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 sulfonamide containing ring system, linked to the carbapenem through a CH2 group.
• the sulfonamide containing ring system is further substituted with various substituents including cationic groups.
• 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).
• MRS A methicillin resistant Staphylococcus aureus
• MRSE methicillin resistant Staphylococcus epidermidis
• MRCNS methicillin resistant coagulase negative Staphylococci
• R 1 represents H or methyl
• CO 2 M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group
• P represents hydrogen, hydroxy 1, F or hydroxy 1 protected by a hydroxy 1-protecting group
• X 1 and X 2 represent hydrogen or X *and X 2 taken together represent a carbonyl group
• each R is independently selected from: -R*; -Q; hydrogen; halo; -CN; -N0 2 ; -NRaRb; -OR c ; -SRc; -C(0)NR a R b ; -C(0)OR h ; -S(0)R c ; -S0 2 R ; -S0 2 NR a R b ; -NR a S0 2 R b ; -C(0)R « ; -OC(0)Ra; -OC(0)NRaRh ; -NR«C(0)NR»Rc; -NR"C0 2 R b ; -OC0 2 R h ; -NR a C(0)R b ; -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d groups; and -C3- 7 cycloalkyl, unsubstituted or substituted with one to four R d groups;
• each R a , R b and R c independently represents hydrogen, -R*, -C i-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R d groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four R d groups; or R a nd 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 1 groups; or R b and R c taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three 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
• each R d independently represents halo; -CN; -N0 ; -NR ⁇ Rf; -ORs; -SR g ; -CONR ⁇ R f ; -COOR g ; -SORs; -S0 2 R ⁇ ; -S0 2 NR ⁇ R*; -NR ⁇ S0 2 R»; -COR e ; -NR ⁇ COR ⁇ ; -OCOR « ; -OCONR ⁇ R ⁇ ; -NReCONR ⁇ R g ; -NReC0 2 R h ; -OC0 2 R h ; -C(NR e )NR f R g ; -NR e C(NH)NR*R g ; -NR ⁇ C(NR R g ; -R* or -Q;
• R e , R f and Re represent hydrogen; -R*; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups; or R e and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, -C(O)- or NR g with RS as defined above, said ring being unsubstituted or substituted with one to four R' groups;
• each R' independently represents halo; -CN; -NO2; phenyl; -NHS0 2 R h ; -ORh, -SR h ; -N(R h ) ; -N + (R h ) 3 ; -C(0)N(Rh) 2 ; -S ⁇ 2N(Rh) 2 ; heteroaryl; heteroarylium; -CO2R 11 ; -C(0)R h ; -OCOR h ; -NHCOR h ; guanidinyl; carbamimidoyl or ureido;
• each R h independently represents hydrogen, a -C i-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two R h groups are present, said R h groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3;
• Q is selected from the group consisting of:
• a and b are 1 , 2 or 3;
• L" is a pharmaceutically acceptable counterion; a represents O, S or NR S ; ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CR l , N or N + R s , provided that o more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N+R s ; R* is selected from the group consisting of:
• d represents O, S or NR k ;
• e, g, x, y and z represent CR , N or N + R k , provided that no more than one of e, g, x, y and z in any given structure represents N + Rk;
• each R independently represents a member selected from the group consisting of: hydrogen; halo; -CN; -N0 2 ; -NR n R°;
• R n and R° represent hydrogen, phenyl; -Ci-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R' groups;
• each R s independently represents hydrogen; phenyl or -Ci- 6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
• each R 1 independently represents hydrogen; halo; phenyl; -CN; -N0 2 ; -NR «R V ; -OR"; -SR"; -CONR"R v ; -COOR h ; -SOR"; -S0 2 R"; -S0 2 NR"R v ; -NR u S0 2 R v ; -COR"; -NR"COR v ; -OCOR”; -OCONR u R v ; -NR u C0 2 R v ; -NR u CONR v R w ; -OC0 2 R v ; -Ci-6 straight- or branched- chain alkyl, unsubstituted or substituted with one to four R' groups;
• R u and R v represent hydrogen or -Ci-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups; or 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;
• each R w independently represents hydrogen; -Cl -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R' groups; C3-6 cycloalkyl optionally substituted with one to four Ri groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1 -4 Ri groups; or R n and R taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, S02, NH or NCH3;
• R represents hydrogen or a Cj .g straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR W , N+R n R w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, OR w , SR , SOR , S ⁇ 2R w , NRhR , N+(Rh)2R , -C(0)-RW, C(0)NRhRW ?
