USRE39071E1 - Anhydro-and isomer-a-21978c cyclic peptides - Google Patents
Anhydro-and isomer-a-21978c cyclic peptides Download PDFInfo
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- USRE39071E1 USRE39071E1 US09/547,357 US54735700A USRE39071E US RE39071 E1 USRE39071 E1 US RE39071E1 US 54735700 A US54735700 A US 54735700A US RE39071 E USRE39071 E US RE39071E
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- 0 *N([4*])C(CC1=CNC2=C1C=CC=C2)C(=O)NC(CC(N)=O)C(=O)NC(CC(=O)O)C(=O)NC1C(=O)NCC(=O)NC(CCCN([2*])[5*])C(=O)NC(CC(=O)O)C(=O)NC(C)C(=O)NC2CC(=O)N(CC(=O)NC(CO)C(=O)NC(C(C)CC(=O)O)C(=O)NC(CC(=O)C3=CC=CC=C3N([1*])[3*])C(=O)OC1C)C2=O Chemical compound *N([4*])C(CC1=CNC2=C1C=CC=C2)C(=O)NC(CC(N)=O)C(=O)NC(CC(=O)O)C(=O)NC1C(=O)NCC(=O)NC(CCCN([2*])[5*])C(=O)NC(CC(=O)O)C(=O)NC(C)C(=O)NC2CC(=O)N(CC(=O)NC(CO)C(=O)NC(C(C)CC(=O)O)C(=O)NC(CC(=O)C3=CC=CC=C3N([1*])[3*])C(=O)OC1C)C2=O 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N CC(C)=O Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- GPMSRVMHHIYQHF-KBDPCFLNSA-N CNC.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.[2H-].[2H-].[CH2+]C[CH2-].[CH2+][CH2-] Chemical compound CNC.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.[2H-].[2H-].[CH2+]C[CH2-].[CH2+][CH2-] GPMSRVMHHIYQHF-KBDPCFLNSA-N 0.000 description 4
- HNUKTDKISXPDPA-UHFFFAOYSA-N C=C(C)=O Chemical compound C=C(C)=O HNUKTDKISXPDPA-UHFFFAOYSA-N 0.000 description 1
- FUSUHKVFWTUUBE-UHFFFAOYSA-N C=CC(C)=O Chemical compound C=CC(C)=O FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 1
- PHOKVZUNOLXIQP-RIEXDWNKSA-N C=CC.CC.CC.CC(C)=O.CCC.CCCC/C=C\CCCCCCCC(C)=O.CCCCC(C)=O.CCCCCC(C)=O.CCCCCCC(C)=O.CCCCCCCC.CCCCCCCCC(C)=O.CCCCCCCCCC(C)=O.CCCCCCCCCCC.CCCCCCCCCCC(C)=O.CCCCCCCCCCCC(C)=O.CCCCCCCCCCCCC.CCCCCCCCCCCCC(C)=O.CCCCCCCCCCCCCC(C)=O.CCCCCCCCCCCCCCC(C)=O Chemical compound C=CC.CC.CC.CC(C)=O.CCC.CCCC/C=C\CCCCCCCC(C)=O.CCCCC(C)=O.CCCCCC(C)=O.CCCCCCC(C)=O.CCCCCCCC.CCCCCCCCC(C)=O.CCCCCCCCCC(C)=O.CCCCCCCCCCC.CCCCCCCCCCC(C)=O.CCCCCCCCCCCC(C)=O.CCCCCCCCCCCCC.CCCCCCCCCCCCC(C)=O.CCCCCCCCCCCCCC(C)=O.CCCCCCCCCCCCCCC(C)=O PHOKVZUNOLXIQP-RIEXDWNKSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N CCC(C)=O Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- RSQKDYRLVQJCQM-RCEXDENJSA-N CNC.CNC.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.[2H-].[2H-].[2H-].[2H-].[CH2+]C[CH2-].[CH2+]C[CH2-] Chemical compound CNC.CNC.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.C[C@H]1[N-]C[C+2][C-](=O)C[N-][CH+]O[CH-][C+2][C-](=O)[C@H](CO)NC(=O)C[N-][C+2][C-]1=O.[2H-].[2H-].[2H-].[2H-].[CH2+]C[CH2-].[CH2+]C[CH2-] RSQKDYRLVQJCQM-RCEXDENJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to two new groups of derivatives of A-21978C cyclic peptides, designated “anhydro-A-21978C peptide derivatives” (formula 1 compounds) and “isomer-A-21978C peptide derivatives” formula 2 compounds).
