 2005-09-09 | 2007-03-15 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate |
WO2007029217A1 (en) * | 2005-09-09 | 2007-03-15 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate |
US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
US20080139457A1 (en) * | 2005-09-16 | 2008-06-12 | Virginia Commonwealth University | Therapeutic compositions comprising chorionic gonadotropins and HMG CoA reductase inhibitors |
CA2547216A1 (en) | 2005-09-21 | 2007-03-21 | Renuka D. Reddy | Process for annealing amorphous atorvastatin |
US8119358B2 (en) | 2005-10-11 | 2012-02-21 | Tethys Bioscience, Inc. | Diabetes-related biomarkers and methods of use thereof |
DE102005049293A1 (de) * | 2005-10-15 | 2007-04-26 | Bayer Healthcare Ag | Kombinationspräparate von Salzen oder o-Acetylsalicylsäure |
US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
AR056155A1 (es) * | 2005-10-26 | 2007-09-19 | Bristol Myers Squibb Co | Antagonistas del receptor 1 de la hormona de concentracion de melanina no basica |
US7488725B2 (en) | 2005-10-31 | 2009-02-10 | Bristol-Myers Squibb Co. | Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase IV and methods |
AU2006313430B2 (en) | 2005-11-08 | 2012-09-06 | Ranbaxy Laboratories Limited | Process for (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt |
PT1957452E (pt) | 2005-11-21 | 2010-05-25 | Warner Lambert Co | Novas formas de ácido [r-(r*,r*)]-2-(4-fluorofenil)-b,b--di-hidroxi-5-(1-metiletil)-3-fenil-4-[(fenilamino)-carbonil]-1h-pirrole-1-heptanóico magnésico |
EP1957452B1 (en) | 2005-11-21 | 2010-05-05 | Warner-Lambert Company LLC | Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept anoic acid magnesium |
US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
BRPI0619154A2 (pt) * | 2005-12-01 | 2011-09-20 | Hoffmann La Roche | inibidores do transportador da serotonina (sert) |
BRPI0610344A2 (pt) * | 2005-12-13 | 2016-11-29 | Teva Pharma | forma cristalizada do atorvastatin hemi-calcium, processo para sua preparação, produto famacêutico derivado e seu uso medicinal |
US7592461B2 (en) | 2005-12-21 | 2009-09-22 | Bristol-Myers Squibb Company | Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
WO2007073935A1 (en) * | 2005-12-29 | 2007-07-05 | Lek Pharmaceuticals D.D. | Heterocyclic compounds |
ES2374963T3 (es) | 2006-01-05 | 2012-02-23 | Essentialis, Inc. | Sales de agentes de apertura del canal de potasio dependiente de atp y usos de las mismas. |
EP1976873A2 (en) * | 2006-01-11 | 2008-10-08 | Brystol-Myers Squibb Company | Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions |
EP1810667A1 (en) | 2006-01-20 | 2007-07-25 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising amorphous atorvastatin |
US7553836B2 (en) * | 2006-02-06 | 2009-06-30 | Bristol-Myers Squibb Company | Melanin concentrating hormone receptor-1 antagonists |
EP1818049A3 (en) * | 2006-02-10 | 2008-11-19 | LifeCycle Pharma A/S | Stabilized Atorvastatin |
GB0603041D0 (en) | 2006-02-15 | 2006-03-29 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
WO2007096751A1 (en) * | 2006-02-21 | 2007-08-30 | Cadila Healthcare Limited | Process for the preparation of atorvastatin calcium |
JP2007231018A (ja) * | 2006-03-01 | 2007-09-13 | Teva Pharmaceutical Industries Ltd | アトルバスタチンヘミカルシウムの結晶形の調製方法 |
US20070238770A1 (en) * | 2006-04-05 | 2007-10-11 | Bristol-Myers Squibb Company | Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations |
SI22255A (sl) * | 2006-04-14 | 2007-10-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Novi polimorfi statinovih soli in njihova uporabav farmacevtskih formulacijah |
PL2010528T3 (pl) | 2006-04-19 | 2018-03-30 | Novartis Ag | 6-0-podstawione związki benzoksazolowe i benzotiazolowe i sposoby hamowania sygnalizacji csf-1r |
ES2564250T3 (es) * | 2006-05-03 | 2016-03-21 | Msn Laboratories Private Limited | Nuevo proceso para estatinas y sus sales farmacéuticamente aceptables de las mismas |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
CA2873524C (en) | 2006-05-04 | 2018-02-20 | Boehringer Ingelheim International Gmbh | A polymeric form of 1-((4-methyl-quinazolin-2-yl)methyl)-3-7-(2-butyn-1-yl)-8-(3-(r)-aminopiperidin-1-yl)xanthine |
PE20110235A1 (es) * | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
US20070265456A1 (en) * | 2006-05-09 | 2007-11-15 | Judith Aronhime | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
WO2007132472A1 (en) * | 2006-05-11 | 2007-11-22 | Biocon Limited | A crystalline form b4 of atorvastatin magnesium and a process thereof |
US20070269503A1 (en) * | 2006-05-16 | 2007-11-22 | James Walter Burgess | Combinations of HMG CoA reductase inhibitors and negatively charged phospholipids and uses thereof |
WO2007139589A1 (en) | 2006-05-26 | 2007-12-06 | Bristol-Myers Squibb Company | Sustained release glp-1 receptor modulators |
WO2007146229A2 (en) | 2006-06-07 | 2007-12-21 | Tethys Bioscience, Inc. | Markers associated with arteriovascular events and methods of use thereof |
EP2037928B1 (en) | 2006-06-26 | 2012-01-11 | Amgen Inc. | Methods for treating atherosclerosis |
US7919598B2 (en) | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
US20090203701A1 (en) | 2006-06-29 | 2009-08-13 | Kowa Co., Ltd | Prophylactic and/or therapeutic agent for rheumatoid arthritis |
US20080044326A1 (en) * | 2006-07-04 | 2008-02-21 | Esencia Co., Ltd. | Sterilizer for baby products |
