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WO1996004282A1 - Composes de carbapenems, compositions et procedes de traitement - Google Patents

Composes de carbapenems, compositions et procedes de traitement Download PDF

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Publication number
WO1996004282A1
WO1996004282A1 PCT/US1995/010029 US9510029W WO9604282A1 WO 1996004282 A1 WO1996004282 A1 WO 1996004282A1 US 9510029 W US9510029 W US 9510029W WO 9604282 A1 WO9604282 A1 WO 9604282A1
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Prior art keywords
substituted
unsubstituted
groups
straight
branched
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PCT/US1995/010029
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English (en)
Inventor
Sherman T. Waddell
Ronald W. Ratcliffe
Timothy A. Blizzard
Kenneth J. Wildonger
Robert R. Wilkening
Sandra P. Szumiloski
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Merck & Co., Inc.
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Priority to AU32153/95A priority Critical patent/AU3215395A/en
Publication of WO1996004282A1 publication Critical patent/WO1996004282A1/fr

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    • 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
    • C07D477/16—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 hetero atoms or carbon atoms 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 3
    • C07D477/20—Sulfur atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to antibacterial agents of the carbapenem class in which the five membered pyrrolidine ring of the carbapenem nucleus is substituted by various cationic and neutral -S- heteroaryl substituents.
  • Thienamycin was an early carbapenem antibacterial agent having a broad spectrum; it has the following formula:
  • the carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRS A), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS).
  • MRSA/MRCNS methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • carbapenems of the present invention have a relatively low level of inactivation by dehydropeptidase and penicillinase, two enzymes known to reduce the serum levels of conventional beta lactam antibiotics.
  • the present invention addresses a compound represented by the structural formula:
  • R 1 represents hydrogen or methyl
  • CO 2 M represents a carboxylic acid, a carboxylate anion with or without a pharmaceutically acceptable counterion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
  • P* represents hydrogen or a hydroxyl protecting group
  • Het represents a heterocyclic group which is uncharged or positively charged, with no more than three positive charged atoms, and is selected from the group consisting of:
  • X, Y and Z independently represent CR, N or N + R a , provided that for any given compound at least one of X, Y and Z represents CR and no more than one of X, Y and Z represents N + R a :
  • R represents a member selected from the group consisting of hydrogen; halo; -CN; -NO 2 ; -NR a R b ; -OR c ; -SR c ;
  • R a and R b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR c , with R c as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R i groups;
  • R b and R c taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR a , with R a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R 1 groups;
  • R e , R f and R g independently represent hydrogen; -C 1 -6 straight- or branched-chain alkyl, either unsubstituted or substituted with one to four R i groups or -R*; C 2-6 straight- or branched-chain alkyl, either unsubstituted or substituted with one to four R i groups or -R*; or
  • R e and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, -C(O)- or NR s with R g as defined above, said ring being unsubstituted or substituted with one to four R i groups;
  • R h represents hydrogen or a -C 1 -6 straight or branched-chain alkyl group or phenyl
  • R i represents halo; -OR h ; -CN; -NO 2 ; phenyl, 2- imidazolyl, -NHSO2R h ; -NH(R h ); -N(R h ) 2 ; -N+(R h ) 3 ; -C(O)NHR h ; -C(O)N(R h )2; -SO 2 N(R h )2; pyridyl; pyridinium; methyl-imidazolium; -CO 2 R h ; -C(O)R h ; guanidinyl; carbamimidoyl or ureido;
  • R* is a member selected from the group consisting of:
  • d represents the point of attachment: d represents -C(O)-, NR k , O, or S;
  • E, G, e, g, x, y and z independently represent CR m , N or N + R k , provided that no more than one of E, G, e, g, x, y and z represents N + R k ;
  • R m represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO 2 ; -NHR n ; -NR n R o ; -OR n ; -SR n ; -CONR n R o ; -COOR n ; -SOR n ; -SO 2 R n ; -SO 2 NR n R o ; -NR n SO 2 R o ; -COR n ; -NR n COR o ; -OCOR n ; -OCONR n R o ; -NR n CO 2 R h ; -NR h CO 2 R n ;
  • R n and R o taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR h , with R h as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R i groups and/or Q;
  • Q represents a member selected from the group consisting of:
  • a and b independently represent 1 , 2 or 3;
  • ⁇ represents NR S , O or S
  • ⁇ , ⁇ , ⁇ , ⁇ and ⁇ independently represent CR 1 , N or N + R s provided that no more than two of ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ may be N + R s and that Q as a whole has at least one but not more than three positive charges;
  • R s represents hydrogen; phenyl; -NH 2 ; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; -C 2-6 straight- or branched-chain alkenyl, unsubstituted or substituted with one to four R i groups; or -C 2-6 straight- or branched- chain alkynyl, unsubstituted or substituted with one to four R i groups;
  • R t represents hydrogen; halo; phenyl; -CN; -NO 2 ; -NHR u ; -NR u R v ; -OR u : -SR u : -CONR u R v ; -COOR h ; -SOR u ; -SO 2 R u ; -SO 2 NR u R v ; -NR u SO 2 R v ; -COR u ; -NR u COR v ; -OCOR u ; -OCONR u R v ; -NR u CO 2 R v ; -NR u CONR v R w ; -OCO 2 R v ; pyridyl; pyridinium; methyl- pyridinium; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R- groups; -C 2
  • R u and R v independently represent hydrogen; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups;
  • R u and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR W or -C(O)-, said ring being unsubstituted or substituted with one to four R- groups;
  • R w represents hydrogen or -C 1 -6 straight- or
  • R x ,R y ,and R z independently represent hydrogen; phenyl; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups and optionally interrupted by O, S,
  • R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S,
  • R x and R y together represent a 4-6 membered ring as described above R z is as described above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by
  • R x and R y taken together, optionally interrupted by O, S, NR w or -C(O)-, said rings being unsubstituted or substituted with one to four R i groups;
  • L- represents a pharmaceutically acceptable counterion .
