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WO1999000125A1 - 9a-aza-3-cetolides, compositions contenant ces composes et procedes de traitement - Google Patents

9a-aza-3-cetolides, compositions contenant ces composes et procedes de traitement Download PDF

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Publication number
WO1999000125A1
WO1999000125A1 PCT/US1998/013061 US9813061W WO9900125A1 WO 1999000125 A1 WO1999000125 A1 WO 1999000125A1 US 9813061 W US9813061 W US 9813061W WO 9900125 A1 WO9900125 A1 WO 9900125A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
groups
substituted
accordance
Prior art date
Application number
PCT/US1998/013061
Other languages
English (en)
Inventor
Timothy A. Blizzard
Sherman T. Waddell
Gina M. Santorelli
Jerry D. Ii Morgan
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9800457.5A external-priority patent/GB9800457D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU79860/98A priority Critical patent/AU7986098A/en
Publication of WO1999000125A1 publication Critical patent/WO1999000125A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to 9a-aza-3-ketolides, compositions containing such compounds and methods of use therefore.
  • Azalides are structurally similar to erythromycin A, except for the presence of a ring nitrogen atom at the 9a-position.
  • the compounds of the invention are further distinguished from erythromycins and erythromycin-like compounds in that the cladinose moiety has been cleaved from the molecule, and a carbonyl group is present at position 3.
  • R 11 is selected from the group consisting of: NR'R", 0(CH 2 ) n Ar and S(CH 2 ) n Ar; and R 12 represents a member selected from the group consisting of: H, Cl-6 alkyl, uninterrupted or interrupted by 1-3 of O, S(0) y , N, NH, NCH 3 or C(O), and unsubstituted or substituted with 1-3
  • R n represents H, Cl-6 alkyl, Cl-6 alkyl interrupted by 1-3 of O, S(0) y , N, NH, NCH 3 or C(O), unsubstituted or substituted with 1-
  • R z represents Cl-6 alkyl or phenyl
  • R' is selected from H, C ⁇ alkyl, NHR"and (CH2) n Ar, and
  • R" represents H, C 3 alkyl or (CH2) n Ar.
  • composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • Also included is a method of treating a bacterial infection in a mammalian patient in need of such treatment which is comprised of administering to said patient a compound of formula I in an amount which is effective for treating a bacterial infection.
  • Alkyl refers to Cl-6 straight or branched chain alkyl groups.
  • the alkyl group can be uninterrupted or interrupted of O, S(0) y wherein y is 0, 1 or 2, N, NH, NCH 3 or C(O) as specified.
  • interrupted a methylene spacer can be present which is adjacent to an interrupting moiety. Thus, this would include, for example, -CH2-O- and -0-CH2-. When two or three of these interrupting groups is present, they may be separate or together.
  • Me represents methyl.
  • Acyl refers to C 1-5 alkyl-C(O)-.
  • the alkyl portion - (CH2)n can be uninterrupted or interrupted as described above, with O, S(0) y wherein y is 0, 1 or 2, NH, NCH 3 or C(O).
  • -C(O)- phenyl, -NH-phenyl, -C(0)NH-(CH2)i-io-phenyl, -CH2-0-phenyl as well as like groups are included.
  • the alkylene portion can be substituted with 1-3 groups selected from R a .
  • Ar and Ar substituted with 1-3 R a groups include phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, imidazolyl, pyrrolyl, thiophenyl, benzothiazolyl, thiazolyl, furanyl, benzofuranyl, indolyl, fluorenonyl, dibenzofuranyl and naphthosultamyl.
  • Halo means Cl, F, Br or I.
  • R n represents H, Cl-6 alkyl, Cl-6 alkyl substituted with 1-3 R a groups or (CH2) n Ar. Within this subset of compounds all other variables are as originally defined.
  • Another preferred aspect of the invention relates to compounds wherein R represents CH 3 .
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR",
  • RU and Rl are taken separately, and RU is selected from the group consisting of: OH and 0(CH 2 ) n Ar, in which (CH 2 ) n and Ar are as previously defined, and
  • the cladinose removal may be best effected at either an early or late stage of the synthesis.
  • This is generally accomplished by treating the macrolide with acid in either aqueous or alcoholic solution.
  • a solution of the macrolide in an alcohol such as methanol, ethanol, or the like containing from 0.5 to 5% of a strong acid such as hydrochloric acid, sulfuric acid, or the like is stirred for 1 to 36 hours at a temperature ranging from 0°C to 30°C.
  • Some reactions may also necessitate protection of other hydroxyl groups. This may be accomplished by protection as a silyl ether, an ester, a mixed carbonate, or any of a variety of hydroxyl protecting groups well-known to those skilled in the art.
  • Many of the compounds of the present invention contain fewer oxygen atoms attached to the macrolide ring than are present in erythromycin.
  • Such deoxy analogs can be prepared by employing one of many deoxygenation methods for reductive removal of a hydroxyl group.
  • a solution of the methyl xanthate in a suitable solvent such as toluene, benzene, and the like is treated with a radical initiator such as azobis-isobutyrylnitrile (AIBN), triethylborane, and the like and an excess of a hydride source such as tributyltin hydride, triphenyltin hydride, and the like at a temperature ranging from room temperature to 125°C for 1 to 24 hours.
  • a radical initiator such as azobis-isobutyrylnitrile (AIBN), triethylborane, and the like
  • a hydride source such as tributyltin hydride, triphenyltin hydride, and the like
  • the 11,12-cyclic carbamate can be introduced at a stage in the sequence with the 9a nitrogen.
  • Introduction of the 3-keto group is accomplished by oxidation of a suitably protected precursor with a hydroxyl group at C- 3 using one of the many methods for oxidation of secondary alcohols which are well-known to those skilled in the art.
  • the compounds of this invention may be used in a variety of pharmaceutical preparations. They may be employed in powder or crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically, orally and parenterally by injection. Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions. The oral compositions may utilize conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.
  • the preferred pharmaceutical composition is a table, capsule, suspension or solution, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • a dose of about 1000-2000 mg three to four times daily may be recommended.
  • Step 6 3-descladinosyl-9-deoxo-9a-aza-9a-homoerythromycin A 11.12- carbonate-9a-N,-6-0-carbamate
  • Step 1 2 , -0-acetyl-9a-N.6-0— methylene-9-deoxo-9a-aza-9a- homoerythromycin A
  • methylene-9-deoxo-9a-aza-9a- homoerythromycin A To a solution of 2.98 g of 9-deoxo-9a-aza-9a- homoerythromycin A in 70 mL of chloroform is added 0.750 mL of 37% aq. formaldehyde. The mixture is refluxed for 1.5 hours, after which time the reaction is diluted with 150 mL chloroform and extracted with 50 mL of sat. aq. potassium carbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent removed under reduced pressure.
  • the mixture is refluxed for 1 hour, after which time the reaction is diluted with 150 mL chloroform and extracted with 50 mL of sat. aq. potassium carbonate. The organic layer is separated, dried over anhydrous potassium carbonate, and the solvent is removed under reduced pressure to afford the title compound.
  • Step 5 2'-acetoxy-3-descladinosyl-3-oxo-9a-N,6-0-methylene-9-deoxo- 9a-aza-9a-homoerythromycin A- 11.12 carbonate To a solution of 0.158 g of 2'-0-acetyl-3-descladinosyl-9a-