US20080033045A1 (en) * | 2006-07-07 | 2008-02-07 | Myriad Genetics, Incorporated | Treatment of psychiatric disorders |
US7795291B2 (en) | 2006-07-07 | 2010-09-14 | Bristol-Myers Squibb Company | Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method |
US7727978B2 (en) | 2006-08-24 | 2010-06-01 | Bristol-Myers Squibb Company | Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors |
KR101455413B1 (ko) | 2006-08-30 | 2014-10-27 | 고쿠리쓰다이가쿠호진 규슈다이가쿠 | 스타틴-캡슐화된 나노입자를 함유하는 약학적 조성물 |
EP2946778A1 (en) | 2006-09-22 | 2015-11-25 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
WO2008042876A2 (en) | 2006-10-02 | 2008-04-10 | Codexis, Inc. | Compositions and methods for producing stereoisomerically pure statins and synthetic intermediates therefor |
WO2008044243A2 (en) * | 2006-10-09 | 2008-04-17 | Manne Satyanarayana Reddy | Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof |
WO2008044236A2 (en) * | 2006-10-10 | 2008-04-17 | Dexcel Pharma Technologies Ltd. | Improved release of statins in the intestine |
US20080118572A1 (en) * | 2006-10-10 | 2008-05-22 | Harold Richard Hellstrom | Methods and compositions for reducing the risk of adverse cardiovascular events associated with the administration of artificial blood |
WO2008057862A2 (en) | 2006-11-01 | 2008-05-15 | Bristol-Myers Squibb Company | MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF |
US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
WO2008053312A2 (en) * | 2006-11-02 | 2008-05-08 | Cadila Pharmaceuticals Limited | Process for preparing amorphous atorvastatin hemi calcium salt and its intermediate |
KR100793321B1 (ko) * | 2006-11-29 | 2008-01-11 | 사회복지법인 삼성생명공익재단 | 후각장애 치료 및 예방용 조성물 |
EP2109608B1 (en) | 2007-01-10 | 2011-03-23 | Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. | Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors |
US7834195B2 (en) * | 2007-01-24 | 2010-11-16 | Apotex Pharmachem Inc. | Atorvastatin calcium propylene glycol solvates |
KR100878140B1 (ko) * | 2007-01-29 | 2009-01-12 | 한미약품 주식회사 | 아토바스타틴의 스트론튬염 또는 이의 수화물, 및 이를포함하는 약학 조성물 |
EA019951B1 (ru) | 2007-03-01 | 2014-07-30 | Новартис Аг | Ингибиторы киназы pim и способы их применения |
EP2132171A4 (en) * | 2007-03-02 | 2010-11-17 | Dong A Pharm Co Ltd | NOVEL CRYSTALLINE FORMS OF PYRROLYLHEPTANOIC ACID DERIVATIVES |
US20080227846A1 (en) * | 2007-03-13 | 2008-09-18 | Musc Foundation For Research Development | Methods of treating juvenile type 1 diabetes mellitus |
TW200904405A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Pharmaceutical formulations containing an SGLT2 inhibitor |
WO2008124121A1 (en) * | 2007-04-06 | 2008-10-16 | Scidose, Llc | Co-therapy with and combinations of statins and 1,4-dihydropyridine-3,5-dicarboxydiesters |
WO2008124122A1 (en) * | 2007-04-09 | 2008-10-16 | Scidose, Llc | Combinations of statins and anti-obesity agent and glitazones |
MX2009010925A (es) * | 2007-04-09 | 2009-11-02 | Scidose Llc | Combinaciones de estatinas y agente anti-obesidad. |
WO2008130951A1 (en) | 2007-04-17 | 2008-10-30 | Bristol-Myers Squibb Company | Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type i inhibitors |
EP2541254B1 (en) | 2007-04-18 | 2014-11-12 | Health Diagnostic Laboratory, Inc. | Diabetes-related biomarkers and methods of use thereof |
PE20090696A1 (es) | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | Formas cristalinas de saxagliptina y procesos para preparar las mismas |
ES2425969T3 (es) | 2007-04-27 | 2013-10-18 | Kyushu University, National University Corporation | Agente para el tratamiento de enfermedades pulmonares |
US8048880B2 (en) * | 2007-05-03 | 2011-11-01 | Anthera Pharmaceuticals, Inc. | Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitors and SPLA2 inhibitor combination therapies |
US20080280970A1 (en) * | 2007-05-08 | 2008-11-13 | Czarnik Anthony W | Deuterium-enriched atorvastatin |
CN101754972A (zh) * | 2007-05-18 | 2010-06-23 | 百时美施贵宝公司 | Sglt2抑制剂的晶体结构及其制备方法 |
KR20100017866A (ko) | 2007-05-21 | 2010-02-16 | 노파르티스 아게 | Csf-1r 억제제, 조성물 및 사용 방법 |
CN101820757A (zh) | 2007-06-01 | 2010-09-01 | 普林斯顿大学托管委员会 | 通过调节宿主细胞代谢途径治疗病毒感染 |
GB0711250D0 (en) * | 2007-06-12 | 2007-07-18 | Cbz Chemicals Ltd | Furanose derivatives |
DE102007028407A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028406A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028319A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE102007028320A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
CA2707360A1 (en) | 2007-06-20 | 2008-12-24 | Merck Sharp & Dohme Corp. | Diphenyl substituted alkanes |
EP3103791B1 (en) | 2007-06-27 | 2018-01-31 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
US20090011994A1 (en) * | 2007-07-06 | 2009-01-08 | Bristol-Myers Squibb Company | Non-basic melanin concentrating hormone receptor-1 antagonists and methods |
WO2009013633A2 (en) * | 2007-07-20 | 2009-01-29 | Actavis Group Ptc Ehf | Amorphous coprecipitates of atorvastatin pharmaceutically acceptable salts |
EP2489730B1 (en) | 2007-07-26 | 2015-12-30 | Amgen, Inc | Modified lecithin-cholesterol acyltransferase enzymes |
JP2010534644A (ja) * | 2007-07-27 | 2010-11-11 | シプラ・リミテッド | 医薬組成物およびその製造方法 |
EP2173717B9 (en) * | 2007-07-27 | 2013-06-26 | Bristol-Myers Squibb Company | Novel glucokinase activators and methods of using same |
ES2733348T3 (es) * | 2007-08-17 | 2019-11-28 | Boehringer Ingelheim Int | Derivados de purina para uso en el tratamiento de enfermedades relacionadas con FAP |
