CA2388077A1 - Novel succinic acid metallo-beta-lactamase inhibitors and their use in treating bacterial infections - Google Patents

Novel succinic acid metallo-beta-lactamase inhibitors and their use in treating bacterial infections Download PDF

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CA2388077A1
CA2388077A1 CA002388077A CA2388077A CA2388077A1 CA 2388077 A1 CA2388077 A1 CA 2388077A1 CA 002388077 A CA002388077 A CA 002388077A CA 2388077 A CA2388077 A CA 2388077A CA 2388077 A1 CA2388077 A1 CA 2388077A1
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James M. Balkovec
Gail Hammond
Mark L. Greenlee
Steven H. Olson
Gregory P. Rouen
Jeffrey H. Epstein-Toney
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Merck and Co Inc
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/76—Dibenzothiophenes

Abstract

This invention relates to novel substituted succinic acid metallo-.beta.-lactamase inhibitors which are useful potentiators of .beta.-lactam antibiotics. Accordingly, the present invention provides a method of treating bacterial infections in animals or humans which comprises administering, together with a .beta.-lactam antibiotic, a therapeutically effective amount of a compound of formula (I) including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof.

Description

TITLE OF THE INVENTION
NOVEL SUCCINIC ACID METALLO-BETA-LACTAMASE INHIBITORS AND
THEIR USE IN TREATING BACTERIAL INFECTIONS
BACKGROUND OF THE INVENTION
The present invention relates to compounds which have metallo-(3-lactamase inhibitory characteristics. The invention also relates to methods of preparing, pharmaceutical compositions and uses of the compounds.
Metallo-(3-lactamases are bacterial enzymes which confer resistance to virtually all clinically relevant ~i-lactam antibiotics, including carbapenems and jeopardize the future use of all such agents. The increased treatment of infections with carbapenems and other (3-lactam antibiotics may lead to the proliferation of clinical bacterial strains which are able to produce metallo-(3-lactamases and thus resist the effects of ~3 -lactam antibiotics. In fact, metallo-~i-lactamases have now been identified in a number of pathogenic bacterial species including Bacillus cereus, Bacteroides fragilis, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Shigella flexneri, Legionella gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Acinetobacter baumannii, Citrobacter freundii, and Aeromonas veronii.
Accordingly, there is an increasing need for agents which when combined with a (3-lactam antibiotic, e.g. imipenem, will restore the effectiveness of the [3-lactam antibiotics and which are at the same time relatively free from undesirable side effects.
WO 98/17639, 97/30027, 98/40056,98/39311 and 97/10225 teach certain beta-thiopropionyl-amino acid derivatives and their use as inhibitory agents against metallo-(3-lactamases. Goto et. al., Biol. Pharm. Bull. 20, 1136 (1997), Payne et. al., FEMSMicrobiology Letters 157, 171 (1997), Payne et al., Antimicrob.
Agents Chemother. 41, 135 (1997), Page et. al., Chem. Commun. 1609 (1998) and Page et al., Biochem. J. 331, 703 (1998) also disclose certain thiols and thioesters as metallo-(3-lactamase inhibitors. Additionally, Toney et al., Chemistry and Biology 5, 185 (1998), Fastrez et al., Tetrahedron Lett. 36, 9313 (1995), Schofield et al., Tetrahedron 53, 7275 (1997), Schofield et. al., Bioorg. & Med. Chem. Lett. 6, 2455 (1996) and WO 97/19681 disclose other metallo-(3-lactamase inhibitors. However, the above noted references do not teach the compounds of the instant invention.

Other references which disclosed the general state of the art are Bush et al., Antimicrob. Agents Chemother. 41, 223 (1997); Livermore, D. M. J.
Antimicrob.
Chemother. 1998, 41 (Suppl. D), 25; Bush, K. Clin. Infect. Dis. 1998, 27 (Suppl 1), 548; Livermore, D. M. J. Antimicrob. Chemother. 1997, 39, 673 and Payne, D. J.
J.
Med. Microbiol. 1993, 39, 93.
SUMMARY OF THE INVENTION
This invention relates to novel substituted succinic acid metallo-(3-lactamase inhibitors, which are useful potentiators of (3-lactam antibiotics.
Accordingly, the present invention provides a method of treating bacterial infections in animals or humans which comprises administering, together with a (3 -lactam antibiotic, a therapeutically effective amount of a compound of formula I:
M20 ~OM1 O O
I
including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:
M1 and M2 are independently selected from:
(a) Hydrogen, (b) Pharmaceutically acceptable canon, and (c) Pharmaceutically acceptable esterifying group;
R1 and RZ are independently selected from the following:
(a) Hydrogen, provided that Rl and R2 are not hydrogen at the same time;
(b) a C1 to C~6 straight, branched or unsaturated alkyl group optionally substituted with 1 to 3 RX groups and optionally interrupted by one of the following O, S, 502, -C(O)-, -C(O)-NRa-, -COZ-;