  • Carboxylic acid refers to -COOH.
  • Carboxylate anion refers to a negatively charged group
  • Carbamoyl and the carbamoyl portion of carbamoyloxy when referring to a value of R, are defined as -C(O)NR a R b ; when referring to a value of R d , carbamoyl represents -C(O)NR e R f ; when referring to a value of R i , carbamoyl is -C(O)NHR h or -C(O)N(R h )2; when referring to a value of R m , carbamoyl is -C(O)NR n R o ; and when referring to a value of R t , carbamoyl is -C(O)NR u R v .
  • Sulfinyl when referring to a value of R, represents -S(O)R c ; when referring to a value of R d , sulfinyl is -S(O)R g ; when referring to a value of R m , sulfinyl is -S(O)R n ; and when referring to a value of R t , sulfinyl is -S(O)R u .
  • Sulfonyl when referring to a value of R, represents
  • Sulfamoyl when referring to a value of R, represents -SO 2 NR a R b ; when referring to a value of R d , sulfamoyl is
  • Sulfonamido when referring to a value of R, represents
  • acyl and the acyl portion of acylamino and acyloxy when referring to a value of R, represents -C(O)R a ; when referring to a value of R d , acyl is -C(O)R e ; when referring to a value of R m , acyl is -C(O)R n ; and when referring to a value of R t , acyl is C(O)R u .
  • Amidino when used in connection with the values of R d , refers to -C(NR e )NR f R g ; when used in connection with the values of R m , amidino refers to -C(NR n )NR o R h .
  • R d refers to -NR e C(NH)NR f R g ; when used in connection with the values of R m , guanidino refers to -NR n C(NH)NR o R h .
  • Carbamimidoyl when used in connection with the values of R d , refers to -NR e C(NR f )R g ; when used in connection with the values of R m , carbamimidoyl refers to -NR n C(NR o )R h .
  • ureido is -NR u C(O)NR v R w .
  • N + R a is a substituted (quatemized) nitrogen atom which has a formal positive charge due to the presence of substituent R a .
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred 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 groups, R 1 , at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”. 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, groups 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, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. said heteroaryl group being optionally substituted as described herein.
  • Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrole, pyridine, oxazole. thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
  • 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 said hetero atoms.
  • quaternary nitrogen refers to a tetravalent positively charged nitrogen atom including, e.g., the positively charged nitrogen in a tetraalkylammonium group (eg. tetramethyl- ammonium, N-methylpyridinium), the positively charged nitrogen in protonated ammonium species (eg. trimethylhydroammonium, N- hydropyridinium), the positively charged nitrogen in amine N-oxides (eg. N-methylmorpholine-N-oxide, pyridine-N-oxide), and the positively charged nitrogen in an N-amino-ammonium group (eg. N-aminopyridinium).
  • a tetraalkylammonium group eg. tetramethyl- ammonium, N-methylpyridinium
  • protonated ammonium species eg. trimethylhydroammonium, N- hydropyridinium
  • the positively charged nitrogen in amine N-oxides eg. N-methylmorpho
  • 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 1 -C 4 alkyl-O-, with the alkyl group optionally substituted as described herein.
  • alkoxy carbonyl is represented by the formula: -C(O)OR h , where the R h group is a straight or branched C 1 -6 alkyl group.
  • R d the group -COORS represents an alkoxycarbonyl group where R g is a C 2-6 straight or branched alkyl group.
  • R m and R t the group -COOR h is an alkoxycarbonyl group.
  • substituted When a group is termed "substituted”, unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon.
  • R, R a , R b and R c the substituents available on the alkyl, alkenyl and alkynyl groups are selected from the values of R d .
  • Many of the variable groups are optionally substituted with up to four R- groups.
  • R e , R f and R g when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R i .
  • R k when R k is a substituted alkyl, alkenyl or alkynyl group, the substituents available thereon are selected from the values of R 1 .