JOP20080381B1 (ar) | 2007-08-23 | 2023-03-28 | Amgen Inc | بروتينات مرتبطة بمولدات مضادات تتفاعل مع بروبروتين كونفيرتاز سيتيليزين ككسين من النوع 9 (pcsk9) |
US20090209608A1 (en) * | 2007-08-29 | 2009-08-20 | Protia, Llc | Deuterium-enriched asenapine |
KR100921195B1 (ko) | 2007-10-25 | 2009-10-13 | 주식회사 대웅제약 | 아토르바스타틴의 제조 방법 |
JP2011503081A (ja) | 2007-11-01 | 2011-01-27 | ブリストル−マイヤーズ スクイブ カンパニー | グルココルチコイド受容体、AP−1および/またはNF−κB活性の調節剤として有用な非ステロイド性化合物、並びにその使用 |
WO2009063476A1 (en) * | 2007-11-16 | 2009-05-22 | Biocon Limited | A crystalline form of atorvastatin hemi magnesium salt and a process thereof |
US20090163452A1 (en) * | 2007-12-20 | 2009-06-25 | Schwartz Janice B | Compositions and methods for lowering serum cholesterol |
PL2222636T3 (pl) | 2007-12-21 | 2014-04-30 | Ligand Pharm Inc | Selektywne modulatory receptorów androgenowych (SARM) i ich zastosowania |
CN101205209B (zh) * | 2007-12-25 | 2010-06-02 | 浙江新东港药业股份有限公司 | 一种阿伐他汀中间体的精制方法 |
KR100850558B1 (ko) * | 2008-01-02 | 2008-08-06 | 조동옥 | 아토르바스타틴의 효율적인 제조방법 |
JP5421126B2 (ja) * | 2008-01-10 | 2014-02-19 | 武田薬品工業株式会社 | カプセル製剤 |
EA022166B1 (ru) | 2008-01-11 | 2015-11-30 | Ритэ Фамэсутиклс, Инк. | Синтетические тритерпеноиды и их применение в лечении заболеваний |
US20090226516A1 (en) * | 2008-03-04 | 2009-09-10 | Pharma Pass Ii Llc | Sartan compositions |
US20090226515A1 (en) * | 2008-03-04 | 2009-09-10 | Pharma Pass Ii Llc | Statin compositions |
WO2009113061A1 (en) * | 2008-03-10 | 2009-09-17 | Dexcel Pharma Technologies Ltd. | Humidity-resistant drug formulations and methods of preparation thereof |
KR100980379B1 (ko) | 2008-04-02 | 2010-09-06 | 주식회사 파마코스텍 | 광학활성을 갖는 5-히드록시-3-옥소헵타노에이트 유도체의제조방법 |
PE20140960A1 (es) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
EP2130819A3 (en) * | 2008-04-10 | 2009-12-23 | Ranbaxy Laboratories Limited | Crystalline forms of atorvastatin magnesium |
US20110112053A1 (en) * | 2008-04-16 | 2011-05-12 | University Of Utah Research Foundation | Pharmacological targeting of vascular malformations |
EP2285352A2 (en) * | 2008-05-13 | 2011-02-23 | Dr. Reddy's Laboratories Ltd. | Atorvastatin compositions |
PE20091928A1 (es) * | 2008-05-29 | 2009-12-31 | Bristol Myers Squibb Co | Tienopirimidinas hidroxisustituidas como antagonistas de receptor-1 de hormona concentradora de melanina no basicos |
PE20100156A1 (es) * | 2008-06-03 | 2010-02-23 | Boehringer Ingelheim Int | Tratamiento de nafld |
ES2330184B1 (es) | 2008-06-03 | 2010-07-05 | Neuron Biopharma, S.A. | Uso de estatinas como anticonvulsivantes, antiepilepticos y neuroprotectores. |
EP2138178A1 (en) | 2008-06-28 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidninones for the treatment fo chronic obstructive pulmonary disease (COPD) and/or asthma |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
BRPI0916997A2 (pt) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | Inibidor de dpp-4 e seu uso |
WO2010019435A2 (en) * | 2008-08-14 | 2010-02-18 | Teva Pharmaceutical Industries Ltd. | Solid states of atorvastatin potassium |
US20110190322A1 (en) * | 2008-08-14 | 2011-08-04 | Boehringer Ingelheim International Gmbh | Purin derivatives for use in the treatment of fab-related diseases |
EP2161024A1 (de) | 2008-09-05 | 2010-03-10 | Universitätsklinikum Hamburg-Eppendorf | Kombinationspräparat zur Behandlung von Krebs |
CN102149407A (zh) | 2008-09-10 | 2011-08-10 | 贝林格尔.英格海姆国际有限公司 | 治疗糖尿病和相关病症的组合疗法 |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
JO3672B1 (ar) | 2008-12-15 | 2020-08-27 | Regeneron Pharma | أجسام مضادة بشرية عالية التفاعل الكيماوي بالنسبة لإنزيم سبتيليسين كنفرتيز بروبروتين / كيكسين نوع 9 (pcsk9). |
US20130064834A1 (en) | 2008-12-15 | 2013-03-14 | Regeneron Pharmaceuticals, Inc. | Methods for treating hypercholesterolemia using antibodies to pcsk9 |
BRPI0923121A2 (pt) | 2008-12-23 | 2015-08-11 | Boehringer Ingelheim Int | Formas salinas de compostos orgânico |
AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
EP2387561A4 (en) | 2009-01-19 | 2012-07-25 | Msn Lab Ltd | IMPROVED PROCESS FOR THE PREPARATION OF HIGH-PURITY (3R, 5S) -7-β-CYCLOPROPYL-4- (4-FLUOROPHENYL) QUINOLIN-3-YL-3,5-DIHYDROXY-6 (E) -HEPTENOIC ACID, INCLUDING ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
US8115015B2 (en) * | 2009-01-26 | 2012-02-14 | Cadila Healthcare Limited | Process for the preparation of amorphous atorvastatin calcium |
WO2010093601A1 (en) | 2009-02-10 | 2010-08-19 | Metabasis Therapeutics, Inc. | Novel sulfonic acid-containing thyromimetics, and methods for their use |
GB0904102D0 (en) | 2009-03-10 | 2009-04-22 | Bradford Pharma Ltd | Use of atorvastatin lactols as medicaments |
GB0904100D0 (en) | 2009-03-10 | 2009-04-22 | Bradford Pharma Ltd | Use of rosuvastatin lactols as medicaments |
GB0904104D0 (en) | 2009-03-10 | 2009-04-22 | Bradford Pharma Ltd | Atorvastatin and rosuvastatin derivatives |
BRPI1013500A2 (pt) | 2009-03-27 | 2016-04-05 | Astrazeneca Uk Ltd | métodos para previnir eventos cardiovasculares adversos maiores com inibidores de dpp-iv |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
CN102976996B (zh) * | 2009-05-27 | 2015-08-19 | 峡江和美药业有限公司 | 阿伐他汀半锶盐多晶型物、其制备和作为HMG-CoA酶抑制剂的应用 |
CA2761934C (en) | 2009-05-28 | 2018-01-09 | Exelixis Patent Company Llc | Substituted 1-(biphenyl-4-yl)-2-benzyl-4-hydroxyalkyl-1h-imidazole compounds and their use as lxr modulators |