(c) a group of the formula:
(RX)o-s wherein -A- represents a single bond, C1 to Cg straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 Rx groups and optionally interrupted by one of the following O, S, S02, -C(O)-, -C(O)-NRa-, -CO2-;
~ represents:
( 1 ) a C6 to C 14 aryl group;
(2) a C3 to Clo alicyclic group;
1 S (3) a C3 to C14 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C3 to Clo heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
(d) a group of the formula:
A' c (RX)o-2 (RX)o-2 wherein:
-A- is as defined above;
A' is a single bond, O, S, or a C1 to C( straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 Rx groups and optionally interrupted by one of the following groups O, S, 502, -C(O)-, -C(O)-NRa-, -COZ-;
O and are independently selected from:

( 1 ) a C6 to C ~ o aryl group;
(2) a C3 to Cg alicyclic group;
(3) a C2 to C9 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C3 to Cg heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
where each RX is independently selected from the group consisting of (a) F, Cl, Br, I , (b) CF3, (c) ORb, (d) CN, (e) -C(O)-Rc , (~ -s(02)-Rf (g) -C(O)-ORa (h) -O-C(O)-Rc, (i) -s-Rb ~) -N(Ra)-C(O)-Rc~

NORa -C-R~ , /ORb CI) _C_N\
Ra / Rd (m) -O-C_N\
Re , O d R
O) _C_N/
Re , O d ) OS~N/R
\Re , Ra O Rd ~P) -N-CI-N/
Re , (c~ -N(Ra)-C(O)-ORf (r) -S(O)-Rf (s) -N(Ra)-S(02)-Rf (t) N02, and (u) C1 to Cg straight, branched or unsaturated alkyl optionally substituted with one of the substituents (a) through (t) above;
(v) -CH2-aryl wherein the aryl is optionally substituted with one of the substituents (a) through (t) above;
or two adjacent RX groups on an aromatic ring may consist of the following divalent moiety, -O-CH2-O-;
wherein:
Ra is H, C 1 to C6 alkyl optionally substituted with RY;
Rb is H, C1 to C6 alkyl optionally substituted with RY, CH2_aryl, or aryl, said aryls optionally substituted with 1-2 RY groups;
Rc is H, C1 to C6 alkyl optionally substituted with RY, CF3, or aryl, said aryl optionally substituted with 1 to 2 RY groups;
Rd and Re are independently hydrogen, C1 to C4 alkyl optionally substituted with RY
1 S or Rd and Re taken together may represent a 3 to 5-membered alkyl radical to form a ring, or Rd and Re taken together may represent a 2 to 4-membered alkyl radical interrupted by O, S, SO or S02 to form a ring;
Rf is C1 to C6 alkyl optionally substituted with RY, or aryl, said aryl optionally substituted with 1 to 2 RY groups; and RY is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, C02CH3, CONH2, CN, SOCH3, S02CH3, S02NH2, F, Cl, Br, I or CF3.
The invention is intended to include all of the isomeric forms of the compounds of formula I, including racemic, enantiomeric and diastereomeric forms.
Also included in this invention are compositions containing the compounds of formula I and method of treatments using the same.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 16 carbon atoms unless otherwise defined. It may be straight or branched. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and hexyl. When substituted, alkyl groups may be substituted with up to substituent groups, selected from RX 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". When the alkyl chain is interrupted by a group, eg. O, this may occur between any two saturated carbons of the alkyl chain.
The term unsaturated alkyl refers to "alkenyl" or "alkynyl". The term "alkenyl" refers to an unsaturated alkyl such as a hydrocarbon radical, straight or branched containing from 2 to 16 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include propenyl, hexenyl and butenyl.
The term "alkynyl" refers to an unsaturated alkyl such as a hydrocarbon radical straight or branched, containing from 2 to 16 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include propynyl, hexynyl and butynyl.
The term "alicyclic" refers to non-aromatic monocyclic or bicyclic C3-C10 hydrocarbons, including unsaturated, which can be substituted with 0-3 groups of Rx. Examples of said groups include cycloalkyls such as cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hepta-2,5-dienyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octa-2,5-dienyl.
The term "alkylidene" refers to an alkyl group which is attached through two bonds on the same carbon atom of the alkyl group to a single attachment atom, Examples of said groups include methylene, ethylidene, isopropylidene and the like.
Examples of when Rd and Re are taken together along with the adjacent nitrogen atom to represent a 3 to 5 membered alkyl radical forming a ring or a 2 to 4 membered alkyl radical interrupted by O, S, SO, 502, to form a ring are pyrrolidinyl, piperidinyl, morpholinyl and the like.
The term "heterocyclic" refers to a monocyclic non-aromatic moiety containing 3-8 ring atoms or a bicyclic non-aromatic moiety containing 6-10 ring atoms, at least one of which ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur and where one additional ring atom may be oxygen or sulfur.
Examples of heterocyclic groups are furanyl, pyranyl, morpholinyl, dioxanyl and quinuclidinyl:
7_ O O O N
O
N .O
furan pyran H dioxane quinuclidine morpholine Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl fluorenonyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up S to three such rings being present, containing up to 14 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl, naphthyl, and fluorenone. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl, fluorenonyl and naphthyl.
The term "heteroaryl" (Het) refers to a monocyclic aromatic group having 5 or 6 ring atoms, a bicyclic aromatic group having 8 to 10 atoms, or tricyclic having 12-14 ring 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 1 S heteroatoms, said heteroaryl group being optionally substituted as described herein.
Examples of this type are pyrrole, pyridine, oxazole, thiazole, dibenzofuran, dibenzothiophene, carbazole, phenanthrene, anthracene, dibenzothiophene sulfone, fluorenone, quinoline 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:
_g_ N N S
I I /~ /
CO C N
N
pyrrole imidazole thiazole O O S
I / I /
N
oxazole furan thiophene O
N N~ I / N
/N, N
pyrazole isoxazole triazole S \ N
I /N
CO
N N
isothiazole pyridine pyrazine I \~ ~ N NON
N: N , I J , ~ J , N N
pyridazine pyrimidine triazine / I
I \ \ / I w Ni / \ N J
quinoline ' phenanthridine \ \ \ \
I I and I
O / / S
dibenzofuran dibenzothiophene The term "heteroatom" means O, S or N, selected on an independent basis.
Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.

