WO1999000124A1 - 9a-azalides, compositions a base de ces composes et procedes therapeutiques - Google Patents

9a-azalides, compositions a base de ces composes et procedes therapeutiques Download PDF

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Publication number
WO1999000124A1
WO1999000124A1 PCT/US1998/012174 US9812174W WO9900124A1 WO 1999000124 A1 WO1999000124 A1 WO 1999000124A1 US 9812174 W US9812174 W US 9812174W WO 9900124 A1 WO9900124 A1 WO 9900124A1
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WIPO (PCT)
Prior art keywords
alkyl
deoxo
aza
homoerythromycin
carbonate
Prior art date
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PCT/US1998/012174
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English (en)
Inventor
Timothy A. Blizzard
Sherman T. Waddell
Gina M. Santorelli
Jerry D. Ii Morgan
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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 GBGB9812249.2A external-priority patent/GB9812249D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU79614/98A priority Critical patent/AU7961498A/en
Publication of WO1999000124A1 publication Critical patent/WO1999000124A1/fr

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    • 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-azalides, compositions containing such compounds and methods of use therefore.
  • Azalides are structurally similar to erythromycin A, with the exception of 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.
  • the 9a-azalides of the present invention are potent antibiotics which are useful for the treatment of gram positive and gram negative organisms. As such the compounds find utility in human and veterinary medicine for the treatment of infections caused by susceptible organisms.
  • RU and Rl2 are taken separately or together; when taken together, Rl 1 and R ⁇ taken with the intervening atoms form an additional ring as shown in the following structure:
  • R' and Z are as defined below; when taken separately, RU is selected from the group consisting of: OH, OCH 3 , NR'R", 0(CH2) n Ar and S(CH2) 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,
  • R a groups or (CH2)nAr wherein (CH2) and Ar are as defined below,
  • (CH 2 ) n is alkylene, wherein n is an integer of from 1 to 10, uninterrupted or interrupted by 1-3 of O, S(0) y wherein y is 0, 1 or 2, NH, NCH 3 or C(O), and unsubstituted or substituted with 1-3 R a groups;
  • Ar represents a 5-10 membered monocyclic or bicyclic aromatic ring system containing from 0-3 heteroatoms, which are selected from O, S(0) y and N, unsubstituted or substituted with from 1-3 R a groups which are selected from halo, OH, OMe, N0 2 , NH 2 , CN, S0 2 NH 2 , C j.3 alkyl, and when two R a groups are present, said two substituents may be taken in combination with any intervening atoms to represent a 5-6 membered ring, aromatic or non-aromatic, optionally containing 1-3 of O, S(O) , N, NH, NCH 3 or C(O);
  • R represents H, CS2CH3, phenyl or Cl-6 alkyl, uninterrupted or interrupted by 1-3 of O, S(0) y , N, NH, NCH 3 or
  • R n represents 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 a groups, or (CH2)nAr wherein (CH2) and Ar are as defined above, and
  • R6 represents H or CH3, or R" and R are taken in conjunction with the intervening atoms and form an additional ring as shown in the following structure:
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR", Si(R z )2, SO, S02, CH2CO, COCH2, COCH2CH2, CH2CH2CO, CH2CH2 or CH2XCH2 in which X is as defined above;
  • R z represents Cl-6 alkyl or phenyl;
  • R' is selected from H, C 3 alkyl, NHR"and (CH2) n Ar wherein (CH2)n and Ar are as previously defined, and R" represents H, C ⁇ _ 3 alkyl or (CH2)nAr wherein (CH2)n and Ar are as previously defined.
  • composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • 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 by 1-3 of O, S(0) y wherein y is 0, 1 or 2, N, NH, NCH 3 or C(O), and unsubstituted or substituted with 1-3 R a groups. Included are moieties where the interrupting heteroatom is at either end of the alkyl group. Thus, a methylene spacer can be present which is adjacent to an interrupting moiety. Thus, this would include, for example,
  • 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, -CH 2 -0-phenyl as well as like groups are included.