WO2011002422A2 (en) | 2009-07-02 | 2011-01-06 | Bilgic Mahmut | Solubility enhancing pharmaceutical formulation |
US9334266B2 (en) | 2009-09-04 | 2016-05-10 | The University Of Toledo | Catalysts and related processes for producing optically pure beta-lactones from aldehydes and compositions produced thereby |
CN104945382B (zh) | 2009-10-14 | 2020-02-07 | 默沙东公司 | 提高p53活性的取代的哌啶和其用途 |
JP5784623B2 (ja) | 2009-11-13 | 2015-09-24 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | 速放性錠剤製剤 |
ES2689107T3 (es) | 2009-11-13 | 2018-11-08 | Astrazeneca Ab | Formulaciones de tabletas bicapa |
US20120294936A1 (en) | 2009-11-13 | 2012-11-22 | Astrazeneca Uk Limited | Reduced mass metformin formulations |
CN102753161A (zh) | 2009-11-27 | 2012-10-24 | 贝林格尔.英格海姆国际有限公司 | 基因型糖尿病患者利用dpp-iv抑制剂例如利拉利汀的治疗 |
AR079336A1 (es) * | 2009-12-11 | 2012-01-18 | Irm Llc | Antagonistas de la pro-proteina convertasa-subtilisina/quexina tipo 9 (pcsk9) |
US20130115622A1 (en) | 2009-12-14 | 2013-05-09 | Kyoto University | Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis |
EP2526099B1 (en) | 2010-01-18 | 2016-03-30 | MSN Laboratories Limited | Improved process for the preparation of amide intermediates and their use thereof |
CZ201039A3 (cs) | 2010-01-19 | 2011-07-27 | Zentiva, K. S | Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme |
EP2531163A1 (en) | 2010-02-01 | 2012-12-12 | The Hospital For Sick Children | Remote ischemic conditioning for treatment and preventon of restenosis |
TWI562775B (en) | 2010-03-02 | 2016-12-21 | Lexicon Pharmaceuticals Inc | Methods of using inhibitors of sodium-glucose cotransporters 1 and 2 |
SG10201908570RA (en) | 2010-03-31 | 2019-11-28 | Hospital For Sick Children | Use of remote ischemic conditioning to improve outcome after myocardial infarction |
EP2555692A2 (en) | 2010-04-08 | 2013-02-13 | The Hospital For Sick Children | Use of remote ischemic conditioning for traumatic injury |
WO2011130459A1 (en) | 2010-04-14 | 2011-10-20 | Bristol-Myers Squibb Company | Novel glucokinase activators and methods of using same |
US8372877B2 (en) | 2010-04-16 | 2013-02-12 | Cumberland Pharmaceuticals | Stabilized statin formulations |
WO2011138421A1 (en) | 2010-05-05 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Combination therapy |
IT1400310B1 (it) | 2010-05-10 | 2013-05-24 | Menarini Int Operations Lu Sa | Associazione di inibitori della xantina ossidasi e statine e loro uso. |
US20130072519A1 (en) | 2010-05-21 | 2013-03-21 | Edward Lee Conn | 2-phenyl benzoylamides |
EP2575757A1 (en) | 2010-06-03 | 2013-04-10 | Mahmut Bilgic | Water soluble formulation comprising a combination of amlodipine and a statin |
US8999957B2 (en) | 2010-06-24 | 2015-04-07 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as ERK inhibitors |
EP3124041A1 (en) | 2010-06-24 | 2017-02-01 | Boehringer Ingelheim International GmbH | Diabetes therapy |
TR201005326A2 (tr) | 2010-06-30 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Çoklu dozaj formları. |
CN107080846A (zh) | 2010-07-09 | 2017-08-22 | 詹姆斯.特林卡.格林 | 用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统 |
KR20120011249A (ko) | 2010-07-28 | 2012-02-07 | 주식회사 경보제약 | 아토바스타틴 헤미칼슘염의 신규한 결정형, 이의 수화물, 및 그의 제조방법 |
JP6043285B2 (ja) | 2010-08-02 | 2016-12-14 | サーナ・セラピューティクス・インコーポレイテッドSirna Therapeutics,Inc. | 低分子干渉核酸(siNA)を用いたカテニン(カドヘリン結合型タンパク質)β1(CTNNB1)遺伝子発現のRNA干渉媒介性阻害 |
CN108676800B (zh) | 2010-08-17 | 2022-11-11 | 瑟纳治疗公司 | 使用短干扰核酸(siNA)的乙型肝炎病毒(HBV)基因表达的RNA干扰介导的抑制 |
EP2608669B1 (en) | 2010-08-23 | 2016-06-22 | Merck Sharp & Dohme Corp. | NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
EP2613782B1 (en) | 2010-09-01 | 2016-11-02 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
US9242981B2 (en) | 2010-09-16 | 2016-01-26 | Merck Sharp & Dohme Corp. | Fused pyrazole derivatives as novel ERK inhibitors |
JPWO2012046772A1 (ja) | 2010-10-06 | 2014-02-24 | 国立大学法人 東京大学 | リンパ浮腫予防治療剤 |
WO2012056509A1 (ja) * | 2010-10-25 | 2012-05-03 | 興和株式会社 | 医薬組成物 |
ES2663009T3 (es) | 2010-10-29 | 2018-04-10 | Sirna Therapeutics, Inc. | Inhibición de la expresión génica mediada por interferencia por ARN utilizando ácidos nucleicos de interferencia cortos (ANic) |
TWI462739B (zh) | 2010-11-02 | 2014-12-01 | Univ Kaohsiung Medical | Sildenafil-同族物四級銨哌嗪鹽類之製備及醫療用途 |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
HU230737B1 (hu) | 2010-11-16 | 2018-01-29 | EGIS Gyógyszergyár Nyrt | Eljárás rosuvastatin só előállítására |
EP2654748B1 (en) | 2010-12-21 | 2016-07-27 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
TWI631963B (zh) | 2011-01-05 | 2018-08-11 | 雷西肯製藥股份有限公司 | 包含鈉-葡萄糖共同輸送體1與2之抑制劑的組合物與應用方法 |
ES2618812T3 (es) | 2011-01-20 | 2017-06-22 | Merck Sharp & Dohme Corp. | Antagonistas del receptor mineralocorticoide |
AR084938A1 (es) | 2011-01-28 | 2013-07-10 | Sanofi Sa | Anticuerpos humanos contra la proproteina convertasa subtilisina/kexina tipo 9 (anti pcsk9) para usar en metodos para tratar grupos de pacientes |
SG191772A1 (en) | 2011-01-31 | 2013-08-30 | Cadila Healthcare Ltd | Treatment for lipodystrophy |
WO2012112363A1 (en) | 2011-02-14 | 2012-08-23 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
JP5705580B2 (ja) | 2011-02-21 | 2015-04-22 | 公益財団法人微生物化学研究会 | チオアミド化合物、チオアミド化合物の製造方法、[(4r,6r)−6−アミノエチル−1,3−ジオキサン−4−イル]アセテート誘導体の製造方法、及びアトルバスタチンの製造方法 |
EP2680874A2 (en) | 2011-03-04 | 2014-01-08 | Pfizer Inc | Edn3-like peptides and uses thereof |