• Ry and R z represent hydrogen; phenyl; -Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R' groups, and optionally interrupted by O, S, NR W , N+R h R or -C(O)-; or R x and R y together with any intervening atoms represent a 4-8 membered saturated ring optionally interrupted by O, S, SO2,
• R x and Ry together represent a 4-6 membered ring as defined above, R 7 is as defined above or R z represents an additional saturated 4-8 membered ring fused to the ring represented by R x and Ry taken together, optionally interrupted by O, S, NR or -C(O)-, said rings being unsubstituted or substituted with one to four R' groups.
• compositions and methods of treatment are also included herein.
• Carboxylate anion refers to a negatively charged group
• alkyl refers to a monovalent alkane (hydro- carbon) 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, selected from R d and R 1 , as defined, 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, 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 is 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. 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.
• Examples include the following: pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl)
• triazole triazole
• pyrazole pyrazolyl
• isoxazole isoxazole
• Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen 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.
• the terms "quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl- pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus 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 C1 -C4 alkyl-O-, with the alkyl group optionally substituted as described herein.
• Ureido means the group -NHC(0)NH2, the hydrogens of which may be replaced with alkyl groups.
• Guanidinyl means the group -NHC(NH)NH2, the hydrogens of which may be replaced with alkyl groups.
• Carbamimidoyl means the group -C(NH)NH2, the hydrogens of which may be replaced with alkyl groups. When a group is termed "substituted”, unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon. With respect to R, Ra, Rb and Rc, the substituents available on alkyl groups are selected from the values of R d . Many of the variable groups are optionally substituted with up to four Ri groups. With respect to R e , R f and Rg, when these variables represent substituted alkyl, the substituents available thereon are selected from the values of R 1 .
• 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 hydroxy 1- protecting group.
• Such conventional protecting groups consist of known 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.
• C-6 hydroxyethyl 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.
• pharmaceutical 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.
• compositions 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.
• salts include 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, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate,
• 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”. 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, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. 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-l ,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, 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.
• L represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA)
• EDTA ethylenediaminetetraacetate
• One subset of compounds which is of particular interest relates to compounds in which at least one of the R groups attached to the sulfonamide containing platform contains a positively charged moiety. Thus, it can include -R* or Q, or a moiety which in turn contains a positively charged group.
• a further subset of compounds of formula I which is of interest relates to compounds of formula I wherein one R represents a group which contains a positively charged moiety, and the remaining R groups are selected from hydrogen, R* and Ci-c straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups. More particularly, this subset of interest includes compounds of formula I wherein one R represents a group containing a positively charged moiety and the remaining R groups are hydrogen or R*.
• the positively charged moiety or moieties that are contained in one or more R groups it is preferred that from 1-3 positive charges be present, and most preferably two positive charges be present, balanced by the carboxylate anion and a negatively charged counterion.
• Another subset of compounds which is of interest is represented by formula I wherein one R group represents a -Cj -6 straight or branched chain alkyl group, substituted with one to four R d groups, wherein one R d group represents -R* or Q.
• a positively charged moiety -R* or 0 is attached to an alkyl group.
• Another subset of compounds of formula I which is of interest relates to those compounds where CO 2 M 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 R group.
• a positively charged group such as in the positively charged R group.
• a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
• L- - a and b are as originally defined, and R x is as originally defined, and represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, 0 r -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N ⁇ 2, ORw, SRw, SORW, S02R W , NRhRw, N+(Rh) 2 RW, -C(0)-Rw, C(0)NRhRw, S02NRhRw, C ⁇ 2R w , OC(0)R , OC(0)NRhRw,
• NR n C(0)R w NR n C(0)NR h R
• a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two Cl -3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups.
• e, g, x, y and z represent CR m , N or N+R k , provided that no more than one of e, g, x, y and z in any given structure represents N + R k .
• R k and R m are as originally defined.
• a preferred subset of compounds of formula I which is of particular interest relates to compounds represented by formula I wherein:
• CO2M represents a carboxylate anion
• one R group which is attached to the sulfonamide containing ring system contains at least one positively charged moiety, and the remaining R groups are selected from hydrogen and Ci-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R d groups;
• Rd is as originally defined;
• R h represents hydrogen or a C 1 .5 straight or branched chain alkyl group;
• Q is selected from the group consisting of:
• R x represents a member selected from the group consisting of: hydrogen or a Cl -g straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S ⁇ 2, NR W , N+R h R , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, N02, ORw, SRw, SORw, S ⁇ 2R w , NRhRw, N+(Rh)2R w , -C(0)-R , C(0)NRhRw, S ⁇ 2NRhRw, C ⁇ 2R w , OC(0)R , OC(0)NRhRW > NRhc(0)R , NRhC(0)NRhR , 0 r a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two Cl
• R k and R m represent CR m , N or N + R k , provided that no more than one of e, g, x, y and z in any given structure represents N + R k .