  • Ar represent a monocyclic or bicyclic aromatic ring system containing from 0-3 heteroatoms, which are selected from O, S and N, unsubstituted or substituted with from 1-3 groups selected from
  • Ar examples include phenyl, naphthyl, quinolinyl, isoquinolinyl, pyridyl, imidazolyl, pyrrolyl, thiophenyl, benzothiazolyl, thiazolyl, furanyl, benzofuranyl, indolyl, fluorenonyl, dibenzofuranyl and naphthosultamyl.
  • Each R is independently selected from halo, OH, OMe, N ⁇ 2, NH2, CN, SO2NH2, Cl-3 alkyl, and when two R substituent groups are present, said substituents may be taken in combination with any intervening atoms to represent a 5-6 membered aromatic or non- aromatic ring, uninterrupted or interrupted by 1-3 of O, S(0)y , NH, NCH 3 or C(O) wherein y is as previously defined.
  • Halo means Cl, F, Br or I.
  • a preferred aspect of the invention relates to compounds of formula I wherein X contained in the azalide ring represents CH2, CHF or CF2- Within this subset of compounds, all other variables are as originally defined.
  • Yet another aspect of the invention relates to compounds of formula I wherein X contained in the azalide ring represents CHCH 3 or CHOR. Within this subset of compounds, all other variables are as originally defined.
  • R n represents H, Cl-6 alkyl or (CH 2 ) n Ar, and R is H or CH 3 .
  • R n represents H, Cl-6 alkyl or (CH 2 ) n Ar, and R is H or CH 3 .
  • Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from
  • RU is selected from the group consisting of: OH and 0(CH2)nAr, in which (CH2)n and Ar are as previously defined.
  • Rl2 represents H, Cl-6 alkyl or (CH2)nAr.
  • Rl2 represents H, Cl-6 alkyl or (CH2)nAr.
  • Another preferred aspect of the invention relates to compounds wherein Rl 1 and R ⁇ are taken together with the intervening atoms and form an additional ring of the following structure:
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR", Si(R z )2, SO, S ⁇ 2, CH2CO, COCH2, COCH2CH2, CH2CH2CO or CH2XCH2 wherein R', R" and X are as originally defined. Within this subset of compounds, all other variables are as originally defined.
  • Another preferred aspect of the invention relates to compounds wherein R6 a nd R n taken together with the intervening atoms form a ring as shown in the following structure:
  • a preferred subset of compounds of the present invention relates to compounds of formula I wherein:
  • X represents CH2, CHF or CF2
  • R n represents H, Cl-6 alkyl or (CH 2 ) n Ar; R 6 is H or CH 3 . or R6 an d R n taken together with the intervening atoms form a ring as shown in the following structure:
  • Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from O, S and N, unsubstituted or substituted with from 1-3 R groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and Cl-3 alkyl; R11 is selected from the group consisting of OH and 0(CH2)nAr, in which (CH2)n and Ar are as originally defined;
  • Rl2 represents H, Cl-6 alkyl or (CH2)nAr; or R! 1 and R ⁇ are taken together with the intervening atoms and form an additional ring disclosed in the following structure:
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR",
  • R n represents H, Cl-6 alkyl or (CH 2 ) n Ar;
  • R 6 is H or CH 3 . or R6 and R n taken together with the intervening atoms form a ring as shown in the following structure:
  • Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from O, S and N, unsubstituted or substituted with from 1-3 R groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and Cl-3 alkyl;
  • RU is selected from the group consisting of OH and 0(CH2)nAr, in which (CH2)n and Ar are as originally defined; Rl2 represents H, Cl-6 alkyl or (CH2)nAr; or RU and R ⁇ are taken together with the intervening atoms and form an additional ring disclosed in the following structure:
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR",
  • X represents CHCH 3 or CHOR
  • R n represents H, Cl-6 alkyl or (CH 2 ) n Ar;
  • R 6 is H or CH 3 . or R6 a nd R n taken together with the intervening atoms form a ring as shown in the following structure:
  • Ar represents a monocyclic or bicyclic aromatic ring system containing from 0-2 heteroatoms, which are selected from O, S and N, unsubstituted or substituted with from 1-3 R groups which are selected from halo, OH, OMe, NO2, NH2, CN, SO2NH2 and Cl-3 alkyl;
  • RU is selected from the group consisting of OH and 0(CH2)nAr, in which (CH2)n and Ar are as originally defined;
  • R12 represents H, Cl-6 alkyl or (CH2)nAr; or RU and R ⁇ are taken together with the intervening atoms and form an additional ring disclosed in the following structure:
  • Z represents CH2, C(O), C(NR"), P(0)OR", P(0)NRnR",
  • the compounds of the present invention are prepared from 9a-aza-9-deoxo-9a-homo-erythromycin A by a variety of synthetic routes. The process is illustrated by the following generic scheme:
  • 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.