TW201242953A (en) | 2011-03-25 | 2012-11-01 | Bristol Myers Squibb Co | Imidazole prodrug LXR modulators |
US9050342B2 (en) | 2011-03-29 | 2015-06-09 | Pfizer Inc. | Beneficial effects of combination therapy on cholesterol |
EP2697203B1 (en) | 2011-04-13 | 2017-05-24 | Merck Sharp & Dohme Corporation | Mineralocorticoid receptor antagonists |
CN103732592A (zh) | 2011-04-21 | 2014-04-16 | 默沙东公司 | 胰岛素样生长因子-1受体抑制剂 |
MX2013015272A (es) | 2011-07-01 | 2014-04-14 | Dsm Sinochem Pharm Nl Bv | Cristales micronizados. |
ES2713566T3 (es) | 2011-07-15 | 2019-05-22 | Boehringer Ingelheim Int | Derivado de quinazolina dimérico sustituido, su preparación y su uso en composiciones farmacéuticas para el tratamiento de la diabetes de tipo I y II |
AR087305A1 (es) | 2011-07-28 | 2014-03-12 | Regeneron Pharma | Formulaciones estabilizadas que contienen anticuerpos anti-pcsk9, metodo de preparacion y kit |
AU2012308797B2 (en) | 2011-09-16 | 2017-06-01 | Regeneron Pharmaceuticals, Inc. | Methods for reducing lipoprotein(a) levels by administering an inhibitor of proprotein convertase subtilisin kexin-9 (PSCK9) |
WO2013055606A1 (en) | 2011-10-13 | 2013-04-18 | Merck Sharp & Dohme Corp. | Mineralocorticoid receptor antagonists |
WO2013063214A1 (en) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
IN2014CN04119A (fi) | 2011-11-15 | 2015-07-10 | Reddys Lab Ltd Dr | |
KR101466617B1 (ko) | 2011-11-17 | 2014-11-28 | 한미약품 주식회사 | 오메가-3 지방산 및 HMG-CoA 환원효소 억제제를 포함하는 안정성이 증가된 경구용 복합 제제 |
CN104220460A (zh) | 2011-12-08 | 2014-12-17 | 安姆根有限公司 | 激动人lcat抗原结合蛋白和它们在疗法中的用途 |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
MX2014012349A (es) | 2012-04-30 | 2015-01-12 | Hoffmann La Roche | Nueva formulacion. |
EP3358013B1 (en) | 2012-05-02 | 2020-06-24 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
ES2698950T3 (es) | 2012-05-10 | 2019-02-06 | Bayer Pharma AG | Anticuerpos capaces de unirse al Factor XI de coagulación y/o a su forma activada, Factor XIa, y usos de los mismos |
NZ728724A (en) | 2012-05-11 | 2018-03-23 | Reset Therapeutics Inc | Carbazole-containing sulfonamides as cryptochrome modulators |
WO2013171167A1 (en) | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
BR112014031310A2 (pt) | 2012-06-15 | 2017-07-25 | Genentech Inc | anticorpos anti-pcsk9, formulações, dosagem e métodos de uso |
WO2014022195A1 (en) | 2012-08-01 | 2014-02-06 | Tavakoli Zahra | Free flowing, frozen compositions comprising a therapeutic agent |
CN105050598B (zh) | 2012-09-28 | 2018-04-27 | 默沙东公司 | 作为erk抑制剂的新型化合物 |
DK2925735T3 (da) | 2012-11-20 | 2019-06-17 | Lexicon Pharmaceuticals Inc | Inhibitorer for natriumglucose-cotransporter 1 |
CA2892361A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Use of a wee1 inhibitor for treating a cancer characterized by low pkmyt1 expression levels |
CN103012240B (zh) * | 2012-12-11 | 2015-05-27 | 保定市龙瑞药物技术有限责任公司 | 一种阿托伐他汀钙的制备方法 |
AU2013361694B2 (en) | 2012-12-20 | 2017-10-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as HDM2 inhibitors |
CN103121964A (zh) * | 2013-01-17 | 2013-05-29 | 复旦大学 | 一种制备阿托伐他汀钙关键中间体的方法 |
WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
JP6442475B2 (ja) | 2013-03-15 | 2018-12-19 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Lxr調節因子 |
EP2976062B1 (en) | 2013-03-21 | 2021-11-03 | Eupraxia Pharmaceuticals USA LLC | Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith |
CN105143203A (zh) | 2013-04-17 | 2015-12-09 | 辉瑞大药厂 | 用于治疗心血管疾病的n-哌啶-3-基苯甲酰胺衍生物 |
AU2013387996B2 (en) | 2013-04-22 | 2015-12-10 | Cadila Healthcare Limited | A novel composition for nonalcoholic fatty liver disease (NAFLD) |
US20160107989A1 (en) | 2013-05-30 | 2016-04-21 | Cadila Healthcare Limited | A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities |
US10111953B2 (en) | 2013-05-30 | 2018-10-30 | Regeneron Pharmaceuticals, Inc. | Methods for reducing remnant cholesterol and other lipoprotein fractions by administering an inhibitor of proprotein convertase subtilisin kexin-9 (PCSK9) |
KR20160024906A (ko) | 2013-06-07 | 2016-03-07 | 사노피 바이오테크놀로지 | Pcsk9의 억제제를 투여함에 의한 죽상경화증의 억제 방법 |
TW201513857A (zh) | 2013-07-05 | 2015-04-16 | Cadila Healthcare Ltd | 協同性組成物 |
IN2013MU02470A (fi) | 2013-07-25 | 2015-06-26 | Cadila Healthcare Ltd | |
WO2015027021A1 (en) | 2013-08-22 | 2015-02-26 | Bristol-Myers Squibb Company | Imide and acylurea derivatives as modulators of the glucocorticoid receptor |
EP3041938A1 (en) | 2013-09-03 | 2016-07-13 | Moderna Therapeutics, Inc. | Circular polynucleotides |
IN2013MU02905A (fi) | 2013-09-06 | 2015-07-03 | Cadila Healthcare Ltd | |
WO2015051479A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
AU2014332250B2 (en) | 2013-10-08 | 2018-07-19 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
EP3882273A1 (en) | 2013-11-12 | 2021-09-22 | Sanofi Biotechnology | Dosing regimens for use with pcsk9 inhibitors |
CN105111123A (zh) * | 2013-11-25 | 2015-12-02 | 李兴惠 | 阿托伐他汀钙及组合物 |
JP6536871B2 (ja) | 2013-12-02 | 2019-07-03 | 国立大学法人京都大学 | Fgfr3病の予防および治療剤ならびにそのスクリーニング方法 |
US10441567B2 (en) | 2014-01-17 | 2019-10-15 | Ligand Pharmaceuticals Incorporated | Methods and compositions for modulating hormone levels |
WO2015120580A1 (en) | 2014-02-11 | 2015-08-20 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
ES2950384T3 (es) | 2014-02-28 | 2023-10-09 | Boehringer Ingelheim Int | Uso médico de un inhibidor de DPP-4 |