- anhydro-A-21978C peptide derivatives formula 1 compounds
- “isomer-A-21978C peptide derivatives” formula 2 compounds.
- the two new groups of derivatives and their salts are useful semi-synthetic antibacterial agents or are intermediates to such agents.
- This invention also provides processes for preparing the anhydro- and isomer-derivatives by trans-peptidation of the parent peptides.
- this invention provides an improved antibacterial composition
- an improved antibacterial composition comprising the new drug substance LY146032, or a pharmaceutically-acceptable salt thereof, in substantially pure form.
- This invention further provides 1) methods of treating infections caused by susceptible Gram-positive bacteria which comprises administering a formula 1 or 2 compound to the animal to be treated, and 2) pharmaceutical formulations comprising a formula 1 or 2 compound or LY146032 in a pharmaceutically purified form as the active ingredient.
- the invention relates to new antibiotics and an improved form of the known antibiotic LY146032, which inhibit the growth of Gram-positive bacteria.
- the invention relates to two new groups of A-21978C cyclic peptide derivatives.
- the first group of derivatives, the anhydro-A-21978C peptide derivatives are compounds which have formula 1: in which R, R 1 and R 2 are, independently, hydrogen, C 4 -C 14 -alkyl, optionally substituted C 2 -C 19 -alkanoyl, C 5 -C 19 -alkenoyl or an amino-protecting group; R 3 , R 4 and R 5 are hydrogen or (i) R 3 and R 1 and/or (ii) R 4 and R and/or (iii) R 5 and R 2 , taken together, may represent a C 4 -C 14 alkylidene group; provided that 1) at least one of R, R 1 or R 2 must be other than hydrogen or an amino-protecting group, 2) at least one of R 1 or R 2
- the second group of A-21978C cyclic peptide derivatives are compounds which have formula 2: in which R, R 1 , R 2 , R 3 , R 4 and R 5 are as defined supra with the same provisos; and their salts.
- C 4 -C 14 -alkylidenyl refers to a group of the formula wherein R 3 a and R 4 a are hydrogen or an alkyl group of from 3 to 13 carbon atoms, provided that one of R 3 a and R 4 a must be other than hydrogen and further provided that the sum of the carbon atoms in R 3 a and R 4 a must be no greater than 13.
- Those compounds wherein one of R and R 4 , R 1 and R 3 or R 2 and R 5 is C 4 -C 14 -alkylidenyl are known as Schiff's bases.
- C 4 -C 14 -alkyl refers to a univalent saturated, straight- or branched-chain alkyl group containing from 4 to 14 carbon atoms.
- Those compounds wherein one of R, R 1 or R 2 are C 4 -C 14 -alkyl, referred to herein as “reduced Schiff's bases”, are prepared by reduction of the corresponding compounds where R and R 4 , R 1 and R 3 or R 2 and R 5 represent a C 4 -C 14 -alkylidenyl group.
- C 2 -C 19 -alkanoyl and “C 5 -C 19 -alkenoyl” refer to acyl groups derived from carboxylic acids containing from 2 to 19 and 5 to 19 carbon atoms, respectively.
- the alkyl portion is a univalent saturated, straight-chain or branched-chain hydrocarbon radical which can optionally bear one hydroxyl, carboxyl, or C 1 -C 3 -alkoxy group or from one to three halo substituents selected from chlorine, bromine, and fluorine.
- the alkenyl portion is a univalent, unsaturated, straight-chain or branched-chain hydrocarbon radical containing not more than three double bonds.
- the double bond portion(s) of the unsaturated hydrocarbon chain may be either in the cis or trans configuration.
- amino-protecting group refers to a recgonized amino-protecting group which is compatible with the other functional groups in the A-21978C molecule.
- amino-protecting groups are those which can be readily removed from the subsequently acylated compound. Examples of suitable protecting groups can be found in “Protective Groups in Organic Synthesis” by Theodora W. Greene, John Wiley and Sons, New York, 1981, chapter 7.