  • aqueous solution 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 about 0°C to 30°C.
  • the reaction is worked up and the product macrolide isolated by first making the reaction mixture basic by adding an aqueous solution of a base such as sodium hydroxide, sodium bicarbonate, potassium carbonate and the like then extracting the macrolide product with a suitable organic solvent such as chloroform, ethyl acetate, and the like. If the reaction is run in an alcoholic solvent, the extraction procedure may be improved by first concentrating the reaction mixture under vacuum, preferably after addition of aqueous base to neutralize the acid.
  • a strong acid such as hydrochloric acid, sulfuric acid, or the like
  • 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.
  • Alkylation of the C-3, 6, 11, or 12 hydroxyl group may be accomplished by treating a solution of a suitably protected macrolide in a suitable solvent such as dimethylformamide, tetrahydrofuran, and the like with a strong base such as sodium hydride, potassium hexamethyl- disilazide, and the like at a temperature ranging from -40°C to 25°C for 1 to 30 minutes then adding a suitable alkylating reagent such as an alkyl iodide, an alkyl bromide, an alkyl trifluoromethanesulfonate, and epoxide, and the like and stirring the resulting reaction mixture at a temperature ranging from -40°C to 45°C for 15 minutes to 4 hours (appropriate temperature and length of time depends on the exact nature of the alkylating reagent).
  • a suitable solvent such as dimethylformamide, tetrahydrofuran, and the like
  • a strong base such as sodium hydride, potassium
  • 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.
  • the hydroxyl group can be converted to a xanthate ester by reaction with a base such as sodium hydride, potassium hexamethyldisilazide, and the like in a solution of a suitable solvent such as tetrahydrofuran, ether, dioxane and the like at temperatures ranging from -20°C to 30°C for 1 to 30 minutes followed by reaction of the resulting alkoxide with excess carbon disulfide and iodomethane to form a methyl xanthate.
  • the methyl xanthate can be purified using standard techniques or, alternatively, may be subjected to the radical deoxygena- tion procedure without purification.
  • 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), triethyl- borane, 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), triethyl- borane, and the like
  • AIBN azobis-isobutyrylnitrile
  • a hydride source such as tributyltin hydride, triphenyltin hydride, and the like
  • the cyclic carbamate may be introduced into the erythromycin molecule before the ring expansion and incorporation of the 9a-nitrogen using standard techniques of macrolide chemistry which have been published in the literature and are well known to those skilled in the art. Once the cyclic carbamate moiety is in place, the 9a-nitrogen may be installed using the standard ring expansion techniques which have been previously published.
  • the alkyl group may either be incorporated during the construction of the cyclic carbamate or may be added to the completed cyclic carbamate via an alkylation procedure.
  • the 11,12-cyclic carbamate can be introduced at a stage in the sequence with the 9a nitrogen.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art.