TWI690521B (zh) | 2014-04-07 | 2020-04-11 | 美商同步製藥公司 | 作為隱花色素調節劑之含有咔唑之醯胺類、胺基甲酸酯類及脲類 |
EP3148587B1 (en) | 2014-05-30 | 2021-02-24 | Pfizer Inc | Carbonitrile derivatives as selective androgen receptor modulators |
KR20170029613A (ko) | 2014-07-16 | 2017-03-15 | 사노피 바이오테크놀로지 | 이형접합성 가족성 고콜레스테롤혈증(heFH) 환자의 치료방법 |
JO3589B1 (ar) | 2014-08-06 | 2020-07-05 | Novartis Ag | مثبطات كيناز البروتين c وطرق استخداماتها |
US10822411B2 (en) | 2014-09-15 | 2020-11-03 | The Board Of Trustees Of The Leland Stanford Junior University | Targeting aneurysm disease by modulating phagocytosis pathways |
WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
EP3811972B1 (en) | 2015-02-27 | 2023-01-11 | The Board of Trustees of the Leland Stanford Junior University | Combination therapy for treatment of atherosclerosis |
EP3288584A2 (en) | 2015-04-30 | 2018-03-07 | President and Fellows of Harvard College | Anti-ap2 antibodies and antigen binding agents to treat metabolic disorders |
EP3337828A1 (en) | 2015-08-18 | 2018-06-27 | Regeneron Pharmaceuticals, Inc. | Anti-pcsk9 inhibitory antibodies for treating patients with hyperlipidemia undergoing lipoprotein apheresis |
FR3040303B1 (fr) * | 2015-08-27 | 2019-04-05 | Les Laboratoires Servier Suivi Par Sabine Goudeau-Wenger | Composition pharmaceutique comprenant un inhibiteur de la hmg-coa reductase et un inhibiteur eca |
US10385017B2 (en) | 2015-10-14 | 2019-08-20 | Cadila Healthcare Limited | Pyrrole compound, compositions and process for preparation thereof |
KR20180069055A (ko) | 2015-10-27 | 2018-06-22 | 유프락시아 파마수티컬스 인코포레이티드 | 국소 마취제의 지속 방출 제형 |
JP2019517542A (ja) | 2016-06-10 | 2019-06-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | リナグリプチンおよびメトホルミンの組合せ |
EP3525785A4 (en) | 2016-10-12 | 2020-03-25 | Merck Sharp & Dohme Corp. | KDM5 INHIBITORS |
BR112019011740A2 (pt) | 2016-12-09 | 2019-10-29 | Cadila Healthcare Ltd | composição farmacêutica e método para o tratamento de colangite biliar primária |
EP3630185A4 (en) | 2017-05-30 | 2020-06-17 | The Board of Trustees of the Leland Stanford Junior University | TREATMENT OF NEURO-INFLAMMATORY DISEASE |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
JP7356968B2 (ja) | 2018-05-08 | 2023-10-05 | 国立大学法人 岡山大学 | 心血管疾患に有用な医薬 |
US20210299331A1 (en) | 2018-07-19 | 2021-09-30 | Kyoto University | Pluripotent stem cell-derived plate-shaped cartilage and method for producing the same |
WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
US11981701B2 (en) | 2018-08-07 | 2024-05-14 | Merck Sharp & Dohme Llc | PRMT5 inhibitors |
EP3856714A1 (en) | 2018-09-26 | 2021-08-04 | Lexicon Pharmaceuticals, Inc. | Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis |
WO2020130147A1 (ja) | 2018-12-21 | 2020-06-25 | 国立大学法人京都大学 | ルブリシン局在軟骨様組織、その製造方法及びそれを含む関節軟骨損傷治療用組成物 |
CN113574055B (zh) | 2019-01-18 | 2024-07-23 | 阿斯利康(瑞典)有限公司 | Pcsk9抑制剂及其使用方法 |
MX2021010987A (es) | 2019-03-13 | 2021-12-15 | National Univ Corporation Hamamatsu Univ School Of Medicine | Composicion farmaceutica para el tratamiento contra aneurisma aortico. |
EP3976805A1 (en) | 2019-05-27 | 2022-04-06 | Immatics US, Inc. | Viral vectors and their use in adoptive cellular therapy |
CN115087638B (zh) | 2019-12-17 | 2023-11-24 | 默沙东公司 | Prmt5抑制剂 |
JPWO2021167088A1 (fi) | 2020-02-21 | 2021-08-26 | ||
DE102020111571A1 (de) | 2020-03-11 | 2021-09-16 | Immatics US, Inc. | Wpre-mutantenkonstrukte, zusammensetzungen und zugehörige verfahren |
WO2022023206A1 (en) | 2020-07-27 | 2022-02-03 | Krka, D.D., Novo Mesto | Bilayer tablet comprising ezetimibe and atorvastatin |
TW202227616A (zh) | 2020-08-21 | 2022-07-16 | 美商英麥提克斯股份有限公司 | 分離cd8+選擇t細胞的方法 |
EP4180036A4 (en) | 2020-09-29 | 2024-01-31 | Laboratorios Silanes, S.A. de C.V. | PHARMACEUTICAL COMBINATIONS OF STATINS AND FIBRATES FOR THE TREATMENT AND PREVENTION OF HYPERLIPIDEMIA AND CARDIOVASCULAR DISEASES |
WO2023275715A1 (en) | 2021-06-30 | 2023-01-05 | Pfizer Inc. | Metabolites of selective androgen receptor modulators |
GB2624171A (en) | 2022-11-08 | 2024-05-15 | Novumgen Ltd | An orally disintegrating tablet containing atorvastatin and process of preparing the same |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3808254A (en) | 1971-06-10 | 1974-04-30 | Syntex Corp | Resolution-racemization of alpha-amino-alpha-phenylacetonitrile |
US3965129A (en) | 1973-10-10 | 1976-06-22 | Hoffmann-La Roche Inc. | Optical resolution of organic carboxylic acids |
JPS5612114B2 (fi) | 1974-06-07 | 1981-03-18 | ||
DE2620369C3 (de) | 1976-05-08 | 1979-01-04 | Bayer Ag, 5090 Leverkusen | Verfahren zur Wiedergewinnung von (l-S)-2-Oxo-bornansulfonat-(10) |
US4137322A (en) | 1976-11-02 | 1979-01-30 | Sankyo Company Limited | ML-236B carboxylic acid derivatives and their use as antihyperlipemic agents |
US4197297A (en) | 1976-11-17 | 1980-04-08 | Smithkline Corporation | 6-Halo-7,8-dihydroxy-1-(hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines |
US4072698A (en) | 1976-12-02 | 1978-02-07 | The Upjohn Company | Resolution of aminonitriles |
US4281132A (en) | 1977-10-29 | 1981-07-28 | John Wyeth & Brother Limited | Piperidino ureas and thioureas |
US4171359A (en) | 1978-04-12 | 1979-10-16 | Smithkline Corporation | Benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines |
IL58849A (en) | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