- suitable protecting groups can be found in “Protective Groups in Organic Synthesis” by Theodora W. Greene, John Wiley and Sons, New York, 1981, chapter 7.
- amino-protecting groups are the tert-butoxycarbonyl and benzyloxycarbonyl groups.
- the invention contemplates the following preferred embodiments of the compound of formulas 1 and 2
- the compounds of the formulas 1 and 2 are capable of forming salts. These salts are also part of this invention. Such salts are useful, for example, for separating and purifying the compounds.
- the compounds of formulas 1 and 2 have several free carboxyl groups which can form salts. Partial, mixed and complete salts of these carboxyl groups are, therefore, contemplated as part of this invention. In preparing these salts, pH levels greater than 10 should be avoided due to the instability of the compounds at such levels.
- Representative and suitable alkali-metal and alkaline-earth metal salts of the compounds of formulas 1 and 2 include the sodium, potassium, lithium, cesium, rubidium, barium, calcium and magnesium salts.
- the alkali-metal and alkaline-earth-metal cationic salts of the compounds for formula 1 and 2 are prepared according to procedures commonly used for the preparation of cationic salts.
- a suitable solvent such as warm methanol or ethanol.
- a solution containing a stoichiometric quantity of the desired inorganic base in aqueous methanol is added to this solution.
- the salt thus formed can be isolated by routine methods, such as filtration or evaporation of the solvent.
- a convenient method of preparing salts is by the use of ion-exchange resins.
- Suitable amine salts of the formula 1 and 2 compounds include the ammonium and the primary, secondary, and tertiary C 1 -C 4 -alkylammonium and hydroxy-C 2 -C 4 -alkylammonium salts.
- Illustrative amine salts include those formed by reaction of a formula 1 or 2 compound with ammonium hydroxide, methylamine, sec-butylamine, isopropylamine, diethylamine, di-isopropylamine, cyclohexylamine, ethanolamine, triethylamine, 3-amino-1-propanol and the like.
- the salts formed with organic amines can also be prepared by well known procedures.
- the gaseous or liquid amine can be added to a solution of a formula 1 or 2 compound in a suitable solvent such as ethanol.
- the solvent and excess amine can be removed by evaporation.
- acid addition salts are also part of this invention.
- Representative and suitable acid-addition salts of the compounds of formula 1 or 2 include those salts formed by standard reaction with both organic and inorganic acids such as, for example, hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic and like acids.
- alkali-metal, alkaline-earth-metal, amine and acid-addition salts are a particularly useful group of compounds of this invention.
- the formula 1 and 2 compounds are prepared from previously known A-21978C cyclic peptides, which in turn are prepared from the A-21978C antibiotics.
- the A-21978C antibiotics a group of closely related, acidic peptide antibiotics, are described by Robert L. Hamill and Marvin M. Hoehn in U.S. Pat. No. 4,208,403, issued Jun. 17, 1980.
- the A-21978 antibiotic complex contains a major component, factor C, which is itself a complex of closely related factors.
- A-21978 factor C which is called the A-21978C complex, contains individual factors C 0 , C 1 , C 2 , C 3 , C 4 and C 5 .
- Factors C 1 , C 2 and C 3 are major factors; and factors C 0 , C 4 and C 5 are minor factors.
- the A-21978C factors have the structure shown in formula 3: wherein R N represents a specific fatty acid moiety.
- R N represents a specific fatty acid moiety.
- the specific R N groups of the factors are as follows:
- A-21978C Factor R N Moiety C 1 8-methyldecanoyl C 2 10-methylundecanoyl C 3 10-methyldodecanoyl C o C 1,0 -alkamoyl* C 4 C 1,2 -alkamoyl** C 5 C 1,2 -alkamoyl** *A-21978C o was later found to be a mixture of two compounds in approximately 2:1 ratio, the R N of the major component being a cresched C 10 -alkamoyl, and the R N of the minor component being a n-decanoyl **Identity not yet determined
- the parent A-21978C cyclic peptides are prepared from the A-21978C antibiotics as described by Abbott, Manuel Debono and David S. Fukuda in U.S. Pat. No. 4,537,717.
- the preparation involves removing the fatty acid side chain (R N ) from the naturally occurring antibiotics with an enzyme produced by Actinoplanes utahensis NRRL 12052 to give the common A-21978C cyclic peptide (the A-21978C nucleus).