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des composés de formule (I) ainsi que des sels et des hydrates de ces derniers. Des compositions pharmaceutiques et des procédés de traitement sont également décrits.
PCT/US1998/013061 1997-06-27 1998-06-24 9a-aza-3-cetolides, compositions contenant ces composes et procedes de traitement WO1999000125A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU79860/98A AU7986098A (en) 1997-06-27 1998-06-24 9a-aza-3-ketolides, compositions containing such compounds and methods of treatment

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5111597P 1997-06-27 1997-06-27
US60/051,115 1997-06-27
GB9800457.5 1998-01-09
GBGB9800457.5A GB9800457D0 (en) 1998-01-09 1998-01-09 9a-Aza-3-ketolides, compositions containing such compounds and methods of treatment

Publications (1)

Publication Number Publication Date
WO1999000125A1 true WO1999000125A1 (fr) 1999-01-07

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AU (1) AU7986098A (fr)
WO (1) WO1999000125A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014397A1 (fr) * 1999-08-24 2001-03-01 Abbott Laboratories 9a-azalides a activite antibacterienne
US6764996B1 (en) 1999-08-24 2004-07-20 Abbott Laboratories 9a-azalides with antibacterial activity
US7271155B2 (en) 2005-01-07 2007-09-18 Enanta Pharmaceuticals, Inc. 9A, 11-2C-bicyclic 9a-azalide derivatives
US7276487B2 (en) 2003-09-23 2007-10-02 Enanta Pharmaceuticals, Inc. 9a, 11-3C-bicyclic 9a-azalide derivatives
US7402568B2 (en) 2004-09-29 2008-07-22 Enanta Pharmaceuticals, Inc. Bicyclic 9a-azalide derivatives
EP2625185A4 (fr) * 2010-10-10 2014-03-26 Synovo Gmbh Macrolides antiinflammatoires
CN105246334A (zh) * 2013-04-04 2016-01-13 哈佛大学的校长及成员们 大环内酯及其制备和使用方法
JP2018509452A (ja) * 2015-03-25 2018-04-05 プレジデント アンド フェローズ オブ ハーバード カレッジ 修飾デソサミン糖をもつマクロライドおよびその使用
US10633407B2 (en) 2014-10-08 2020-04-28 President And Fellows Of Harvard College 14-membered ketolides and methods of their preparation and use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283055A2 (fr) * 1987-09-03 1988-09-21 SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. Dérivés de 10-dihydro-10-déoxo-11-azaérythronolide-A, procédés et intermédiaires pour leur préparation et leur utilisation dans et pour la préparation de médicaments
FR2691464A1 (fr) * 1992-05-21 1993-11-26 Roussel Uclaf Nouveaux dérivés de la 1-oxa 6-azacyclopentadécane 13,15-dione, leur procédé de préparation et leur application comme médicaments.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0283055A2 (fr) * 1987-09-03 1988-09-21 SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. Dérivés de 10-dihydro-10-déoxo-11-azaérythronolide-A, procédés et intermédiaires pour leur préparation et leur utilisation dans et pour la préparation de médicaments
FR2691464A1 (fr) * 1992-05-21 1993-11-26 Roussel Uclaf Nouveaux dérivés de la 1-oxa 6-azacyclopentadécane 13,15-dione, leur procédé de préparation et leur application comme médicaments.