  • R m when R m represents a substituted straight or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group, the subtituents available thereon are selected from the values of Ri.
  • R n , R o , R u , R v or R w represents a substituted alkyl group, the substituents present thereon are selected from the values of R i .
  • R s , R t , R x , Ry and R z when these variables represent a substituted alkyl, alkenyl or alkynyl group, the substituents present thereon are selected from the values of R i .
  • 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.
  • a subset of compounds of the present invention includes compounds with a positively charged (cationic) atom, balanced by a negatively charged carboxylate anion, and when necessary for charge balance, such as in bis-cationic compounds, an additional negatively charged counterion or counterions. It is noted that the overall molecule contains no more than three positively charged atoms. Thus, when it is said that Het contains no more than three positively charged atoms, this includes positively charged substituent groups attached to Het.
  • compounds is comprised of those which contain a positively charged atom in the Het ring.
  • R 1 - and P* are as previously defined; CO 2 M is a carboxylate anion (M represents a negative charge).
  • M represents a negative charge.
  • X, Y and Z represents N + R a , with R a as previously defined.
  • Another group of compounds within this subset is comprised of compounds which contain a positively charged moiety on a group which is attached to the -Het group. For example, when X,
  • Y or Z represents CR
  • R represents -R*
  • one of the values of e, g, x, y and z is N+R k with R k as previously defined.
  • Yet another group of compounds within this subset is comprised of compounds wherein one of e, g, x, y and z represents CR m , and R m represents 0 or -(CH 2 ) n -Q.
  • one of the values of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N + R s , and R s is as previously defined,
  • Another subset of compounds of formula I is comprised of compounds in which -Het and groups attached thereto are
  • Y and Z represent CR or N.
  • R is as previously defined except that it does not represent a positively charged moiety.
  • none of e, g, x, y, z, ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represents a quaternary nitrogen atom N+R k or N+R s .
  • Preferred compounds of the invention include those compounds of formula I wherein:
  • R 1 represents hydrogen or methyl
  • CO 2 M represents a carboxylic acid or a carboxylate anion with or without a pharmaceutically acceptable counterion
  • Het represents a heterocyclic group which is positively charged, with no more than three positive charged atoms, and is selected from the group consisting of: /
  • A represents S
  • Z represents N;
  • X and Y represent CR or N, provided that for any given compound at least one of X and Y represents CR;
  • R a and R b taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NR c , with R c as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R i groups;
  • R d represents halo; -CN; -NR e R f ; -OR g ; -CONR e R f ;
  • R e , R f and R g independently represent hydrogen; -C 1 -6 straight- or branched-chain alkyl, either unsubstituted or substituted with one to four R i groups or -R*; C 2-6 straight- or branched-chain alkyl, either unsubstituted or substituted with one to four R i groups or -R*;
  • R e and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, -C(O)- or NR g with R g as defined above, said ring being unsubstituted or substituted with one to four R i groups;
  • R h represents hydrogen or a -C 1 -6 straight or branched-chain alkyl group or phenyl; R i represents halo; -OR h ; -CN; -NO 2 ; phenyl, 2- imidazolyl; -NHSO 2 R 11 ; NH(R h ); N(Rh) 2 ; N + (R h ) 3 ; C(O)NHR h ;
  • R* is a member selected from the group consisting of:
  • e, g, x, y and z independently represent CR m , N or N + R k , provided that no more than one of e, g, x, y and z represents N + R k ;
  • R m represents a member selected from the group consisting of: hydrogen; halo; -CN; -NO 2 ; -NHR n ; -NR n R o ; -OR n ; -SR n ; -CONR n R o ; -COOR n ; -NR n SO 2 R o ; -COR n ; -NR n COR o ; -NR n CO 2 R h ; -NR b CO 2 R n ; -NR n CONR o R h ; -CNR n NR o R h ; -NR n C(NH)NR o R b ;
  • -NR n C(NR o )R h -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R- groups and/or Q; -C 3-7 cycloalkyl, unsubstituted or substituted with one to four R i groups and/or Q; -C 2-6 straight- or branched-chain alkenyl.