- the nucleus, or an appropriately substituted derivatives of the nucleus is then reacylated with the desired acyl group to give the parent group of cyclic peptides.
- the stable intermediate was found to be the compound of formula 1 wherein R is n-decanoyl and R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen. In discussions herein, this compound is designated “anhydro-LY146032”.
- the third compound was found to be the ⁇ -aspartyl isomer of LY146032, i.e. the formula 2 compound wherein R is n-decanoyl and R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen. In discussions herein this compound is designated “isomer-LY146032”.
- the formula 1 and 2 compounds are formed by aspartyl transpeptidation of the parent cyclic peptides, which include LY146032.
- the transpeptidation involves two distinct, reversible steps: (1) formation of the compounds of formula 1 (the anhydro intermediates) from either the parent ⁇ -aspartyl peptide or from the formula 2 peptides (the ⁇ -aspartyl peptides) and (2) hydrolysis of the intermediate formula 1 compounds to either the parent ⁇ -aspartyl peptides or to the ⁇ -aspartyl peptides of formula 2.
- the mechanism of transpeptidation involves formation of a succinimide intermediate, probably through intramolecular dehydration of the free carboxyl group of aspartic acid and the amino group of the neighboring glycine. This step is followed by nucleophilic hydroxide attack of either the ⁇ - or ⁇ -carbonyl of the succinimido intermediate which results in formation of the corresponding ⁇ - or ⁇ -aspartyl peptide. Formation of the ⁇ -aspartyl peptide predominates by a factor of 2-3, presumably because of the greater electrophilicity of the ⁇ -carbonyl of the succinimide intermediate.
- the transpeptidation reactions are shown in Scheme 1.
- this invention provides an improved antibacterial composition comprising the new drug substance LY146032 in substantially pure form.
- new drug substance LY146032 refers to LY146032 in bulk pharmaceutical form prior to its formulation as a pharmaceutical.
- substantially pure form refers to LY146032 which contains less than 2.5 percent of a combined total of anhydro-LY146032 and isomer-LY146032.
- the new drug substance LY146032 contained a combined total amount of anhydro- and isomer-LY146032 in amounts of at least 6 percent.
- the new derivatives of this invention inhibit the growth of a broad spectrum of pathogenic bacteria, especially Gram-positive bacteria.
- Table I summarizes the minimal inhibitory concentrations (MIC's) at which the two illustrative compounds, anhydro-LY146032 and isomer-LY146032, inhibit certain organisms, as determined by standard agar-dilution assays.
- the new derivatives of this invention have also shown in vivo antimicrobial activity against experimental bacterial infections.
- ED 50 value Effective dose in mg/kg to protect 50% of the test animals: see Warren Wick, et al., J. Bacteriol. 81, 233-235 (1961)].
- ED 50 values observed for the two illustrative derivatives are given in Table II.
- compositions of the compounds of formulas 1, and 2 or their salts and of pharmaceutically purified LY146032 or its salts are also part of this invention.
- the compounds preferably as a pharmaceutically acceptable salts, can be formulated for oral or parenteral administration for the therapeutic or prophylactic treatment of bacterial infections.
- a compound of this invention can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like.
- the compositions comprising a compound of this invention will contain from about 0.1 to about 90% by weight of the active compound, and more generally from about 10 to about 30%.
- compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid.
- common carriers and excipients such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid.
- Disintegrators commonly used in the formulations of this invention include croscarmellose sodium, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
- Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
- Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
- Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used.
- IV intravenous
- a water soluble form of the compound can be dissolved in one of the commonly used intravenous fluids and administered by infusion.
- Fluids such as, for example, physiological saline can be used.
- a sterile formulation of a suitable soluble salt form of the compound for example the hydrochloride salt
- a pharmaceutical diluent such as Water-for-Injection, physiological saline or 5% glucose.
- a suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate.
- solid formulations such as tablets and capsules are particularly useful.
- Sustained release or enterically coated preparations may also be devised.
- suspensions, syrups and chewable tablets are especially suitable.
- the unit dosage form of the antibiotic can be a solution of the compound or preferably a salt thereof in a suitable diluent in sterile, hermetically sealed ampoules.
