WO1999020269A1 - Antibacterial carbapenems, compositions and methods of treatmemt - Google Patents
Antibacterial carbapenems, compositions and methods of treatmemt Download PDFInfo
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- WO1999020269A1 WO1999020269A1 PCT/US1998/022009 US9822009W WO9920269A1 WO 1999020269 A1 WO1999020269 A1 WO 1999020269A1 US 9822009 W US9822009 W US 9822009W WO 9920269 A1 WO9920269 A1 WO 9920269A1
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- 0 C1C2(C3)C1C*3*2 Chemical compound C1C2(C3)C1C*3*2 0.000 description 17
- PCSNXMBPQXXNQA-RTQQRQAJSA-O C/C=C/N(/C=C\C)C=[NH2+] Chemical compound C/C=C/N(/C=C\C)C=[NH2+] PCSNXMBPQXXNQA-RTQQRQAJSA-O 0.000 description 1
- ZBXPMUZMELWNGP-UHFFFAOYSA-P C=CC=C(CC[NH3+])C=C[NH3+] Chemical compound C=CC=C(CC[NH3+])C=C[NH3+] ZBXPMUZMELWNGP-UHFFFAOYSA-P 0.000 description 1
- IKTWPGRQHXUALY-UHFFFAOYSA-R CC(CC[NH3+])=CN(CCCC[NH+]1CC[NH+](C)CC1)C=[NH+]C Chemical compound CC(CC[NH3+])=CN(CCCC[NH+]1CC[NH+](C)CC1)C=[NH+]C IKTWPGRQHXUALY-UHFFFAOYSA-R 0.000 description 1
- IQWPLEGWFFBFBZ-UHFFFAOYSA-N CC(OCCc(cc(C)c1c(C)cccc11)c1Br)=O Chemical compound CC(OCCc(cc(C)c1c(C)cccc11)c1Br)=O IQWPLEGWFFBFBZ-UHFFFAOYSA-N 0.000 description 1
- WLIWYHMAZWESFH-UHFFFAOYSA-N CC(OCCc(cc(c(c1ccc2)c2[N+]([O-])=O)S(Cl)(=O)=O)c1Br)=O Chemical compound CC(OCCc(cc(c(c1ccc2)c2[N+]([O-])=O)S(Cl)(=O)=O)c1Br)=O WLIWYHMAZWESFH-UHFFFAOYSA-N 0.000 description 1
- WSCVXBXQOFWWDV-UHFFFAOYSA-N CC(OCCc(cc(c1ccccc11)S(Cl)(=O)=O)c1Br)=O Chemical compound CC(OCCc(cc(c1ccccc11)S(Cl)(=O)=O)c1Br)=O WSCVXBXQOFWWDV-UHFFFAOYSA-N 0.000 description 1
- MEZKKZTWNNWYBQ-UHFFFAOYSA-P CCC[NH+](C)CC[NH3+] Chemical compound CCC[NH+](C)CC[NH3+] MEZKKZTWNNWYBQ-UHFFFAOYSA-P 0.000 description 1
- QVXNAHXNJMRYLR-UHFFFAOYSA-N CN(c1cccc2c1c1ccc2)S1(=O)=O Chemical compound CN(c1cccc2c1c1ccc2)S1(=O)=O QVXNAHXNJMRYLR-UHFFFAOYSA-N 0.000 description 1
- JDGIHRISPOPFMH-UHFFFAOYSA-N CN(c1cccc2c1c1ccc2CCO)S1(=O)=O Chemical compound CN(c1cccc2c1c1ccc2CCO)S1(=O)=O JDGIHRISPOPFMH-UHFFFAOYSA-N 0.000 description 1
- JNSNZDTWADRPFR-UHFFFAOYSA-O C[N+]1(CC2)CC[NH+]2CC1 Chemical compound C[N+]1(CC2)CC[NH+]2CC1 JNSNZDTWADRPFR-UHFFFAOYSA-O 0.000 description 1
- QSOSFMGPADLESD-UHFFFAOYSA-O C[N+]1(CCCCCCCc2cc[n+](C)cn2)CC[NH2+]CC1 Chemical compound C[N+]1(CCCCCCCc2cc[n+](C)cn2)CC[NH2+]CC1 QSOSFMGPADLESD-UHFFFAOYSA-O 0.000 description 1
- NODAGNHTQCVGRA-UHFFFAOYSA-Q C[NH+](CCCCCCC[n]1c[n+](CCC[NH3+])cc1)CC[NH3+] Chemical compound C[NH+](CCCCCCC[n]1c[n+](CCC[NH3+])cc1)CC[NH3+] NODAGNHTQCVGRA-UHFFFAOYSA-Q 0.000 description 1
- CEKCEJMDRKHLFJ-UHFFFAOYSA-Q C[NH+]1CC[NH+](CCC[n]2cnc(CC[NH3+])c2)CC1 Chemical compound C[NH+]1CC[NH+](CCC[n]2cnc(CC[NH3+])c2)CC1 CEKCEJMDRKHLFJ-UHFFFAOYSA-Q 0.000 description 1
- MYKHTDSUPPRTCE-UHFFFAOYSA-Q C[NH+]1CC[NH+](CC[n]2c[n+](C)c(CC[NH3+])c2)CC1 Chemical compound C[NH+]1CC[NH+](CC[n]2c[n+](C)c(CC[NH3+])c2)CC1 MYKHTDSUPPRTCE-UHFFFAOYSA-Q 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-P C[NH+]1CC[NH2+]CC1 Chemical compound C[NH+]1CC[NH2+]CC1 PVOAHINGSUIXLS-UHFFFAOYSA-P 0.000 description 1
- NAACEDILBCNIPR-UHFFFAOYSA-Q C[NH+]1CC[N](C)(CCC[NH2+]C=CC(CC[NH3+])=CC=C)CC1 Chemical compound C[NH+]1CC[N](C)(CCC[NH2+]C=CC(CC[NH3+])=CC=C)CC1 NAACEDILBCNIPR-UHFFFAOYSA-Q 0.000 description 1