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DJOKIC ET AL.: "Erythromycin Series. Part 11. Ring Expansion of Erythromycin A Oxime by the Beckmann Rearrangement", JOURNAL OF THE CHEMICAL SOCIETY, PERKINS TRANS I, no. 11, 1986, pages 1881 - 1890, XP002913052 *
DJOKIC ET AL.: "Erythromycin Series. Part 13. Synthesis and Structure Elucidation of 10-Dihydro-10-deoxo-11-methyl-11-azaerythromycin A", JOURNAL OF CHEMICAL RESEARCH, no. 5, May 1988 (1988-05-01), pages 152 - 153, XP002913051 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014397A1 (fr) * 1999-08-24 2001-03-01 Abbott Laboratories 9a-azalides a activite antibacterienne
JP2003507487A (ja) * 1999-08-24 2003-02-25 アボット・ラボラトリーズ 抗菌活性を有する９ａ−アザライド類
US6764996B1 (en) 1999-08-24 2004-07-20 Abbott Laboratories 9a-azalides with antibacterial activity
US7276487B2 (en) 2003-09-23 2007-10-02 Enanta Pharmaceuticals, Inc. 9a, 11-3C-bicyclic 9a-azalide derivatives
US7402568B2 (en) 2004-09-29 2008-07-22 Enanta Pharmaceuticals, Inc. Bicyclic 9a-azalide derivatives
US7271155B2 (en) 2005-01-07 2007-09-18 Enanta Pharmaceuticals, Inc. 9A, 11-2C-bicyclic 9a-azalide derivatives
EP2625185A4 (fr) * 2010-10-10 2014-03-26 Synovo Gmbh Macrolides antiinflammatoires
US9145436B2 (en) 2010-10-10 2015-09-29 Michael W. Burnet Anti-inflammatory macrolides
JP2016520551A (ja) * 2013-04-04 2016-07-14 プレジデント アンド フェローズ オブ ハーバード カレッジ マクロライドならびにそれらの調製および使用の方法
JP2019055968A (ja) * 2013-04-04 2019-04-11 プレジデント アンド フェローズ オブ ハーバード カレッジ マクロライドならびにそれらの調製および使用の方法
CN105246334A (zh) * 2013-04-04 2016-01-13 哈佛大学的校长及成员们 大环内酯及其制备和使用方法
US11634449B2 (en) 2013-04-04 2023-04-25 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US9982005B2 (en) * 2013-04-04 2018-05-29 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US20180298048A1 (en) * 2013-04-04 2018-10-18 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
AU2014248014B2 (en) * 2013-04-04 2018-11-08 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US20160052951A1 (en) * 2013-04-04 2016-02-25 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
US10913764B2 (en) 2013-04-04 2021-02-09 President And Fellows Of Harvard College Macrolides and methods of their preparation and use
CN111825733A (zh) * 2013-04-04 2020-10-27 哈佛大学的校长及成员们 大环内酯及其制备和使用方法
US10633407B2 (en) 2014-10-08 2020-04-28 President And Fellows Of Harvard College 14-membered ketolides and methods of their preparation and use
US11466046B2 (en) 2014-10-08 2022-10-11 President And Fellows Of Harvard College 14-membered ketolides and methods of their preparation and use
US10640528B2 (en) 2015-03-25 2020-05-05 President And Fellows Of Havard College Macrolides with modified desosamine sugars and uses thereof
US11535643B2 (en) 2015-03-25 2022-12-27 President And Fellows Of Harvard College Macrolides with modified desosamine sugars and uses thereof
JP2018509452A (ja) * 2015-03-25 2018-04-05 プレジデント アンド フェローズ オブ ハーバード カレッジ 修飾デソサミン糖をもつマクロライドおよびその使用

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Publication number Publication date
AU7986098A (en) 1999-01-19

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