- concentration of the antibiotic in the unit dosage may vary, e.g. from about 1 percent to about 50 percent, depending on the compound used and its solubility and the dose desired by the physician.
- this invention provides a method for treating infectious diseases, especially those caused by Gram-positive bacteria, in animals.
- the term “treating” is used to denote both the prevention of infectious diseases and the control of such diseases after the host animal has become infected.
- the method comprises administering to the animal an effective dose of a compound of this invention.
- An effective dose is generally between about 0.1 and about 100 mg/kg of the compound or its pharmaceutically acceptable salt.
- a preferred dose is from about 1 to about 30 mg/kg of compound.
- a typical daily dose for an adult human is from about 100 mg to about 1.0 g.
- the antibiotic compound can be administered as a single daily dose or in multiple doses per day.
- the treatment regime may require administration over extended periods of time, e.g., for several days or for from two to four weeks.
- the amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the antibiotic and the microorganism or microorganisms involved in the infection.
- a convenient method of practicing the treatment method is to administer the antibiotic orally, using tablets, capsules, suspensions, syrups and the like.
- the antibiotic may also be administered by other methods, e.g. as a suppository or parenterally via IV infusion.
- t-BOC derivative of LY146032 which contained t-BOC-anhydro-LY146032 (1.494 g) was chromatographed over an RP C-18 silica-gel prep-pak column (Prep 500 Unit), using a gradient containing H 2 O/MeOH/CH 3 CN with 0.1% pyridinium acetate as follows: 8 L of 2/1/1 ⁇ 32 L of 1/1/1, collecting 250-mL fractions. Fractions were combined based on TLC and UV analysis Fractions containing t-BOC-anhydro-LY146032 (Nos. 26-31) were combined, concentrated in vacuo to a volume of 100 mL and lyophilized to yield 320 mg of the product as a creme powder.
- the developing solvent was made up as follows:
- Diaion HP-20ss resin (18 L, Mitsubishi Chemical) which had previously been equilibrated with the developing solvent.
- the column was eluted at a flow-rate of 0.5 column volumes (CV)/hour.
- the developing solvent was chilled to 7° C. prior to applying it to the column.
- 4-L fractions were collected and assayed by analytical HPLC.
- fractions containing isomer-LY146032 (Nos. 9, 10, and 11) were pooled and chilled until they were desalted, using Diaion HP-20 resin as follows:
- the pooled fractions were diluted (1:1) with an equal volume of chilled deionized water. This solution was applied to a column of Diaion HP-20 resin (1 L) in the chillroom. The column was eluted at a flow-rate of 6 CV/hr. Effluent was collected and discarded. The column was then washed with 3 CV of chilled, deionized water, which was discarded. Isomer-LY146032 was then eluted from the column with 5 CV of a solution containing 60% acetonitrile and 40% chilled, deionized water. The active eluate was concentrated and freeze-dried to give 4.4 g of an enriched, desalted preparation of isomer-LY146032.
- This preparation was further purified using a reverse-phase C 18 column, followed by a Diaion HP-20 resin column in reverse mode operation.
- the material was dissolved in a developing solvent (200 mL) which consisted of 27% acetonitrile, 28% methanol with 1% acetic acid adjusted to pH 4.8 with sodium hydroxide.
- This solution was applied to a Chromatospac 100 column containing reverse-phase C 18 silica gel (4 L). The column was eluted at a flow-rate of 1 CV/hr, collecting 500-mL fractions and assaying by analytical HPLC. Fractions containing isomer-LY146032 (Nos. 14, 15, 16 and 17) were combined.
- This pooled fraction was further purified by diluting it with an equal volume of chilled, deionized water and adsorbing it onto Diaion HP-20 resin (100 mL) in a batch mode after adjusting the pH to 3.5 with sulfuric acid. After the mixture was stirred for at least one hour in the chillroom, the effluent was removed by filtration and discarded. The charged resin was washed with 2 volumes of chilled, deionized water, filtering and discarding the wash water. The charged resin (100 mL) was slowly added to 10 volumes of acetonitrile while stirring; then the hydrated resin was packed into a column.
- the resin column was then washed with 2.5 CV of a developing solvent consisting of 95% acetonitrile and 5% chilled, deionized water.