- HOBYPSNNFBRLIX-UHFFFAOYSA-N O=S1(Nc2cccc3cccc1c23)=O Chemical compound O=S1(Nc2cccc3cccc1c23)=O HOBYPSNNFBRLIX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
Definitions
- the present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a naphthosultam linked through a CH2 group.
- the naphthosultam is further substituted with various substituent groups including at least one cationic group -A-Q-L-B.
- the carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS) and are also effective against gram negative organisms.
- MRSA methicillin resistant Staphylococcus aureus
- MRSE methicillin resistant Staphylococcus epidermidis
- MRCNS methicillin resistant coagulase negative Staphylococci
- Rl represents H or methyl
- CO2M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group
- P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group
- A-Q-L-B represents a side chain wherein:
- L represents a C]_ -8 alkylene group, straight or branched, and unsubstituted or substituted with 1-3 R c groups;
- Ra is H or C 1-6 alkyl
- Rb is NH2 or Cl-6 alkyl unsubstituted or substituted with 1-3 groups selected from halo, OH, CN, C(O)NH2 and N(R a )2
- Rc is independently selected from halo, ORa, SRa, OC(O)Ra, CO2Ra, CN, C(O)N(Ra) and C(O)Ra,
- Re is H; Rc ; NO2; N(Ra) 2; SO2N(Ra) 2 or Ci-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH2; and each R independently represents H ; R c ; NO2 ; N(R a )2 ; SO2N(Ra)2 or Ci-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH2, or R together with A of the group -A-Q-L-B and any intervening atoms represent a 5-6 membered carbocyclic ring.
- compositions and methods of treatment are also included.
- Carboxylate anion refers to a negatively charged group -COO-.
- alkyl refers to a monovalent alkane
- alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t- butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent at any available point of attachment.
- Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
- alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
- An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
- the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
- Aryl groups may likewise be substituted as defined.
- Preferred substituted aryls include phenyl and naphthyl.
- heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, and in which 1-2 additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and in which from 1-3 additional carbon atoms are optionally replaced by N, said heteroaryl group being optionally substituted as described herein. Examples include the following:
- triazole triazole (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl) isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazme (pyrazinyl)
- heteroarylium refers to heteroaryl groups bearing a quaternary N atom and thus a positive charge. Examples include the following:
- heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
- quaternary nitrogen refers to tetravalent, positively charged N atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium) and the like.
- Cationic groups encompass positively charged nitrogen- containing groups, as well as basic nitrogens which are protonated at physiologic pH.