  • the deprotected final product is then purified, as necessary, using standard techniques such as silica gel chromatography, HPLC on silica gel or on reverse phase silica gel, and the like or by recrystallization.
  • the final product may be characterized structurally by standard techniques such as NMR, IR, MS and UV.
  • the final product if not crystalline, may be lyophilized from, e.g., benzene, tert-butanol and the like, to afford an amorphous, easily handled solid.
  • compositions are useful in various pharmaceutically acceptable salt forms.
  • pharmaceutically acceptable salt refers to those salt forms which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.
  • pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
  • Non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methane- sulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
  • 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.
  • the dosage to be administered depends to a large extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters are left to the routine discretion of the physician according to principles of treatment well known in the antibacterial arts.
  • the compositions for human delivery per unit dosage may contain from about 0.01% to as high as about 99% of active material, the preferred range being from about 10-60%.
  • the composition will generally contain from about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 25 mg to 1000 mg.
  • the preferred method of administration is oral. For adults, about 5-50 mg of the compound per kg of body weight given one to four times daily is preferred.
  • the preferred dosage is 250 mg to 1000 mg of the compound given one to four times per day. More specifically, for mild infections a dose of about 250 mg two or three times daily is recommended. For severe infections caused by organisms at the upper limits of sensitivity to the antibiotic, a dose of about 1000-2000 mg three to four times daily may be recommended.
  • a dose of about 5-25 mg kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg may be recommended.
  • Step 1 9-Deoxo-9a-aza-9a-methyl-3-descladinosyl-9a- homoervthromvcin A
  • Step 2 2'-0-Acetyl-9-deoxo-9a-aza-9a-methyl-3-descladinosyl-9a- homoerythromycin A
  • dichloromethane 30 mL
  • acetic anhydride (0.54 mL, 5.7 mmol)
  • the solvent is removed in vacuo.
  • the residual is dissolved in water (50 mL) and the pH adjusted to between 10-11 with 5N aqueous sodium hydroxide.
  • the aqueous layer is extracted with dichloromethane (3 x 60 mL).
  • the combined organic extracts are dried (anhydrous sodium sulfate), filtered, and evaporated to give the title compound . -21-
  • Step 3 2'-0-Acetyl-9-deoxo-9a-aza-9a-methyl-3-descladinosyl-9a- homoerythromycin A 11,12-carbonate
  • 3-descladinosyl-9a-homoerythromycin A (100 mg, 0.16 mmol) in anhydrous tetrahydrofuran (0.53 mL) is stirred at room temperature as sodium hydride (60% dispersion in mineral oil, 13.3 mg, 0.33 mmol) and l,l'-carbonyldiimidazole (120.4 mg, 0.74 mmol) is added. The resulting mixture is stirred at 55-60°C. The reaction is partitioned between ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous sodium sulfate), and evaporated.
  • Step 1 2 ⁇ 3-bis-(0-Acetyl)-9-deoxo-9a-aza-9a,6-0-methylene-3- descladinosyl-9a-homoerythromycin A 11,12-carbonate
  • a solution of 2'-0-acetyl-9-deoxo-9a-aza-9a,6-0- methylene-3-descladinosyl-l l-0,12-0-carbonyl-9a-homoerythromycin A (32.8 mg, 0.05 mmol) in pyridine (1 mL) is stirred at room temperature as acetic anhydride (0.050 mL, 0.53 mmol) is added. The resulting solution is capped and stirred overnight.
  • Step 2 3-0-Acetyl-9-deoxo-9a-aza-9a,6-0-methylene-3- descladinosyl-9a-homoerythromycin A 11,12-carbonate
  • Step 1 2'-0-Acetyl-9-deoxo-9a-aza-9a,6-0-methylene-3- descladinosyl-3-0-methoxyethoxymethyl-9a- homoervthromycin A 11,12-carbonate
  • a solution of 2'-0-acetyl-9-deoxo-9a-aza-9a,6-0- methylene-3-descladinosyl-9a-homoerythromycin A 11,12-carbonate (100 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) in dichloromethane (0.5 mL) are stirred under a nitrogen atmosphere as 2-methoxyethoxymethyl chloride (0.087 mL, 0.76 mmol) is added dropwise.