  • R n and R o taken together with any intervening atoms represent a 5-6 membered saturated ring optionally interrupted by one or more of O, S, NR h , with R h as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to three R i groups and/or Q;
  • Q represents a member selected from the group consisting of:
  • a and b independently represent 2 or 3;
  • ⁇ represents NR s , O or S
  • ⁇ , ⁇ , ⁇ , ⁇ and ⁇ independently represent CR 1 , N or N + R s provided that no more than two of ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ may be N + R s and that Q as a whole has at least one but not more than three positive charges;
  • R s represents hydrogen; phenyl; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; or -C 2-6 straight- or branched-chain alkenyl, unsubstituted or substituted with one to four R i groups;
  • R t represents hydrogen; halo; -CN; -NO 2 ; -NHR u ; -NR u R v ; -OR u ; phenyl, pyridyl; pyridinium; methyl-pyridinium; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; R u and R v independently represent hydrogen: -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups;
  • R w represents hydrogen or -C 1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups;
  • R x , R y , and R z independently represent hydrogen; phenyl; -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups and optionally interrupted by O, S, NR w , N+R h R w or -C(O)-; -C 2-6 straight- or branched-chain alkenyl, unsubstituted or substituted with one to four R i groups; or -C 2-6 straight- or branched-chain alkynyl, unsubstituted or substituted with one to four R i groups;
  • R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, NR w , N+R h R w or -C(O)-, and,
  • R x and R y together represent a 4-6 membered ring as described above R z is as described above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by R x and Ry taken together, optionally interrupted by O, S, NR w or -C(O)-, said rings being unsubstituted or substituted with one to four R i groups; and
  • L represents a pharmaceutically acceptable counterion . More preferred compounds of the invention are those falling within formula I wherein:
  • R 1 represents methyl
  • CO 2 M represents a carboxylic acid or a carboxylate anion with or without a pharmaceutically acceptable counterion
  • Het represents a heterocyclic group which is positively charged, with no more than two positive charged atoms, and is selected from the group consisting of: wherein: represents the point of attachment to S;
  • X and Y independently represent CR
  • R represents a member selected from the group consisting of hydrogen; halo; -CN; -NO 2 ; C 1-3 straight- or branched- chain alkyl, unsubstituted or substituted with one R d group; and -R*;
  • R d represents -R*
  • R h represents hydrogen or a -C 1 -6 straight or branched-chain alkyl group or phenyl
  • R i represents halo: -OR h ; -CN; -NO 2 ; phenyl, 2- imidazolyl; -NHSO 2 R h ; NH(R h ); N(R h ) 2 ; N + (R h ) 3 ; C(O)NHR h ;
  • R* is a member selected from the group consisting of:
  • e, g, x, y and z independently represent CR m or N;
  • Q represents a member selected from the group consisting of:
  • R s represents hydrogen; or -C 1 -3 straight-chain alkyl, unsubstituted or substituted with one or two R i groups;
  • R w represents hydrogen or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups;
  • R x , R y , and R z independently represent hydrogen; phenyl; or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R i groups and optionally interrupted by O, S, NR w , N+R h R w or -C(O)-;
  • R x and R y together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, NR w , N+R h R w or -C(O)-, and,
  • R x and R y together represent a 4-6 membered ring as described above R z is as described above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by R x and R y taken together, optionally interrupted by O, S, NR w or -C(O)-, said rings being unsubstituted or substituted with one to four R i groups; and
  • L- represents a pharmaceutically acceptable counterion .
  • R 1 represents methyl
  • CO 2 M represents a carboxylate anion with or without a pharmaceutically acceptable counterion
  • Het represents a heterocyclic group which is positively charged, with one or two positive charged atoms, and is selected from the group consisting of:
  • X and Y independently represent CR
  • R represents a member selected from the group consisting of hydrogen; halo; -CN; and -R*;
  • R h represents hydrogen or a -C 1 -3 straight-chain alkyl group
  • R i represents halo; -OR h ; -CN; -NO 2 ; phenyl, 2- imidazolyl; -NHSO 2 R h ; NH(R h ); N(R h ) 2 : N+(R h ) 3 ; C(O)NHR h ;
  • R* is a member selected from the group consisting of:
  • Q represents a member selected from the group consisting of:
  • R s represents hydrogen or C 1 -3 straight-chain alkyl, unsubstituted or substituted with one to two R i groups;
  • R w represents hydrogen or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups;
  • R x ,R y ,and R z independently represent hydrogen; or -C 1 -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to three R i groups and optionally interrupted by O, S, NR w , N + R h R w or -C(O)-;
  • R x and R y together with any intervening atoms represent a 5-6 membered saturated ring optionally interrupted by O, S, NR w , N + R h R w or -C(O)-, and,
  • R x and R y together represent a 4-6 membered ring as described above R z is as described above or R z represents an additional saturated 4-6 membered ring fused to the ring represented by R x and R y taken together, optionally interrupted by O, S, NR w or -C(O)-, said rings being unsubstituted or substituted with one to four R i groups; and
  • L- represents a pharmaceutically acceptable counterion .
  • the compounds of the invention can be synthesized in accordance with the following general schemes and examples.
  • the compounds of the present invention are prepared by reacting a suitably protected carbapen-2-em -3-ca3boxylate having a suitable leaving group at the 2-position with a heterocyclic thiol (mercaptan) under basic conditions, modifying the thus-introduced side chain (if desired), and then removing any protecting groups which are present to afford the desired final product.
  • a suitably protected carbapen-2-em -3-ca3boxylate having a suitable leaving group at the 2-position with a heterocyclic thiol (mercaptan) under basic conditions, modifying the thus-introduced side chain (if desired), and then removing any protecting groups which are present to afford the desired final product.
  • mercaptan a heterocyclic thiol
  • P represents a carboxyl protecting group
  • Het* represents a heterocyclic group selected from the group defined for Het above, but is modified in the reaction and no longer identical to the initial Het group.