- heteroatom means O, S or N, selected on an independent basis.
- Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
- Alkoxy refers to C -G ⁇ alkyl-O-, with the alkyl group optionally substituted as described herein.
- protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
- M is a readily removable carboxyl protecting group
- P represents a hydroxyl which is protected by a hydroxyl-protecting group.
- Such conventional protecting groups consist of groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein.
- These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule.
- Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
- carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.
- Suitable hydroxyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
- the carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects.
- pharmaceutically acceptable ester, salt or hydrate refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and 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, solubility, hygroscopicity and flowability of the resulting bulk drug.
- compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
- -CO2M which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).
- the pharmaceutically acceptable salts referred to above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium.
- a counterion e.g., an alkali metal cation such as sodium or potassium.
- Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
- the pharmaceutically acceptable salts referred to above also include acid addition salts.
- the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate
- the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters".
- Acid addition salts of the compounds of formula I are likely protonated at physiological pH, as mentioned above.
- Compounds such as those containing a basic N-containing moiety are capable of protonation in water at or near pH 7, so that the moiety can exist in its neutral form or as an acid addition (protonated) form.
- X- is a charge balancing group.
- all compounds which have one or more cations are balanced with one or more, as necessary, of a charge balancing group X " .
- Examples of cases where a charge balancing group is required are quarternized substituents such as heteroarylium.
- all compounds having one or more anions are counter balanced with one or more, as necessary, charge balancing counterions.
- Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors.
- biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyl oxyalkyl, cycloalkoxyalkyl, alkenyl oxyalkyl, aryloxyalkyl, alkoxyaryl, alkyl thioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkyl thioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups.
- biolabile ester forming moieties acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1- isopropyloxycarbonyloxy ethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-l,3-dioxolen-4-yl)methyl.
- X- can be present or absent as necessary to maintain the appropriate charge balance. When present, it represents a pharmaceutically acceptable counterion or counterions. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent
- the counterion indicator when more than one negative charge is necessary to maintain charge neutrality, represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA), or an appropriate number of monovalent anions to provide charge neutrality.
- EDTA ethylenediaminetetraacetate
- an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.
- the interrupting groups can be separate or together, and can terminate the ⁇ _ alkylidene group.
- the interrupting or terminating moiety can be between the alkylene group and the naphthosultam or -Q-.
- A can represent -O-Cl-6 alkyl, -Cl-6 alkyl-O-, -NRa-i-6 alkyl and the like.
- variable L represents a Cl-8 alkylene group, which is straight or branched, and which is unsubstituted or substituted with 1-3 R c groups.
- R represents Ci-6 alkyl
- it may be unsubstituted or substituted with 1-3 groups selected from halo, OH, CN, C(O)NH2 and N(Ra) 2 .
- one of the R groups is taken in combination with A from the side chain A-Q-L-B, along with the intervening atoms, it represents a 5-6 membered carbocyclic ring.
- a subset of compounds of formula I which is of interest relates to those compounds where R 1 represents methyl. Within this subset, all other variables are as originally defined.
- Another subset of compounds of formula I which is of interest relates to those compounds where CO2M represents a carboxylate anion.
- M in this instance represents a negative charge which is balanced by a positively charged group, such as in the positively charged Q group.
- a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
- Another subset of compounds of formula I that is of interest relates to those compounds where P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group. Within this subset, all other variables are as originally defined.
- Another subset of compounds of formula I that is of interest relates to compounds of formula I wherein A represents Cl-3 alkylene.
- a preferred subset of compounds of formula I which is of interest relates to those compounds wherein Rl represents methyl; CO2M represents a carboxylate anion;
- P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group
- A represents Cl-3 alkylene
- L represents a Cl-8 alkylene group, which is straight or branched, and unsubstituted
- Q-L-B is selected from:
- Q-L-B is selected from:
- Q-L-B is selected from:
- P, R 1 , R, and M are as defined with respect to the compounds of formula I.
- P** represents a carboxyl protecting group.
- Q*-L-B' represents a group which reacts with intermediate A2 (upon activation of A2) in a manner which results in the incorporation in the final product of a member of the group defined as Q- L-B above, thus Q*-L-B' may be viewed as a precursor for Q-L-B.