- the column was eluted first with 2.5 column volumes of 90% acetonitrile and 10% chilled, deionized water, collecting five 50-mL fractions, and then with 2.5 CV of 85% acetonitrile and 15% chilled, deionized water, collecting 50-mL fractions.
- the fractions were assayed by analytical HPLC.
- the fractions containing isomer-LY146032 were combined, concentrated under vacuum and freeze-dried to give 470 mg of purified isomer-LY146032.
- New drug substance LY146032 in pure form is prepared by purifying LY146032 using procedures like those in Examples 1-3 so that the substance contains no more than 2.5% by weight of a combined total of anhydro-LY146032 and isomer-LY146032.
- HPLC high performance liquid chromatography
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Abstract
Description
-
- Ala: alanine
- Asn: asparagine
- Asp: aspartic acid
- Gly: glycine
- Kyn: kynurenine
- 3-MG: L-threo-3-methylglutamic acid
- Orn: ornithine
- Ser: serine
- Thr: threonine
- Trp: tryptophan
- t-BOC: tert-butoxycarbonyl
- Cbz: benzyloxycarbonyl
- DMF: dimethylformamide
- THF: tetrahydrofuran
- HPLC: high performance liquid chromatography
- NMR: 1H nuclear magnetic resonance
- TLC: thin-layer chromatography
- UV: ultraviolet
in which R, R1 and R2 are, independently, hydrogen, C4-C14-alkyl, optionally substituted C2-C19-alkanoyl, C5-C19-alkenoyl or an amino-protecting group; R3, R4 and R5 are hydrogen or (i) R3 and R1 and/or (ii) R4 and R and/or (iii) R5 and R2, taken together, may represent a C4-C14 alkylidene group; provided that 1) at least one of R, R1 or R2 must be other than hydrogen or an amino-protecting group, 2) at least one of R1 or R2 must be hydrogen or an amino-protecting group, and 3) the R, R1 and R2 groups must together contain at least four carbon atoms; and their salts.
in which R, R1, R2, R3, R4 and R5 are as defined supra with the same provisos; and their salts.
wherein R3
-
- (a) The compounds wherein R is alkanoyl of the formula
- wherein n is an integer from 3 to 17;
- (b) The compounds wherein R is alkanoyl of the formula
- wherein n is 5 to 14;
- (c) The compounds wherein R is alkanoyl of the formula
- wherein n and m are each, independently, an integer from 0 to 14, provided that n+m must be no less than 1 and no greater than 15; and further provided that, when n is 0, m cannot be 8 and, when n is 1, m cannot be 6 or 8;
- (d) The compounds wherein R is cis or trans alkenyl of the formula
- wherein n and m are each, independently, an integer from 0 to 14, provided that nαm must be no less than 1 and no greater than 15;
- (e) The compounds where R is cis or trans alkenyl of the formula
- wherein n is an integer of from 4 to 15;
- (f) The compounds where R is alkyl of the formula CH3(CH2)n— and n is an integer from 5 to 12; and
- (g) The compounds wherein R is:
- (h) The compounds wherein R and R4 together are:
CH3(CH2)10OCH═
CH3(CH2)5CH═
CH3(CH2)8CH═
- (a) The compounds wherein R is alkanoyl of the formula
wherein RN represents a specific fatty acid moiety. The specific RN groups of the factors are as follows:
A-21978C Factor | RN Moiety |
C1 | 8-methyldecanoyl |
C2 | 10-methylundecanoyl |
C3 | 10-methyldodecanoyl |
Co | C1,0-alkamoyl* |
C4 | C1,2-alkamoyl** |
C5 | C1,2-alkamoyl** |
*A-21978Co was later found to be a mixture of two compounds in approximately 2:1 ratio, the RN of the major component being a brusched C10-alkamoyl, and the RN of the minor component being a n-decanoyl | |
**Identity not yet determined |
TABLE I |
Antibacterial Activity of A-21978C Derivativesa |
Compound |
Isomer- | Anhydro- | |||
Organism | LY146032 | LY146032 | ||
Staphylacoccus aureus XL1 | 8 | 4 | ||
Staphylacoccus aureus V41b | 8 | 4 | ||
Staphylacoccus aureus X400c | 8 | 8 | ||
Staphylacoccus aureus S13E | 8 | 4 | ||
Staphylacoccus epidermidis 222 | 8 | 4 | ||
Streptococcus pyogenes C203 | 2 | 1 | ||
Streptococcus pneumoniae Park 1 | 8 | 4 | ||
Streptococcus faecalis X66 | 128 | 64 | ||
Streptococcus faecalis 2041 | 32 | 16 | ||
Haemophilus influenzae CLd | —f | — | ||
Haemophilus influenzae 76e | — | — | ||
aMIC's in μg/mL | ||||
bPenicillin-resistant strain | ||||
cMethicillin-resistant strain | ||||
dAmpicillin-sensitive strain | ||||
eAmpicillin-resistant strain | ||||
f>128 |
TABLE II |
Subcutaneous ED50 Values for A-21978C |
Derivatives against Experimental |
Infections Induced by Organ-positive Bacteria |
Infecting Organism |
Staphylococcus | Streptococcus | Streptococcus | |
Compound | aueus | pyogenes | pneumoniae |
Anhydro- | 9.05 | 1.15 | 3.36 |
LY146032 | |||
Isomer- | 10.68 | <1.25 | 3.40 |
LY146032 | |||
-
- 65% by volume of 0.5 M sodium acetate in water, then pH adjusted to 4.7 with sodium hydroxide.