  • LG represents a suitable leaving group such as trifluoro- methanesulfonate (triflate), diethyl phosphate, diphenyl phosphate, di-(p-chlorophenyl) phosphate, methanesulfonate (mesylate), benzene- sulfonate, p-toluenesulfonate, chloride, bromide, iodide and the like.
  • AR represents a suitable alkylating reagent, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoro- methanesulfonate, triethyloxonium tetrafluoroborate and the like.
  • M is a readily removable carboxyl protecting group.
  • Such conventional groups consist of known groups which are used to protectively block the carboxyl group during the synthesis procedures described therein. 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.
  • ester forming protecting groups include benzhydryl, p-nitrobenzyl (PNB), 2-naphthylmethyl, allyl, benzyl, trichloroethyl, silyl such as trimethyl- silyl (TMS) or 2-trimethylsilylethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, p-methoxyphenyl, 4-pyridylmethyl, and t-butyl.
  • PNB p-nitrobenzyl
  • TMS trimethyl- silyl
  • phenacyl p-methoxybenzyl
  • acetonyl o-nitrobenzyl
  • o-nitrobenzyl p-methoxyphenyl
  • 4-pyridylmethyl 4-pyridylmethyl
  • the C-6 hydroxyethyl group of the carbapenem is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxy- carbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2 -trichloroethyl- oxycarbonyl, allyloxycarbonyl, acetyl, 2-trimethylsilylethoxycarbonyl, and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • heterocyclic thiols used in the synthesis of the compounds of the present invention are, in many cases, commercially available compounds.
  • the necessary thiols are compounds which have been previously described in the chemical literature; such compounds can be readily prepared by following the procedures described in the literature.
  • the requisite thiol is neither commercially available nor known in the literature it is necessary to synthesize the thiol by a newly developed synthesis.
  • heterocyclic thiols are well known in the chemical literature, one skilled in the art can, in many cases, adapt a previously published synthesis of an analogous thiol to prepare the requisite thiol in a straightforward manner without undue experimentation.
  • 2-mercapto-benzothiazoles can be readily prepared from commercially available anilines or nitrobenzenes with the appropriate substitution (Comprehensive Heterocyclic Chemistry Volume 6; K.T. Potts, Ed: Pergamon Press, Oxford, 1984).
  • Other mercapto-heterocycles such as mercapto thiazolopyridines, mercaptobenzoxazoles, mercaptothiazolothiophenes, and the like can be prepared by similar methods well known to those skilled in the art.
  • the compound may exist as an equilibrium mixture of "thiono" and “thiol” tautomers (as shown below) and may, in fact, exist predominantly in the thiono form. However, on treatment with base, the equilibrium will normally shift to favor the salt of the thiol form which can then react with the carbapenem as described below.
  • the addition of the thiol HSHet to the carbapenem is accomplished by treating a solution of the thiol in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylfo ⁇ namide (DMF), benzene, dimethylsulfoxide (DMSO), dimethoxyethyane, dioxane and the like, with a suitable base such as sodium hydride, sodium hydroxide, lithium hydride, lithium hydroxide, lithium trimethylsiloxane, lithium hexamethyldisilazide, potassium hydride, butyl lithium, methyl lithium, cesium hydroxide, and the like at a temperature between about -20°C and 35°C for about 1 to 90 minutes then combining the carbapenem, either as a solid or in solution, with the resulting mixture.
  • a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylf
  • HSHet. base and carbapenem can be mixed together with a suitable solvent without pre-treatment of the thiol with base, although pre-treatment is preferred.
  • the reaction is allowed to proceed at a temperature between about -20°C and 95°C for about 0.5 to 24 hours.
  • the crude 2-heteroarylthio substituted carbapenem is purified by crystallization or by chromatography on silica gel, and eluted with a suitable solvent or mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
  • side chain refers to the heterocyclic group which is linked via a sulfur atom to the carbapenem nucleus.
  • the deprotected final product is then purified, if necessary.
  • the final product if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
  • the purified product may be characterized structurally by standard techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), ultraviolet spectroscopy (UV) and mass spectrum (MS).
  • NMR nuclear magnetic resonance spectroscopy
  • IR infrared spectroscopy
  • UV ultraviolet spectroscopy
  • MS mass spectrum
  • a positive charge may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q, such as N-methyl-imidazole, N-methyl- diazabicyclooctane, N-carbamoylmethyl-diazabicyclooctane, pyridine, N-methylmorpholine and the like which contains a nitrogen atom that can act as a nucleophile.
  • a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
  • Q such as N-methyl-imidazole, N-methyl- diazabicyclooctane, N-carbamoylmethyl-diazabicyclooctane,
  • activation of the hydroxyl group and displacement by Q to produce A4 may be accomplished in a single step by taking advantage of the basic character of compound Q 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 with an activating reagent, such as trifluoromethane- sulfonic anhydride, methanesulfonic anhydride, toluene sulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethylamine, pyridine, 2,6-lutidine and the like at a temperature between about -78°C and 0°C for about 15 to 120 minutes.