  • Step 2 9-Deoxo-9a-aza-9a,6-0-methylene-3-descladinosyl-3-0- methoxyethoxymethyl-9a-homoerythromycin A 11,12- carbonate
  • Step 1 2'-0-Acetyl-9-deoxo-9a-aza-9a,6-0-methylene-3- descladinosyl-3-0-methoxymethyl-9a-homoerythromycin A
  • N,N-diisopro ⁇ ylethylamine (0.046 mL, 0.046 mL, 0.092 mL, & 0.092 mL) and chloromethyl methyl ether (0.018 mL, 0.018 mL, 0.036 mL, & 0.036 mL) are added portionwise.
  • the reaction is partitioned between saturated aqueous potassium carbonate and dichloromethane.
  • the organic layer is dried (anhydrous potassium carbonate), filtered, and concentrated.
  • the mixture is chromatographed on a silica gel column (5g, 1.4 cm dia., 8 mL fractions) and the appropriate fraction is evaporated to give the title compound.
  • Step 2 2'-0-Acetyl-9-deoxo-9a-aza-9a,6-0-methylene-3- descladinosyl-3-0-methoxymethyl-9a-homoerythromycin A
  • Step 1 2 ⁇ 4"-bis(0-Acetyl)-9-deoxo-9a-aza-9a-N,6-0-methylene-
  • Step 2 2',4"-bis(0-Acetyl)-9-deoxo-9a-aza-9a-N,6-0-methylene-
  • Step 3 2',4"-bis(0-Acetyl)-9-deoxo-9a-aza-9a-homoerythromycin A 11.12-carbonate
  • a solution of 0.1 M aqueous acetic acid 250 mL is added to 2',4"-bis(0-acetyl)-9-deoxo-9a-aza-9a,6-0-methylene-9a-homo- erythromycin A 11,12-carbonate (1.09 g, 1.2 mmol).
  • the resulting suspension is stirred at room temperature for 8 hours.
  • the aqueous layer is washed with ethyl acetate (5 mL).
  • the aqueous layer is made basic by the dropwise addition of saturated aqueous potassium carbonate and extracted with ethyl acetate (2 x 250 mL).
  • the combined organic layers are washed with brine, dried over anhydrous potassium carbonate, and evaporated to give the title compound.
  • Step 4 2',4"-bis(0-Acetyl)-9-deoxo-9a-aza-9a-homoerythromycin
  • the crude solid is dissolved in 2:1 hexane: acetone and loaded onto a silica gel column (2.75 cm dia., 22 g of silica, 20 mL fractions), eluted with the same solvent system.
  • the appropriate fractions can be combined, evaporated, and lyophilized (from benzene) to give the title compound.
  • Step 6 3-descladinosyl-9-deoxo-9a-aza-9a-homoerythromycin A 11.12-carbonate-9a-N.-6-Q-carbamate
  • a solution of 2'-0-acetyl-9-deoxo-9a-aza-9a,6-0-carbonyl- l l-0,12-0-carbonyl-3-descladinosyl-9a-homoerythromycin A (11.1 mg, 0.017 mmol) is stirred in methanol (3 mL). The solvent is evaporated and the residue lyophilized (from benzene) to give the title compound.
  • Step 1 2'-0-Acetyl-3-descladinosyl-3-0-methylxanthyl-9-deoxo-
  • a solution containing 2'-0-acetyl-3-descladinosyl-9-deoxo- 9a-aza-9a-homoerythromycin A l l,12-carbonate-9a-N,6-0-carbamate (78.4 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) is cooled to -20°C and placed under a nitrogen atmosphere. After 15 minutes, the reaction is treated with carbon disulfide (0.011 mL, 0.18 mmol). After stirring for 2 minutes, iodomethane (0.011 mL, 0.18 mmol) is added. After 15 minutes, the resulting solution is allowed to warm to room temperature and stir for 3.33 hours.