- the naphthosultam side chain group used in the synthesis of the compounds of the present invention have, in some cases, been described in the chemical literature. In other cases, precursor compounds which may be readily converted to the requisite naphthosultam have been described in the literature. In cases where the requisite naphthosultam is not known in the literature it is neceessary to synthesize the naphthosultam by a newly developed synthesis.
- One skilled in the art can adapt a previously published synthesis of an analogous naphthosultam to prepare the requisite compound in a straightforward manner without undue experimentation. Examples of naphthosultam synthesis are described herein (see
- the naphthosultam side chain group is initially reacted with a suitably protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position.
- the carbapenem nucleus having a -CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference.
- the carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2- trimethylsilylethyl, and the like.
- PNB p-nitrobenzyl
- allyl allyl
- p-methoxybenzyl trichloroethyl
- 2- trimethylsilylethyl and the like.
- the hydroxyl group of the ⁇ -(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbon l, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxycarbonyl and the like.
- TMS trimethylsilyl
- TES triethylsilyl
- TDMS tert- butyldimethylsilyl
- TDPS tert-butyldiphenylsilyl
- acetyl acetyl, allyloxycarbon l, 2-trimethylsilylethoxy carbonyl, 2- trichloroethoxycarbonyl and the like.
- the addition of the naphthosultam side chain group to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem and the naphthosultam side chain group in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a (premixed) suitable activating reagent such as diethyl azodicarboxylate (DEAD) / triphenylphosphine, diisopropyl azodicarboxylate (DIAD) / tributylphosphine, and the like, at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
- a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DM
- the naphthosultam and carbapenem can be mixed together with either the azodicarboxylate or the phosphine reagent in a suitable solvent and the other component of the activating reagent (the phosphine or the azodicarboxylate, respectively) can be added to that mixture.
- the reaction is allowed to proceed at a temperature between about -20 °C and 35 °C for about 5 to 90 minutes.
- a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group (X) such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q*-L-B', such as a suitably substituted diazabicyclooctane or a suitably substituted N,N-dimethylpiperazine.
- a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
- the charged substituent may be incorporated in the naphthosultam side chain before addition of the naphthosultam to the carbapenem or may be introduced after deprotection of A2.
- introduction of the charged substituent by modification of A2 before deprotection is greatly preferred.
- activation of the hydroxyl group and displacement by Q*-L-B'* to produce A3 may be accomplished in a single step by taking advantage of the basic character of compound Q*-L-B' and using it as a base in the activation reaction.
- the conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethyl- amine, and the like at a temperature between about -100°C and 0°C for about 5 to 120 minutes.
- a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like
- an activating reagent such
- the intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
- a suitable solvent such as acetone, methyl ethyl ketone, and the like
- sodium iodide or potassium iodide for about 0.25 to 24 hours.
- the iodide is obtained in sufficiently pure form that it may be used without further purification.
- the iodide if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
- the activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q*-L-B'.
- activation and displacement of the hydroxyl group may be accomplished in a single step.
- the activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs.
- the resulting activated intermediate is treated with 1-3 molar equivalents of compound Q*-L-B' at a temperature between about -78°C and 50°C for about 15 to 120 minutes.
- the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent.
- the displacement may be conducted without isolation of the intermediate and, in cases where Q*-L-B' is also used as a base, may even be concurrent with the formation of the activated intermediate.
- the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined with an approximately equivalent amount (0.9 - 1.05 molar equivalents) of compound Q*-L-B'.
- a silver salt of a non-nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
- reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
- silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps.
- the resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.
- 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 ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene 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 water to afford an amorphous, easily handled solid.
- Step 1 l-(2-Acetoxy-ethyl)-naphthalene
- Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of l-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling. The reaction mixture was washed sequentially with water (2 1 L), IN HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO 3 (500 mL), water (1
- Step 2 Potassium 4-(2-acetoxy-ethyl)-naphthalene-l-sulfonate Chlorosulfonic acid (69.3 g, 590 mmol) was added dropwise over 17 minutes to a solution of l-(2-acetoxy-ethyl)-naphthalene (105.5 g, 490 mmol) in dichloromethane (200 mL). The reaction was exothermic and periodic ice-bath cooling was employed to maintain the internal temperature at 25-30°C. Approximately 10 minutes into the CLSO3H addition, voluminous evolution of HCl gas was observed. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours then cautiously added to ice (400 g).