  • an activating reagent such as trifluoromethane- sulfonic anhydride, methanesulfonic anhydride, toluene sulfonic anhydride, methanesulfonyl
  • the intermediate thus obtained contains a leaving group, which may be made still more reactive to displacement by conversion to the even better 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 for about 0.25 to 24 hours.
  • a suitable solvent such as acetone, methyl ethyl ketone and the like
  • 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*.
  • Q* is sufficiently reactive to displace an activated hydroxyl group (thus rendering further conversion to the iodide unnecessary)
  • activation and displacement of the hydroxyl group is accomplished in a single step.
  • the activating reagent is added to a solution of the hydroxyl substituted compound and a compound Q* (1.0 to 7.5 molar equivalents) in a suitable solvent such as THF, ether, DMF, benzene, acetonitrile, DMSO, and the like at a temperature between about -78 °C and 50 °C for about 15 to 240 minutes.
  • a solution of the iodide is combined with compound Q* ( 1.0 to 7.5 molar equivalents).
  • a silver salt of a non-nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
  • 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.
  • An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain a nitrogen atom which may be quatemized by reaction with a suitable alkylating reagent AR, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate.
  • the deprotected final product is then purified, as
  • the final product may be characterized structurally by standard techniques. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
  • carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms in the treatment of bacterial infections in animal and human subjects.
  • compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
  • present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
  • the pharmaceutically acceptable salts referred to above may also include non-toxic 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, cyclopentane- propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate
  • -CO 2 M 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.
  • Counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethyl- ammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • the pharmaceutically acceptable esters of the present invention 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.
  • Biolabile esters are biologically hydrolizable, and many are suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid
  • biolabile esters include compounds in which M represents an alkoxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkyl- thioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. All of these groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups.
  • M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1-acetoxyethyl, 1 - acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl- 1 ,3-dioxolen-4-yl)methyl.
  • L- can be present or absent, as necessary to maintain the appropriate charge balance.
  • L- represents a pharmaceutically acceptable counterion.
  • Most anions derived from inorganic or organic acids are suitable.
  • Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylene- citrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolate, 2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate,
  • phosphate/diphosphate polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
  • suitable anionic species will be apparent to the ordinarily skilled chemist.
  • L- represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA)
  • EDTA ethylenediaminetetraacetate
  • the compounds of the present invention are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
  • the compounds of the invention are determined to be active against MRSA.
  • the compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below.
  • the compounds 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 (intravenously or intramuscularly).
  • compositions for injection may be prepared in unit dosage form in ampules, or in multidose containers.
  • the injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents.
  • the active ingredient may be in powder (lyophillized or non-lyophillized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • various buffering agents, preservatives and the like can be included.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Oral compositions may take such forms as tablets, capsules, oral suspensions and oral solutions.
  • the oral composions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms.
  • 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, however, are left to the routine discretion of the physician according to principles of treatment well known in the anti- bacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound.
  • 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 dosage amounts in the range of from about 250 mg to 1000 mg.
  • the unit dosage will typically include the pure compound in sterile water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic.
  • the invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a compound of formula I in an amount effective to treat said infection.
  • the preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v.
  • Formula I antibacterial 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 antibacterial given one to four times per day. More specifically, for mild infections a dose of about 250 mg one to three times daily is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg two to four times daily is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 1000-2000 mg two 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 is recommended.
  • the compounds of Formula I are of the broad class known as carbapenems. Many carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Many of the compounds of the present invention, on the other hand, are less subject to such attack, and therefore may not require the use of a DHP inhibitor. However, such use is optional and
  • Inhibitors of DHP and their use with carbapenems are disclosed in, e.g., [European Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No. 0007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0072 014)].
  • the compounds of the present invention may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application.
  • the cited European Patent Applications define the procedure for determining DHP susceptibility of the present carbapenems and disclose suitable inhibitors, combination compositions and methods of treatment.
  • a preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1 : 1.
  • a preferred DHP inhibitor is 7-(L-2-amino-2-carboxy- ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.
  • reaction mixture was immediately diluted with diethyl ether (50 mL) and washed with water (2 x 50 mL), I M pH7 phosphate buffer, brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to give the title compound (1.09 g) as a white solid.
  • the extract was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to a solid (237 mg).
  • the crude product was flash silica gel column (2 x 15 cm) chromatographed eluting with 2:1 , ethyl acetate:hexane. Product containing fractions were combined and evaporated under vacuum to a semi-solid. The semi-solid was mixed with dichloromethane (10 mL) and filtered to afford the title compound (180 mg) as a white solid.
  • the foam was purified on preparative silica plates (EM Science, 2x1000, eluted with- 5% methanol in methylene chloride). The product band was removed. eluted with 10% methanol in methylene chloride and evaporated to give the title compound (91mg).