  • the reaction is partitioned between dichloromethane and saturated aqueous potassium carbonate.
  • the aqueous layer is extracted twice with dichloromethane.
  • the combined organic layers are washed with water (3x), dried over anhydrous potassium carbonate, filtered, evaporated, and lyophilized (from benzene) to afford the title compound.
  • Step 2 2'-0-Acetyl-3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a- homoerythromycin A 11.12-carbonate-9a-N.6-Q-carbamate A solution of 2'-0-Acetyl-3-descladinosyl-3-0-xanthyl-
  • Step 3 3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a- homoerythromycin A l l,12-carbonate-9a-N.6-Q-carbamate A solution of 2'-0-acetyl-3-descladinosyl-3-deoxy-9-deoxo-
  • Step 1 2'-0-Acetyl-3-descladinosyl-3-0-methylxanthyl-9a-N,-6-
  • the bath is allowed to warm to -10°C, and the flask is removed and stirred at room temperature.
  • the reaction mixture is poured into ethyl acetate.
  • the organic layer is washed with saturated aqueous NaHC ⁇ 3, dried over K2CO3, and filtered. Removal of solvent under reduced pressure affords the crude product.
  • Step 2 2'-0-Acetyl-3-descladinosyl-3-deoxy-9a-N,-6-0-methylene-
  • Step 3 3-descladinosyl-3-deoxy-9a-N,-6-0-methylene-9-deoxo-9a- aza-9a-homoerythromycin A 11,12-carbonate A solution of 2'-0-acetyl-3-descladinosyl-3-deoxy-9a-
  • N,-6-0-methylene-9-deoxo-9a-aza-9a-homoerythromycin A 11,12- carbonate (537 mg) in methanol (30 mL) is stirred at room temperature overnight. The solvent is removed under reduced pressure to afford the crude product which can be purified by silica chromatography eluted with 1 : 1 hexane: acetone to afford the title compound.
  • Step 1 3-descladinosyl-3-0-methylxanthyl-9a ⁇ N,-6-0-methylene-
  • Step 1 2'-0-acetyl-3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a- homoervthromvcin A 11,12-carbonate A solution of 2'-0-acetyl-3-descladinosyl-3-deoxy-9a-N,-6-
  • Step 2 3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a- homoerythromycin A 11,12-carbonate
  • Step 1 2'-0-acetyl-3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a- methyl9a-homoerythromycin A 11,12-carbonate
  • Formaldehyde (0.0080 mL, 0.109 mmol) and formic acid (0.0090 mL, 0.212 mmol) are added to a solution of 2'-0-acetyl-3- descladinosyl-3-deoxy-9-deoxo-9a-aza-9a-homoerythromycin A 11,12- carbonate (64 mg, 0.101 mmol) in chloroform (1 mL).
  • the reaction mixture is stirred at 60°C, then diluted with dichloromethane and water.
  • the pH is adjusted to ⁇ 4-5 with glacial acetic acid.
  • the organic layer is separated and the aqueous layer extracted with dichloromethane.
  • the organic layer is washed, dried over anhydrous K2CO3, filtered, and evaporated to afford the title compound.
  • Step 2 3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a-methyl-9a- homoerythromycin A 11,12-carbonate A solution of 2'-0-acetyl-3-descladinosyl-3-deoxy-9-deoxo-
  • Step 1 2'-0-acetyl-3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a-N- bromoacetyl-9a-homoery thromy cin A- 11 , 12-carbonate
  • Step 2 3-descladinosyl-3-deoxy-9-deoxo-9a-aza-9a ⁇ N,6-0-(l- oxoethylene -9a-homoerythromycin A
  • the product of the previous step is dissolved in 2.5 mL of anhydrous DMF and NaH 26 mg is added .