- the filtrate was concentrated under vacuum to afford a white suspension (355 g) which was stored in a refrigerator overnight.
- the solid was collected by filtration, washed with cold water (100 mL), then dried under vacuum at 60 °C to afford a second crop of potassium 4-(2-acetoxy-ethyl)- naphthalene-1-sulfonate (10.67 g) as a white solid.
- the second crop contained ca. 14% of the isomeric potassium 5-(2-acetoxy-ethyl)-l- naphthalene sulfonate as determined by 1H NMR.
- Step 3 4-(2-Acetoxy-ethyl)-naphthalene-l-sulfonyl chloride
- Step 4 4-(2-Acetoxy-ethyl)-8-nitro-naphthalene-l-sulfonyl chloride 4-(2-Acetoxy-ethyl)-naphthalene-l-sulfonyl chloride (76.96 g,
- Powdered cesium carbonate (76.8 g, 236 mmol) was added to a solution of 4-(2-hydroxy-ethyl)-8-nitro-naphthalene-l-sulfonamide (30.77 g, 94.3 mmol) in anhydrous dimethylformamide (470 mL).
- the mixture was placed under a nitrogen atmosphere, sonicated for 10 minutes, then stirred at room temperature for 20 minutes.
- the mixture was then placed in a 100 °C oil bath and stirred vigorously. After 3.5 hours, the reaction mixture was removed from the heating bath, allowed to cool to room temperature, and left at room temperature overnight. The mixture was then filtered and the collected solid was washed with dimethylformamide.
- Step 7 4-(2-Triethylsilanyloxy-ethyl)-1.8-naphthosultam
- Chlorotriethylsilane 13.57 mL, 80.86 mmol was added dropwise over 1 minute to a vigorously stirred suspension of 4-(2- hydroxy-ethyl)-l,8-naphthosultam (17.53 g, 70.32 mmol) and imidazole (5.99 g, 87.90 mmol) in dichloromethane (351 mL).
- the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes, then water (350 mL) was added.
- the organic layer was washed sequentially with 0.2 N HCl (350 mL) and water (350 mL) then dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark oil (29.07 g).
- the crude product was purified by flash column chromatography on silica gel (5 x 27 cm column, eluted with 4:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc) to afford a deep red oil (23.9 g).
- the oil was mixed with hexanes (225 mL), sonicated to start crystallization, and stirred at room temperature.
- Step 1 Allyl (3-ri(R)-(allyloxycarbonyloxy)-ethyn-2-fl(R -methyl-2-oxo-3- f4-(2-triethylsilanyloxy-ethyl)-l,8-naphthosultamyn-propyl)-(2R.3S)-4- oxo-azetidin- 1-yll -(triphenylphosphoranylidene)-acetate
- Step 2 Allyl (lS.5R.6S)-6 (lR)-(allyloxycarbonyloxy)-ethyl1-l-methyl-2-r4- (2-triethylsilanyloxy-ethyl)-1.8-naphthosultamyl-methyll-carbapen-2-em- 3-carboxylate
- the reaction mixture was allowed to cool to room temperature and evaporated to a paste which was stored overnight in the freezer as a suspension in dichloromethane.
- the crude product was purified by chromatography on silica gel (1.8 kg), eluting with 85:15 hexane-ethyl acetate followed by 4: hexane-ethyl acetate.
- the product containing fractions were combined and evaporated under vacuum to afford the title compound (42.4 g) as a viscous tan oil.
- Step 3 AIM (lS.5R.6S)-6-r(lR)-(allyloxycarbonyloxy)-ethyll-2-f4-(2- hydroxy-propyl)-L8-naphthosultamyl-methyll-l-methyl-carbapen-2-em-
- Step 4 Allyl (lS.5R.6S)-6-f(lR)-(allyloxycarbonyloxy)-ethyll-l-methyl-2-(4- r2-(trifluoromethanesulfonyloxy)-ethyll-1.8-naphthosultamyl-methyl)- carbapen-2-em-3-carboxylate
- Step 1 l-Bromo-2-(2-hydroxy-ethyl)-naphthalene
- Step 3 Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-l-sulfonate
- 2-(2-acetoxy-ethyl)-l-bromo-naphthalene 32.5 g, 0.111 mol
- trifluoroacetic acid 111 mL
- chlorosulfonic acid 8.9 mL, 0.130 mol
- the resulting solution was heated in an oil bath at 50°C for 90 minutes then cooled to room temperature and evaporated under vacuum to dark oil.