  • Acetyl chloride 1.33mL. 18.73mmol was added dropwise to ice cold 3-(2-hydroxyethyl)-thiophene ( 1 mL. 8.92mmol). After the exothermic reaction subsided, perchloric acid (0.05mL) was added. Acetyl chloride (1.33mL, 18.73mmol) was added dropwise to ice cold 3-(2-hydroxyethyl)-thiophene (ImL, 8.92mmol). After the exothermic reaction subsided, perchloric acid (0.05mL) was added.
  • the mixture was diluted with more hexane (25 mL), then cooled in an ice bath for 20 minutes and filtered.
  • the filter cake was washed with cold hexane (3 x 5 mL) and vacuum dried to provide the title compound (1.912 g) as a fluffy white solid.
  • the filtrate and washings were concentrated under vacuum to ca. 10 mL, seeded, and stirred in an ice bath to provide additional product (0.187 g) as a white solid.
  • the mixture was filtered through a Celite pad and the catalyst washed with water (2 x 5 ml).
  • the filtrate was washed with methylene chloride (2 x 5 ml) and ether (1 x 5 ml), centrifuging after each washing to break the emulsions, and then filtered through a 0.45 micron CR acrodisc, concentrated under vacuum to about 5 ml volume, and lyophilized to give the title compound (20 mg) as an amorphous white solid.
  • the mixture was filtered through a Celite pad and the catalyst washed with water (2 x 5 ml).
  • the filtrate was washed with methylene chloride (2 x 5 ml) and ether (1 x 5 ml), centrifuging after each washing to break the emulsions, and then filtered through a 0.45 micron CR acrodisc, concentrated under vacuum to about 5 ml volume, and lyophilized to give the title compound (25 mg) as an amorphous white solid.
  • a solution was prepared of 40 mg (0.076 mmol) of p-nitro- benzyl (5R,6S)-2-[4-phenylthiazol-2-yl]thio-6-[(1R)-hydroxyethyl] carbapen-2-em-3-carboxylate in 4.8 ml of tetrahydrofuran, 2.5 ml of ethanol, and 1.9 ml of water containing 6.1 mg (0.072 mmol) of sodium bicarbonate. This solution was added to a vigorously stirred, prehydro- genated mixture of 33 mg of 10% Pd/C in 2.5 ml of EtOH.
  • the O-desilylated product solution was mixed with n- butanol (4.6 mL), ethyl acetate (2.3 mL), water (4.6 mL), 0.5M pH7 phosphate buffer (2.3 mL), and 10% palladium on carbon (70 mg), nitrogen and hydrogen purged, and vigorously stirred under a balloon of hydrogen at room temperature. After 90 min, the reaction vessel was nitrogen purged and the contents filtered through a prewashed celite pad. The filtrate was allowed to separate into two phases and the aqueous phase was recovered and set aside.
  • aqueous acetonitrile solution containing product was concentrated under vacuum and treated with ammonium chloride (660 mg, 12.3 mmol) and chromatographed in two portions of a Tosohaas Amberchrom ® CG-1000 column (1 x 6 cm) eluting with water.
  • the product in aqueous solution was lyophilized to afford the title compound as an amorphous white fluffy solid (45.3 mg).
  • the O-desilylated product solution was mixed with n- butanol (5.0 mL), ethyl acetate (2.5 mL), water (5.0 mL), 0.5M pH7 phosphate buffer (2.5mL), and 10% palladium on carbon (75 mg), nitrogen and hydrogen purged, and vigorously stirred under a balloon of hydrogen at room temperature. After 90 min, the reaction vessel was nitrogen purged and the contents filtered through a prewashed celite pad. The filtrate was allowed to separate into two phases and the aqueous phase was recovered and set aside.
  • the O-desilylated product solution was mixed with n- butanol (6.4 mL), ethyl acetate (3.2 mL), water (6.4 mL), 0.5M pH7 phosphate buffer (3.2 mL), and 10% palladium on carbon (80 mg), nitrogen and hydrogen purged, and vigorously stirred under a balloon of hydrogen at room temperature. After 90 min, the reaction vessel was nitrogen purged and the contents filtered through a prewashed celite pad. The filtrate was allowed to separate into two phases and the aqueous phase was recovered and set aside.
  • the O-desilylated product solution was mixed with n-butanol (5.0 mL), ethyl acetate (2.5 mL), water (5.0 mL), 0.5M pH7 phosphate buffer (2.5 mL), and 10% palladium on carbon (80 mg), nitrogen and hydrogen purged, and vigorously stirred under a balloon of hydrogen at room temperature. After 90 min, the reaction vessel was nitrogen purged and the contents filtered through a prewashed celite pad. The filtrate was allowed to separate into two phases and the aqueous phase was recovered and set aside.
  • the remaining organic phase was washed with water (10 mL) and the water wash and original aqueous phase were combined and washed with 1 :1, ethyl acetate:diethyl ether (25 mL).