- 25% by volume of acetonitrile
- 10% by volume of methanol
-
- Analytical HPLC System
- Column: Zorbax C8 150Å (DuPont)
- Solvent: 32% CH3CN/68% H2O containing 0.5% (NH4)H2PO4
- Flow Rate: 1.5 mL/min
- Detection: UV at 214 nm
In this system, the LY146032 materials have the following approximate retention times:
- Analytical HPLC System
Compound | Retention Time (Seconds) | ||
LY146032 | 880 | ||
Anydro-LY146032 | 1238 | ||
Isomer-LY146032 | 847 | ||
Claims (31)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/547,357 USRE39071E1 (en) | 1987-06-10 | 2000-04-11 | Anhydro-and isomer-a-21978c cyclic peptides |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6014887A | 1987-06-10 | 1987-06-10 | |
US67037591A | 1991-03-14 | 1991-03-14 | |
US07/809,039 US5912226A (en) | 1987-06-10 | 1991-12-16 | Anhydro- and isomer-A-21978C cyclic peptides |
US09/547,357 USRE39071E1 (en) | 1987-06-10 | 2000-04-11 | Anhydro-and isomer-a-21978c cyclic peptides |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/809,039 Reissue US5912226A (en) | 1987-06-10 | 1991-12-16 | Anhydro- and isomer-A-21978C cyclic peptides |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE39071E1 true USRE39071E1 (en) | 2006-04-18 |
Family
ID=22027675
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/809,039 Ceased US5912226A (en) | 1987-06-10 | 1991-12-16 | Anhydro- and isomer-A-21978C cyclic peptides |
US09/547,357 Expired - Lifetime USRE39071E1 (en) | 1987-06-10 | 2000-04-11 | Anhydro-and isomer-a-21978c cyclic peptides |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US07/809,039 Ceased US5912226A (en) | 1987-06-10 | 1991-12-16 | Anhydro- and isomer-A-21978C cyclic peptides |
Country Status (3)
Country | Link |
---|---|
US (2) | US5912226A (en) |
CA (1) | CA1315229C (en) |
ZA (1) | ZA883887B (en) |
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US20090197799A1 (en) * | 2000-12-18 | 2009-08-06 | Dennis Keith | Methods for preparing purified lipotides |
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US20100310600A1 (en) * | 2008-02-15 | 2010-12-09 | Carter William A | Selective agonist of toll-like receptor 3 |
EP2264047A1 (en) | 2000-01-20 | 2010-12-22 | Cubist Pharmaceuticals, Inc. | High purity lipopeptides, lipopeptide micelles and processes for preparing same |
US20110196020A1 (en) * | 2008-10-10 | 2011-08-11 | Carter William A | Treatment of chronic fatigue syndrome using selective agonists of toll-like receptor 3 (tlr3) |
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Also Published As
Publication number | Publication date |
---|---|
CA1315229C (en) | 1993-03-30 |
US5912226A (en) | 1999-06-15 |
ZA883887B (en) | 1990-02-28 |
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