- the oil was partitioned between methylene chloride (150 mL) and water (150 mL).
- the aqueous phase was washed with methylene chloride (150 mL), briefly pumped under vacuum, then brought to pH 8 with 3M aqueous potassium hydroxide (30 mL) followed by 4M aqueous potassium carbonate (35 mL). The resulting mixture was stirred in a cold room (5°C) for 2 hours and filtered to remove the product. The recovered white solid was vacuum dried to afford the title compound (11.21 g).
- Step 4 3-(2-Acetoxy-ethyl)-4-bromo-naphthalene-l-sulfonyl chloride Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-l- sulfonate (17.75 g, 43.2 mmol) was added at room temperature to a stirred solution of N,N-dimethylformamide (0.334 mL, 4.31 mmol) in thionyl chloride (63 mL, 863 mmol). The resulting mixture was placed in an oil bath at 70°C and stirred. After 10 minutes, additional thionyl chloride (20 mL) was added to facilitate stirring.
- Step 5 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-l-sulfonyl chloride
- Step 6 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-l-sulfonamide Solid 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-l- sulfonyl chloride (5.00 g, 11.45 mmol) was added at room temperature to 0.5M ammonia in dioxane (92 mL, 46 mmol). After stirring at room temperature for 40 minutes, the mixture was evaporated under vacuum to a residue which was mixed with water (100 mL), sonicated, and filtered. The collected pale-yellow solid was washed with water (2 x 20 mL) and vacuum dried to afford the title compound (4.75 g).
- Step 7 4-Bromo-3-(2-hvdroxy-ethyl)-8-nitro-naphthalene-l-sulfonamide Sodium methoxide in methanol (23.7 mL of a 0.5M solution,
- Step 8 4-Bromo-3-(2-hvdroxy-ethyl)-1.8-naphthosultam
- a solution of 4-bromo-3-(2-hydroxy-ethyl)-8-nitro- naphthalene-1-sulfonamide (3.61 g, 9.62 mmol) in anhydrous N,N- dimethylformamide (96 mL) was treated with cesium carbonate (7.84 g, 24.1 mmol). The resulting mixture placed under a nitrogen atmospere, sonicated at room temperature for 10 minutes, stirred at room temperature for 5 minutes, and then heated in an oil bath at 100°C for 2 hours.
- Step 9 3-(2-Hydroxy-ethyl)-l,8-naphthosultam
- ethanol 105 mL
- triethylamine 2.68 mL, 19.2 mmol
- 20% palladium hydroxide on carbon 0.84 g
- the mixture was hydrogenated (45-50 psi H 2 ) on a Parr shaker for 6.5 hours at room temperature, then filtered through a celite pad to remove the catalyst which was washed with additional ethanol (3 x 5 mL).
- Step 10 3-(2-Triethylsilanyloxy-ethyl)-1.8-naphthosultam
- Step 1 Allyl (3-ri(R)-(allyloxycarbonyloxy)-ethyn-2-(l(R)-methyl-2-oxo-3- r3-(2-triethylsilanyloxy-ethyl)-1.8-naphthosultamyll-propyl)-(2R.3S)-4- oxo-azetidin-l-yl)-(triphenylphosphoranylidene)-acetate
- Step 2 Allyl (lS.5R.6S)-6-r(lR)-(allyloxycarbonyloxy)-ethyll-l-methyl-2-r3- (2-triethylsilanyIoxy-ethyl)-1.8-naphthosultamyl-methyl1-carbapen-2-em- 3-carboxylate
- the solution was concentrated under vacuum to 10 mL and applied to a column (4 x 20 cm) of EM silica gel 60.
- the column was eluted with 3:1 hexane-ethyl acetate (28 x 20 mL fractions) followed by 2:1 hexane-ethyl acetate (20 mL fractions).
- the product containing fractions were combined and concentrated under vacuum.
- the residue was lyophilized from benzene to give the title compound (1.894 g) as a gum.