US4374844A (en) | 1979-01-10 | 1983-02-22 | Schering Corporation | Stable derivatives of (5R,6S,8R)-6-hydroxyethyl-2-ethylthiopenem-3-carboxylic acids |
GR69216B (fi) | 1979-06-15 | 1982-05-07 | Merck & Co Inc | |
US4231938A (en) | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
US4319039A (en) | 1979-06-15 | 1982-03-09 | Merck & Co., Inc. | Preparation of ammonium salt of hypocholesteremic fermentation product |
NZ194557A (en) | 1979-08-17 | 1984-09-28 | Merck & Co Inc | Substituted pyranone derivatives;dihydroxy acids therefrom;pharmaceutical compositions |
US4375475A (en) | 1979-08-17 | 1983-03-01 | Merck & Co., Inc. | Substituted pyranone inhibitors of cholesterol synthesis |
US4342761A (en) | 1979-11-01 | 1982-08-03 | John Wyeth & Brother Limited | Piperidine derivatives |
US4342767A (en) | 1980-01-23 | 1982-08-03 | Merck & Co., Inc. | Hypocholesteremic fermentation products |
US4282155A (en) | 1980-02-04 | 1981-08-04 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
US4293496A (en) | 1980-02-04 | 1981-10-06 | Merck & Co., Inc. | 6(R)-[2-(8-Hydroxy-2,6-dimethylpolyhydronaphthyl-1)-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones |
US4444784A (en) | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
DK149080C (da) | 1980-06-06 | 1986-07-28 | Sankyo Co | Fremgangsmaade til fremstilling af derivater af ml-236b-carboxylsyre |
US4450171A (en) | 1980-08-05 | 1984-05-22 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
US4962115A (en) | 1981-10-01 | 1990-10-09 | Janssen Pharmaceutica N.V. | Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives |
DE3226768A1 (de) | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | Derivate der cis, endo-2-azabicyclo-(3.3.0)-octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung |
US4495103A (en) | 1982-07-30 | 1985-01-22 | Sumitomo Chemical Company, Ltd. | Preparation of optically active 4-demethoxydaunomycinone |
US4474971A (en) | 1982-09-29 | 1984-10-02 | Sandoz, Inc. | (Tetrahydropyran-2-yl)-aldehydes |
HU204253B (en) | 1982-11-22 | 1991-12-30 | Sandoz Ag | Process for producing mevalonolactone analogues and derivatives and pharmaceutical compositions containing them |
US4739073A (en) | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
US5354772A (en) | 1982-11-22 | 1994-10-11 | Sandoz Pharm. Corp. | Indole analogs of mevalonolactone and derivatives thereof |
DE3302125A1 (de) | 1983-01-22 | 1984-07-26 | Boehringer Ingelheim KG, 6507 Ingelheim | Aminosaeure-derivate, verfahren zu ihrer herstellung und verwendung |
ATE39691T1 (de) | 1984-04-06 | 1989-01-15 | Zambon Spa | Optisch wirksame ketale, verfahren zu deren herstellung und deren verwendung in der synthese von alpha-arylalkansaeuren. |
US4613610A (en) | 1984-06-22 | 1986-09-23 | Sandoz Pharmaceuticals Corp. | Cholesterol biosynthesis inhibiting pyrazole analogs of mevalonolactone and its derivatives |
CH660358A5 (de) | 1984-07-06 | 1987-04-15 | Lonza Ag | Substituierte p,p'-methylen-bisaniline. |
US4804679A (en) | 1984-07-24 | 1989-02-14 | Sandoz Pharm. Corp. | Erythro-(E)-7-(3'-C1-3alkyl-1'-(3",5"-dimethylphenyl)naphth-2'-yl)-3,5-dihydroxyhept-6-enoic acids and derivatives thereof |
US4647576A (en) | 1984-09-24 | 1987-03-03 | Warner-Lambert Company | Trans-6-[2-(substitutedpyrrol-1-yl)alkyl]-pyran-2-one inhibitors of cholesterol synthesis |
US5001255A (en) | 1984-12-04 | 1991-03-19 | Sandoz Pharm. Corp. | Idene analogs of mevalonolactone and derivatives thereof |
US4611067A (en) | 1985-01-31 | 1986-09-09 | Merck & Co., Inc. | Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein |
US5378729A (en) | 1985-02-15 | 1995-01-03 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
DK170473B1 (da) | 1985-06-20 | 1995-09-11 | Daiichi Seiyaku Co | S(-)-pyridobenzoxazinforbindelser |
US4668699A (en) | 1985-08-05 | 1987-05-26 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
US5208258A (en) | 1985-10-11 | 1993-05-04 | The Regents Of The University Of California | Antihypercholesterolemic compounds and synthesis thereof |
US4950775A (en) | 1985-10-11 | 1990-08-21 | University Of California | Antihypercholesterolemic compounds and synthesis thereof |
US4976949A (en) | 1985-10-25 | 1990-12-11 | The University Of Michigan | Controlled release dosage form |
US4851427A (en) | 1985-10-25 | 1989-07-25 | Sandoz Pharm. Corp. | Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use |
EP0221025A1 (en) | 1985-10-25 | 1987-05-06 | Sandoz Ag | Heterocyclic analogs of mevalonolactone and derivatives thereof, processes for their production and their use as pharmaceuticals |
US4772626A (en) | 1986-01-31 | 1988-09-20 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
CA1327010C (en) | 1986-02-13 | 1994-02-15 | Tadashi Makino | Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production |
GB2189699A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated acid-labile medicaments |
GB2189698A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
US4847306A (en) | 1986-05-05 | 1989-07-11 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
US4864038A (en) | 1986-05-05 | 1989-09-05 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
US4681893A (en) | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
US4940727A (en) | 1986-06-23 | 1990-07-10 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
PT85109A (en) | 1986-06-23 | 1987-07-01 | Merck & Co Inc | Process for the preparation of hydroxy-tetrahydropyranone derivatives or corresponding ring opened dihydroxy acids which are hmg-coa reductase inhibitors |