The term "pro-drug" refers to compounds with a removable group attached to one or both of the carboxyl groups of compounds of formula I (e.g.
biolabile esters). Groups which are useful in forming pro-drugs should be apparent to the medicinal chemist from the teachings herein. Examples include S 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.
The term "hydrate" is used in the conventional sense to include the compounds of formula I in physical association with water.
When a group is termed "substituted", unless otherwise indicated, this means that the group contains from 1 to 3 substituents thereon.
A bond terminated by a wavy line is used herein to signify the point of attachment of a substituent group. This usage is illustrated by the following example:

/

When a functional group is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site.
Suitable 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.
In some of the compounds of the present invention suitable protecting groups represents hydroxyl-protecting or carboxyl-protecting groups. Such conventional protecting groups consist of groups, which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein.

These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
Examples of 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.
Examples of suitable hydroxyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
The compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms are potentiators for the treatment of bacterial infections in animal and human subjects. The term "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. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel metallo-beta-lactamase inhibitors of formula I.
The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following:
acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
The pharmaceutically acceptable cations which can form a salt with one or both of the carboxyls (C02M1 and C02M2) of the compounds of formula I
are known to those skilled in the art. Examples include those where M1 and M2 independently can be alkali metals such as sodium, potassium and the like, ammonium and the like or hydrogen. It is noted that the compounds claimed in the instant invention are, as necessary, charged balanced in accordance with the knowledge of those skilled in the art.
The pharmaceutically acceptable esterifying groups 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 intenstinal mucosa, resistance to gastric acid degradation and other factors.
Some of the compounds of formula I may be crystallized or recrystallized from solvents such as organic solvents. In such cases solvates may be formed. This invention includes within its cope stoichiometric solvates including hydrates as well as compounds containing variable amounts of solvents such as water that may be produced by processess such as lyophilization. The compounds of formula I may be prepared in crystalline form by for example dissolution of the compound in water, preferably in the minimum quantity thereof, followed by admixing of this aqueous solution with a water miscible organic solvent such as a lower aliphatic ketone such as a di-(C1-() alkyl ketone, or a (C1-() alcohol, such as acetone or ethanol.
A subset of compounds of formula I which is of interest relates to those compounds where Rl and RZ are not hydrogen and all other variables are as described above.