- Step 3 Allyl (lS.5R.6S)-6-r(lR)-(allyloxycarbonyloxy)-ethyll-2-[3-(2- hydroxy-propyl)-1.8-naphthosultamyl-methyl1-l-methyl-carbapen-2-em-
- Step 4 AIM (lS.5R.6S)-6-[(lR)-(allyloxycarbonyloxy)-ethvn-l-methyl-2- ⁇ 3- [2-(trifluoromethanesulfonyloxy)-ethyl1-l,8-naphthosultamyl-methyll- carbapen-2-em-3-carboxylate
- Trifluoromethanesulfonic anhydride (0.178 mL, 1.06 mmol) was added and the resulting solution was stirred in the cold for 30 minutes.
- the solution was diluted with methylene chloride (20 mL) and water (20 mL) and shaken.
- the organic phase was separated, washed with 0.2N hydrochloric acid (20 mL) and water (20 mL), dried over magnesium sulfate, filtered and evaporated under vacuum to give the title compound as a foam (0.531 g).
- Step 1 Potassium 4-bromo-naphthalene-l-sulfonate A solution of 1-bromonaphthalene (19 mL, 137 mmol) in carbon tetrachloride (24 mL) was cooled in an ice bath under nitrogen. Chlorosulfonic acid (9.1 mL, 137 mmol) was added dropwise over 20 minutes. After an additional 5 minutes, the heavy grey suspension was removed from the ice bath and was stirred at room temperature for 16 hours to give a grey paste. The mixture was partitioned between methylene chloride (100 mL) and water (300 mL). The aqueous layer was made basic with potassium carbonate and the resulting suspension was filtered. The collected solid was washed with methylene chloride (50 mL) and water (50 mL), and dried under vacuum to give the title compound as a white solid (30 g).
- Step 3 Sodium 4-bromo-8-amino-naphthalene-l-sulfonate
- the crude product was purified by flash chromatography on EM silica gel 60 (5 x 15 cm) eluting with 4:1 hexane-ethyl acetate (200 mL) followed by 2:1 hexane-ethyl acetate (1000 mL). The product-containing fractions were combined and concentrated to give a light brown solid (2.3 g). The product was further purified by recrystallization from 15:1 hexane-ethyl acetate (80 mL) to give the title compound (1.48 g, 50%) as large white needles. The mother liquor was concentrated and washed with cold hexane (10 mL) to provide additional title compound (0.50 g) as smaller white needles.
- Step 1 AIM (3-fl(R)-(allyloxycarbonyloxy)-ethyll-2-[l(R)-methyl-2-oxo-3- r4-(2-triethylsilanyloxy-methyl)-1.8-naphthosultamyn-propyll-(2R.3S)-4- oxo-azetidin-l-yl)-(tripthenylphosphoranylidene)-acetate
- the crude product was purified by flash chromatography on EM silica gel 60 (5 x 15 cm), eluting with 7:3 hexane-ethyl acetate (200 mL) followed by 1:1 hexane-ethyl acetate (1000 mL). The product-containing fractions were combined and concentrated to yield the title compound (3.2 g) as an off-white foam.
- Step 2 AIM (lS.5R.6S)-6-r(lR)-(allyloxycarbonyloxy)-ethyll-l-methyl-2-r4-
- Step 3 AIM (lS.5R.6S)-6-r(lR)-(allyloxycarbonyloxy)-ethyri-2-r4- (hydroxymethyl)-1.8-naphthosultamyl-methyll-l-methyl-carbapen-2-em- 3-carboxylate
- Step 4 AIM (lS.5R.6S)-6-[(lR)-(allyloxycarbonyloxy)-ethyll-2-f4- (iodomethyl)-1.8-naphthosultamyl-methyll-l-methyl-carbapen-2-em-3- carboxylate
- the reaction mixture was then partitioned between dichloromethane (250 mL) and 0.1 N aqueous HCl (200 L), and the organic phase dried over MgS0 4 then concentrated and dried under vacuum for 20 hours.
- the resulting mesylate (1.7 g, quant.) was dissolved in acetone (60 mL) and sodium iodide (1.95 g, 13 mmol) was added. This suspension was stirred for 80 minutes at room temperature under a nitrogen atmosphere.
- the reaction mixture was then partitioned between dichloromethane (200 mL) and water (200 mL).