US4678806A (en) | 1986-09-02 | 1987-07-07 | Merck & Co., Inc. | Prodrugs of antihypercholesterolemic compounds |
US4939159A (en) | 1986-09-10 | 1990-07-03 | Sandoz Pharm. Corp. | Azaindole derivatives useful as cholesterol biosynthesis inhibitors |
US4735958A (en) | 1986-12-22 | 1988-04-05 | Warner-Lambert Company | Trans-6-[2-[2-(substituted-phenyl)-3- (or 4-) heteroaryl-5-substituted-1H-pyrrol-1-yl]-ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one inhibitors of cholesterol biosynthesis |
US4743450A (en) | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
US4898949A (en) | 1987-02-25 | 1990-02-06 | Bristol-Myers Company | Intermediates for the preparation of antihypercholesterolemic tetrazole compounds |
US4897490A (en) | 1987-02-25 | 1990-01-30 | Bristol-Meyers Company | Antihypercholesterolemic tetrazole compounds |
NO881411L (no) | 1987-04-14 | 1988-10-17 | Bayer Ag | Substituerte pyrroler. |
US4775681A (en) | 1987-06-18 | 1988-10-04 | Warner-Lambert Company | Method of treating fungal infections with trans-6-[2-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones |
DE3722809A1 (de) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | 3-desmethyl-4-fluor-mevalonsaeurederivate, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen, ihre verwendung und zwischenprodukte |
DE3722806A1 (de) | 1987-07-10 | 1989-01-19 | Hoechst Ag | 7-(1h-pyrrol-3-yl)-substituierte 3,5-dihydroxy-hept-6-ensaeuren, 7-(1h-pyrrol-3-yl)-substituierte 3,5-dihydroxy-heptansaeuren, ihre entsprechenden (delta)-lactone und salze, verfahren zu ihrer herstellung ihre verwendung als arzneimittel, pharmazeutische praeparate und zwischenprodukte |
US4906624A (en) | 1987-09-08 | 1990-03-06 | Warner-Lambert Company | 6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis |
EP0308736A3 (en) | 1987-09-12 | 1990-02-14 | Nissan Chemical Industries Ltd. | Pyrimidine type mevalonolactones |
DE3739690A1 (de) | 1987-11-24 | 1989-06-08 | Hoechst Ag | Stabilisierte arzneistoffe, verfahren zu ihrer herstellung sowie stabile arzneizubereitungen |
US4866090A (en) | 1988-01-07 | 1989-09-12 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
NO890046L (no) | 1988-01-20 | 1989-07-21 | Bayer Ag | Disubstituerte pyridiner. |
NO177005C (no) | 1988-01-20 | 1995-07-05 | Bayer Ag | Analogifremgangsmåte for fremstilling av substituerte pyridiner, samt mellomprodukter til bruk ved fremstillingen |
US5216174A (en) | 1988-02-22 | 1993-06-01 | Warner-Lambert Co. | Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
US5245047A (en) | 1988-02-22 | 1993-09-14 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
US5097045A (en) | 1989-02-01 | 1992-03-17 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
AU621874B2 (en) | 1988-02-22 | 1992-03-26 | Warner-Lambert Company | Improved process for trans-6-(2-(substituted-pyrrol-1-yl) alkyl)pyran-2-one inhibitors of cholesterol synthesis |
US5149837A (en) | 1988-02-22 | 1992-09-22 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
US5124482A (en) | 1988-02-22 | 1992-06-23 | Warner-Lambert Company | Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis |
US5003080A (en) | 1988-02-22 | 1991-03-26 | Warner-Lambert Company | Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis |
US5030447A (en) | 1988-03-31 | 1991-07-09 | E. R. Squibb & Sons, Inc. | Pharmaceutical compositions having good stability |
US5024999A (en) | 1988-04-26 | 1991-06-18 | Nissan Chemical Industries Ltd. | Pyrazolopyridine type mevalonolactones useful as pharmaeuticals |
US4963538A (en) | 1988-06-29 | 1990-10-16 | Merck & Co., Inc. | 5-oxygenated HMG-CoA reductase inhibitors |
US4870187A (en) | 1988-08-23 | 1989-09-26 | Bristol-Myers Company | Antihypercholesterolemic tetrazol-1-yl compounds |
US5004651A (en) | 1989-01-24 | 1991-04-02 | Abbott Laboratories | Stabilizing system for solid dosage forms |
FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
HRP960313B1 (en) | 1995-07-17 | 2002-08-31 | Warner Lambert Co | Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1) |
EE03606B1 (et) * | 1995-07-17 | 2002-02-15 | Warner-Lambert Company | Kristalliline [R-(R*,R*)]-2-(4-fluorofenüül)-beeta, delta-dihüdroksü-5-(1-metüületüül)-3-fenüül-4-[(fenüülamino)karbonüül]-1H-pürrool-1-hept aanhappehemikaltsiumsool (atorvastatiin) |
HRP960312B1 (en) | 1995-07-17 | 2001-10-31 | Warner Lambert Co | NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS /R-(R*, R*)/-2-(4-FLUOROPHENYL)-"beta", "delta"-DIHYDROXY-5-PHENYL-4-/(PHENYLAMINO)CARBONYL/-1H-PYRROLE -1-HEPTANOIC ACID CALCIUM SALT (2 : 1) |
US6087511A (en) | 1996-07-16 | 2000-07-11 | Warner-Lambert Company | Process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl )-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid) calcium salt (2:1) |
RS100003A (en) * | 2001-06-29 | 2007-02-05 | Warner-Lambert Company, | Crystalline forms of /r-(r*,r*)-2-(4- fluorphenyl)-beta,delta -dihydroxy-5(1- methylethyl)-phenyl-4-/phenylamino) carbonyl/-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
CA2465565A1 (en) | 2003-06-12 | 2004-12-12 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
-
1990
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- 1991-02-26 US US07/660,976 patent/US5273995A/en not_active Ceased
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