  • the reaction mixture is stirred at room temperature for 2.5 hours under a N2 atmosphere, and extracted into ethyl acetate.
  • the organic layer is washed with saturated aqueous NaHC03 and the aqueous wash is back extracted with EtOAc.
  • the combined organic layers are washed with NaHC ⁇ 3, dried over K2CO3, filtered, and the solvent is removed under reduced pressure.
  • the crude product is purified by silica chromatography eluted with 1: 1 hexane:acetone. The fractions containing the desired material are combined and solvent removed under reduced pressure to provide the title compound.

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Abstract

L'invention concerne des composés de formule (I) ainsi que leurs sels et hydrates. Pour une partie des éléments représentés dans ladite formule (I), est CH2, CHF, CF2, C=CH2, CHSR, CHCH3, C=S ou CHOR. L'invention concerne également des compositions pharmaceutiques et des procédés thérapeutiques.
PCT/US1998/012174 1997-06-26 1998-06-22 9a-azalides, compositions a base de ces composes et procedes therapeutiques WO1999000124A1 (fr)

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US5081097P 1997-06-26 1997-06-26
US60/050,810 1997-06-26
GBGB9812249.2A GB9812249D0 (en) 1998-06-06 1998-06-06 9A-Azalides, compositions containing such compounds and methods of treatment
GB9812249.2 1998-06-06

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020639A2 (fr) * 1997-10-16 1999-04-29 Pliva, Farmaceutska Industrija ,Dionicko, Drustvo NOUVEAUX 3,6-HEMICETALS APPARTENANT A LA CLASSE DES 9a-AZALIDES
WO2001014397A1 (fr) * 1999-08-24 2001-03-01 Abbott Laboratories 9a-azalides a activite antibacterienne
US6262030B1 (en) 1998-11-03 2001-07-17 Pfizer Inc. Erythromycin derivatives
US6764996B1 (en) 1999-08-24 2004-07-20 Abbott Laboratories 9a-azalides with antibacterial activity
US7015203B2 (en) 1998-01-02 2006-03-21 Pfizer Inc. Macrolides
JP2006513157A (ja) * 2002-10-29 2006-04-20 ザンボン グループ ソシエタ ペル アチオニ 抗炎症性活性を有する９ａ−アザライド
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
WO2014166503A1 (fr) 2013-04-10 2014-10-16 Probiotic Pharmaceuticals Aps Dérivés antimicrobiens d'azithromycine à effet pharmaceutique non antibiotique

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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.

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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.

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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, XP002912768 *
DJOKIC ET EL: "Erythromycin Series. Part 13. Synthesis and Structure Elucidation of 10-Dihydro-10-deoxo-11-methyl-11-azaerythromycin A", JOURNAL OF CHEMICAL RESEACH, no. 5, May 1988 (1988-05-01), pages 152 - 153, XP002912767 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020639A2 (fr) * 1997-10-16 1999-04-29 Pliva, Farmaceutska Industrija ,Dionicko, Drustvo NOUVEAUX 3,6-HEMICETALS APPARTENANT A LA CLASSE DES 9a-AZALIDES
WO1999020639A3 (fr) * 1997-10-16 1999-07-08 Pliva Pharm & Chem Works NOUVEAUX 3,6-HEMICETALS APPARTENANT A LA CLASSE DES 9a-AZALIDES
US7015203B2 (en) 1998-01-02 2006-03-21 Pfizer Inc. Macrolides
US6262030B1 (en) 1998-11-03 2001-07-17 Pfizer Inc. Erythromycin derivatives
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
JP2006513157A (ja) * 2002-10-29 2006-04-20 ザンボン グループ ソシエタ ペル アチオニ 抗炎症性活性を有する９ａ−アザライド
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
WO2014166503A1 (fr) 2013-04-10 2014-10-16 Probiotic Pharmaceuticals Aps Dérivés antimicrobiens d'azithromycine à effet pharmaceutique non antibiotique

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