• R k and R m are as originally defined. Within this subset, all other variables are as originally defined with respect to formula I.
• CO2M represents a carboxylate anion
• one R group which is attached to the sulfonamide platform contains a positively charged moiety, and the other R groups are selected from hydrogen and R*;
• R d is as originally defined
• Q is selected from the group consisting of:
• R x represents a member selected from the group consisting of: hydrogen or a Cl -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, S02, NRw, N+R n R w , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR , SR W , SOR , S ⁇ 2R w , NR h Rw, N+(Rh)2R , -C(0)-Rw, C(0)NRhRw > S02NRhR , C ⁇ 2R , OC(0)RW, OC(0)NR"RW 5 NRhC(0)RW, NRhC(0)NR"Rw, 0 r a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two Ci -3 straight
• R is as originally defined; R* is selected from:
• d represents NR k ;
• R k represents -C] - ⁇ straight or branched chain alkyl; and
• e, g, x and y represent CR m or N + R k , with R k as defined above and R m representing hydrogen.
• R x , a, b and L- are as originally defined.
• the compounds of the present invention are prepared by reacting a suitably protected, activated 2-hydroxymethyl-carbapen- 2-em-3 -carboxylate with a sulfonamide containing ring system, modifying the thus -introduced side chain as desired, and then removing any protecting groups which are present to afford the desired final product.
• the process is illustrated by the following generic scheme: SCHEME 1
• LG Leaving Group S ⁇ M£ME_2
• P, R I , R and M are ith respect to the compounds of formula I.
• P** represents a protected hydroxyl group.
• PG is also a protected hydroxyl group.
• LG is an appropriate leaving group.
• the chain to which LG is attached can be varied within wide limits to include all other values of R which form a bridge between the cyclic sulfonamide aryl platform and the quaternary group.
• the cyclic sulfonamide platform can be formed with a protected hydroxyl group in place on the ring /, producing 4, which can be converted to the dihydro compound 5.
• the cyclic sulfonamide is then reacted with a protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position, via a Mitsunobu reaction between the cyclic sulfonamide and the carbapenem alcohol.
• 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 2-trimethylsilylethyl
• hydroxyl group of the ⁇ -(hydroxyethyl) side-chain is protected with a hydroxy] protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.
• TMS trimethylsilyl
• TES triethylsilyl
• TDMS tert-butyldimethylsilyl
• TDPS tert-butyldiphenylsilyl
• acetyl allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.
• Addition of the cyclic sulfonamide to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem and the cyclic sulfonamide 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 (DMSO), and the
• the side chain component and the 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.
• the resulting mixture is then subjected to a standard work- up procedure familiar to those skilled in the art to afford a crude 2-methyl substituted carbapenem which is purified, if necessary, by recrystallization or by chromatography on silica gel, eluting 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.
• a suitable solvent or mixture of two or more solvents such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
• Modification of the side chain of compounds 6 or 7 is generally necessary to introduce the charged substituent Q- This may entail conversion of the protected hydroxyl group to a leaving group by deprotection, followed by activation, such as by converting the hydroxyl to a leaving group, e.g., a mesylate or triflate, followed by displacement with a heterocyclic or tertiary nitrogen containing species to the give quaternary compound. Quaternization is best accomplished before removal of the protecting groups.
• 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 such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a quaternary compound, such as N -methyl - imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, 1 -(carbamoylmethyl)-4-aza- 1 -azoniabicy clo-[ 2.2.2.
• a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
• a quaternary compound such as N -methyl - imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooc
• the charged substituent may be incorporated in the side chain before addition of the sulfonamide to the carbapenem or may be introduced after deprotection. However, introduction of the charged substituent by modification before deprotection as in Scheme 4 is greatly preferred.
• 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 trifluoro- methanesulfonic 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, diisopropylethylamine, 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 at about -10°C to 50°C with an excess of 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 frombenzene to afford an amorphous, easily handled, solid.
• the activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q*.
• Q* represents a group which reacts with an activated intermediate in a manner which results in the incorporation in the product of a member of the group defined as Q above.
• Q* may be viewed as a precursor of Q.
• 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.
• 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* at a temperature between about -78°C and 50°C for about 15 to 120 minutes.
• the displacement may be conducted without isolation of the intermediate and, in cases where Q* 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*.
• a silver salt of a non-nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
• the 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.
• An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain (Q) a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent, 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 using standard techniques which are well known to those skilled in the art. This is shown in Scheme 4.
• 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.
• 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.
• a pharmaceutically acceptable carrier examples include: topically, orally and parenterally by injection (intravenously or intramuscularly).