- the aqueous phase was extracted with dichloromethane (50 mL) and the combined organic phase was washed with 5% NaHSO 3 (2 x 75 mL), dried over MgSO and then concentrated. The resulting yellow oil was lyophilized from benzene (40 mL) to afford the title compound (1.5 g, quant.) as an amorphous yellow solid.
- Step 2 l-Methyl-3-(3-(4-aza-l-azonia-bicvclo 2.2.2loct-l- yl)propyl)imidazol-3-ium ditriflate
- Step 1 l-(3-Chloropropyl)imidazole To a solution of imidazole (3 g, 44.1 mmol) and HMPA (7.6 mL, 44.1 mmol) in THF (50 mL) was added NaH (1.94 g, 60% in mineral oil, 48.5 mmol) at 0°C. After stirring for 15 min, l-bromo-3- chloropropane (17.4 mL, 176.4 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hrs. The solid was then filtered off and solvent was removed. The residue was chromatographed over silica gel (eluent: ethyl acetate :hexane v/v 2:1) to give the product (1.6 g).
- Step 2 l-(3-(4-aza-l-azonia-bicyclor2.2.21oct-l-yl)propyl)imidazole triflate
- Step 2 3-(3-allyloxycarbonylimidazole- lyP- 1 ( 1 ,4-diazoniabicyclo [2.2.21 oct- l-yl)-propane ditrifluoromethanesulfonate l-(3-(4-aza-l-azonia-bicyclo[2.2.2]oct-l-yl)propyl)imidazole triflate from Step 2, Preparative Example 8, (35.6 mg, ) was dissolved in acetonitrile (0.5 ml), the product from Step 1, above (22 mg, )were added and the acetonitrile was removed under reduced pressure to give a thick oil, which was allowed to stand at room temperature overnight.
- Step 1 3-(3-Chloropropyl)-l-methylbenzimidazol-3-ium bromide 1-Methylbenzimidazole (lg, 7.6 mmol) was stirred with large excess of l-bromo-3-chloropropane (10 mL) at room temperature overnight. The yellow precipitate formed was collected by filtration and washed with Et 2 0 and hexane then dried under vacuum to give the product (0.16 g).
- Step 2 l-Methyl-3-(3-(4-aza-l-azonia-bicvclo[2.2.2]oct-l- yl)propyl)benzimidazol-3-ium ditriflate
- This halide salt was dissolved in MeOH (2 mL) and treated with a solution of AgOTf (0.16 g, 1.34 mmol) in CH 3 CN (0.5 mL). The mixture was stirred for 1 hr, then filtered to remove the white precipitate. The filter cake was washed with CH 3 CN. The combined filtrate was concentrated to give the white solid product (0.16 g) as a triflate salt.
- Step 2 (1S.5R.6S)- -2-f6-[2-(4-(3-(l-imidazolyl)-propyl)-1.4-diazonia- bicyclo [2.2.21 oct- 1-yP-ethyl] - 1. l-dioxo-2-H- l-thia-2-aza-acenaphthalen-2- yl-methyIl-6-ri(R)-hydroxyethyll-l-methyl-carbapen-2-em-3-carboxylate dichloride
- the concentrated product was applied to a column of Amberchrome CG-161, 1 ml) which was eluted with water (3 ml) followed by 1:1 acetonitrile-water (10 ml). The acetonitrile-water eluate was lyophilized to give the product (2 mg).
- Example 1 The product from Step 2, Example 1, is dissolved in a mixture of acetonitrile and water and treated with excess 3-azidopropyl triflate to quaternarize the imidazole nitrogen.
- the acetonitrile is removed under reduced pressure and the solution is reduced under hydrogen at 1 atmosphere to reduce the azide to the amine.
- Purification by reversed phase HPLC, followed by desalting over Amberchrome 161-C resin provides the title compound.
Abstract
Description
Claims
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EP98953687A EP1032383A4 (en) | 1997-10-23 | 1998-10-19 | Antibacterial carbapenems, compositions and methods of treatmemt |
CA002306965A CA2306965A1 (en) | 1997-10-23 | 1998-10-19 | Antibacterial carbapenems, compositions and methods of treatment |
AU11003/99A AU735599B2 (en) | 1997-10-23 | 1998-10-19 | Antibacterial carbapenems, compositions and methods of treatmemt |
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