  • the washed aqueous solution was concentrated under vacuum and applied to a column (2 x 5 cm) of Bio-Rad Macro-Prep CM resin.
  • the column was water washed (ca. 50 mL) and then washed with 5% aqueous sodium chloride to elute the product.
  • Product containing fractions were combined and concentrated under vacuum (ca.
  • the O-desilylated product solution was mixed with n- butanol (5.0 mL), ethyl acetate (2.5 mL), water (5.0 mL), 0.5M pH7 phosphate buffer (2.5 mL), and 10% palladium on carbon (55 mg), nitrogen and hydrogen purged, and vigorously stirred under a balloon of hydrogen at room temperature. After 90 min, the reaction vessel was nitrogen purged and the contents filtered through a prewashed celite pad. The filtrate was allowed to separate into two phases and the aqueous phase was recovered and set aside.
  • the column was eluted with water (6x15 mL) and then with 5% aqueous sodium chloride. Fractions (15 mL each) were collected and the product eluted in fractions 1-4 of the 5% aqueous sodium chloride eluent. The combined fractions were loaded onto an amberchrom column (8 mL), and the column was washed with water (75 mL) and then eluted with 20% isopropanol/ water (30 mL). The isopropanol/ water eluent was evaporated to ca. ImL and was lyophilized to give the title compound as a white solid (18 mg).
  • the suspension was partitioned between methylene chloride (10 mL) and 5% aqueous sodium bicarbonate (20 mL). The aqueous layer was re-extracted with more methylene chloride (2x 10mL), and the combined methylene chloride extracts were dried with magnesium sulfate, were filtered and evaporated to give the title compound as an oil (150 mg), which contained residual tetrahydrofuran as observed by NMR.
  • the column was eluted with water (5x6mL) and then with 1 % aqueous sodium chloride. Fractions (6 mL each) were collected and the product eluted in fractions 3-10 of the 1 % aqueous sodium chloride eluent. The combined fractions were loaded onto an amberchrom column (6 mL), and the column was washed with water (5x6 mL) and then eluted with 25% methanol/ water (18 mL). The methanol/ water eluent was evaporated to ca. 1 mL and was lyophilized to give the title compound as a white solid (30 mg).
  • the suspension was partitioned between ethyl acetate (30 mL) and 5% aqueous sodium bicarbonate (20 mL). The ethyl acetate layer was washed with brine (15 mL), dried with magnesium sulfate, filtered and evaporated to give the title compound as an oil (350 mg), which contained residual tetrahydrofuran as observed by NMR.
  • the foam was purified by preparative TLC plates (3x1000 micron, eluted with 10% ethyl acetate) to give the title compound as a foam (278 mg).
  • the suspension was partitioned between methylene chloride (10mL) and 5% aqueous sodium bicarbonate (10 mL).
  • the methylene chloride layer was dried with magnesium sulfate, filtered and evaporated to give the title compound as an oil (350mg), which contained residual tetrahydrofuran as observed by NMR.
  • the foam was purified by preparative TLC plates (3x1000 micron, eluted with 10% ethyl acetate) to give the title compound as a foam (235 mg).

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Abstract

Cette invention concerne des carbapenems de formule (I) utilisés comme agents actifs contre le staphylocoque doré résistant à la méthiciline. Dans la formule (I) R1 représente hydrogène ou méthyle; CO¿2?M représente un acide carboxylique avec ou sans un contre-ion pharmaceutiquement acceptable, un groupe ester pharmaceutiquement acceptable ou un acide carboxylique protégé par un groupe protecteur; P* représente hydrogène ou un groupe protecteur hydroxyle; Het représente un groupe hétérocyclique non chargé ou chargé positivement, ne contenant pas plus de trois atomes chargés positivement et sélectionné dans le groupe constitué par: (a) et (b), dans lesquels $(1,3)$ représente le point d'attache à S; A représente O ou S; et X, Y et Z représentent indépendamment CR, N ou N?+Ra¿.
PCT/US1995/010029 1994-07-29 1995-07-25 Composes de carbapenems, compositions et procedes de traitement WO1996004282A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0934942A4 (fr) * 1996-09-04 2000-01-19 Sumitomo Pharma Nouvelles beta-lactamines et leur procede de fabrication
WO2002048149A1 (fr) * 2000-12-12 2002-06-20 Sumitomo Pharmaceuticals Company, Limited Nouveaux composes de ?-lactame et procede de preparation associe
CN101328176B (zh) * 2007-06-15 2010-12-15 山东轩竹医药科技有限公司 四氢嘧啶乙烯基取代的巯基杂环碳青霉烯化合物

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EP0934942A4 (fr) * 1996-09-04 2000-01-19 Sumitomo Pharma Nouvelles beta-lactamines et leur procede de fabrication
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CN101328176B (zh) * 2007-06-15 2010-12-15 山东轩竹医药科技有限公司 四氢嘧啶乙烯基取代的巯基杂环碳青霉烯化合物

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