• Compositions for injection, a preferred route of delivery 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.
• 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.
• 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 antibacterial 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 irom 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. infusion, i.v. bolus and i.m. injection.
• 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 two or three times daily is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg three or 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 three to four times daily may be recommended. For children, 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 typically 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 contemplated to be part of the present invention. 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. 0 007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0 072 014)].
• DHP dehydropeptidase
• 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.
• the acid chloride was dissolved in methylene chloride (30 ml), cooled to 0° and treated with diethylamine (2.5 ml, 24 mmol) added dropwise. The mixture was stirred at 0° for 0.5 hr. then allowed to warm to room temp. The reaction mixture was diluted with methylene chloride, and washed with water, IN HC1 then with satd. NaCl and dried over MgS ⁇ 4. Removal of the solvent gave the crude product which was chromatographed on silica gel using 30% EtOAc/hexane as eluant to give the pure product 2.0 g.
• DIETHYLAMIDE THF (3 ml) was cooled to -78°, under nitrogen, s-butyl lithium (0.92 ml, 1.3 M soln. in cyclohexane) was added, followed by N,N,N',N'-tetramethyl-ethylenediamine (0.165 ml, 1 mmol).
• 4-biphenyl-carboxylic acid diethylamide (0.253 g, 1 mmol) in THF (1.5 ml).
• Sulfur dioxide (1 ml) was condensed into a dropping funnel under a dry-ice condenser, under nitrogen and added to the reaction mixture dropwise.
• the reaction mixture was allowed to stir overnight while allowing it to come to room temperature.
• the solvent was removed under reduced pressure and the residue was dissolved in water/EtOH 4: 1 and cooled to 0°.
• Hydroxylamine-O-sulfonic acid (0.340 g, 3 mmol) was dissolved in water (2 ml) and cooled to 0°.
• NaOH 0.6 ml, 5N soln
• the two solutions were mixed and added to the solution of the sodium salt.
• the ice bath was removed and the reaction mixture was stirred at room temperature for 6 hr..
• the solvent was evaporated to remove most of the EtOH and the residue was extracted with EtOAc.
• the organic phase was washed with water and satd. NaCl solution, dried over MgS ⁇ 4 and evaporated to give the crude product.
• Example 1 (0.044 g, 0.17 mmol) was dissolved in THF (2 ml) under nitrogen. Diborane (0.34 ml, 1 M soln in THF) was added and the mixture refluxed for 5 hr. The reaction mixture was treated with MeOH (2 ml) and evaporated to dryness, the residue was taken up in toluene (5 ml) and evaporated to dryness to give the product.
• Example 1 Following the procedure of Step 4, Example I , but substituting the product of Step 1 , Example 2 in place of the product of Step 3, Example 1, one obtains the title compound.
• ALLYL (IS. 5R. 6S 2-(l .l -DIOXO-5-IODOMETHYL-6- PHENYL-1.2-DIHYDRO-l -BENZOr ⁇ ISOTHIAZOL-3-ONE-2- YL ETHYL-6-r 1 (R)-( ALLYLOX YCARBONYDOXYETHYL1- 1-METHYLCARBAPENEM-2-EM-3-CARBOXYLATE
• the organic phase is dried over MgS ⁇ 4 and evaporated to give the mesylate.
• the mesylate is dissolved in acetone and sodium iodide (5 eq.) is added and the mixture is stirred at room temperature for 75 min.
• the reaction is partitioned between water and methylene chloride and the organic phase is washed with 5% aqueous NaHS ⁇ 3, dried over MgS ⁇ 4 and evaporated to give the title compound.
• ALLYL (IS. 5R. 6S 2-(l .l -DIOXO-1.2-DIHYDRO- l-BENZOr t JlISOTHIAZOL-3-ONE-2-YL)METHYL- 6-ri(R (ALLYLOXYCARBONYL)OXYETHYLl-l - METHYLCARBAPENEM-2-EM-3-CARBOXYLATE
• Example 9 is deblocked following the procewdure of Step 5, Example 1 , to give the title compound.
• lH NMR 3:1 D2O/ CD3CN, 500 MHz
• Example 10 is deblocked following the procewdure of Step 5, Example 1 , to give the title compound.
• l H NMR 3: 1 D2O/ CD3CN, 500 MHz
• 3.38 (dq, H-l) 3.57 (dd, H-6), 4.32 (dd, H-5), 4.37 (dq, H-8), 4.87 and 5.69 (2d's, CH2N), 8.44 (dd, ArH), 8.70 (dd, ArH) and 8.96 (d, ArH).

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• 1997
  • 1997-09-09 CA CA002264605A patent/CA2264605A1/en not_active Abandoned
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