A subset of compounds of formula I which is of interest relates to those compounds where Rl and RZ are not the same and all other variables are as described above.
Another subset of compounds of formula I which is of interest relates to those compounds where Rl and/or RZ represents a C~ to C16 straight, branched or unsaturated alkyl group optionally substituted with 1 to 3 Rx groups and optionally interrupted by one of the following O, S, 502, -C(O)-, -C(O)-NRa-, -COZ- and all other variables are described as above. A subset of this invention is realized when Rl and/or RZ is a CS to C16 alkyl, preferably C7 to C16 alkyl and are not the same.
A subset of compounds of formula I which is of interest relates to those compounds where M1 and M2 are independently hydrogen, sodium or potassium and all other variables are as described above.
Another subset of compounds of formula I which is of interest relates to those compounds where Rl and/or R2 represents CS-16, preferably C~_16 straight, branched or unsaturated alkyl optionally substituted with 1 to 2 RX , wherein all variables are as described above.
Another subset of compounds of formula I which is of interest relates to those compounds where one of Rl or RZ is benzyl or substitued benzyl and all variables are as originally described. A further subset of this invention is realized when the substituted benzyl is substituted with -OH, -OCH3, OCH2Phenyl, or OCH20.
Another subset of compounds of formula I which is of interest relates to those compounds where Rl and/or R2 represents (C) ~Rx)o-3 wherein all other variables are described as above.
Another subset of compounds of formula I which is of interest relates to those compounds where R' and/or RZ represents a A~ c (d) ~Rx)0-2 ~Rx)0-2 wherein all other variables are described as above.

Another subset of compounds of formula I which is of interest relates to those compounds wherein one of Rl or RZ is a benzyl or substituted benzyl and the -A B A~ C
other of Rl and R2 is (Rx)o-2 (Rx)o-z wherein all other variables are described as above.
Another subset of compounds of formula I which is of interest relates to those compounds where the relative and absolute stereochemistry is:
R~
,.

Still another subset of compounds of formula I which is of interest relates to those compounds where RI and/or RZ represents a group of the formula:
A
~Rx)o-2 wherein A is (CH2)1-5 ~d is phenyl, naphthyl, cyclohexyl or dibenzofuranyl.
Still another subset of compounds of formula I that is of interest relates to those compounds where R' and/or RZ represents a group of the formula -A B A~ C
(Rx)0-2 (Rx)0-2 wherein A is (CH2)1-3, A' is a bond, -O- or (CH2)1-2 and and independently represent phenyl, thienyl, pyridyl, furanyl or cyclohexyl.
Still another subset of compounds of formula I that is of interest relates to those compounds where one of R1 or R2 is:
/ \ /
~''~ ~~RX~o-2 and all other variables are as originally defined.

Still another subset of compounds of formula I that is of interest relates to those compounds of the following structure:
(RX o-~ ~RX)o-2 M202C C02M~
wherein RX, M2, and M1 are as originally defined.
Another subset of compounds of formula I which is of interest relates to those compounds where R1 and R2 are not the same and neither is hydrogen.
Yet another subset of compounds of formula I, that is of interest relates to those compounds where one of R1 or R2 is a group of the formula:
A
(RX)o-2 where A is (CH2)1-2 ~d is phenyl or cyclohexyl and the other of R1 or R2 is a group of the formula:
-A B A' C
(Rx)o-z (Rx)o-z where A is (CH2)1-2, A' is a single bond, is phenyl or cyclohexyl and ~ is phenyl, thienyl or pyridyl.
Still another subset of compounds of formula I that is of interest relates to those compounds where:
R1 is CS-7 alkyl substituted with 0 to 2 RX groups, ~RX)o-2 °~ ~ ~ ~RX)o-2 R2 is C~_10 alkyl substituted with 0 to 2 Rx groups, O
or / ~ \~ (RX)o-2 ' \ /
- ~RX)o-z and all other variables are as described above.
A preferred subset of Rx is RY.
The compounds of the invention, which are succinic acids or derivatives thereof, 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 of formula I have metallo-(3-lactamase inhibitory properties, and are useful when combined with a (3-lactam antibiotic for the treatment of infections in animals, especially mammals, including humans. The compounds may be used, for example, in the treatment of infections of, amongst others, the respiratory tract, urinary tract and soft tissues and blood.
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, 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. Alternatively, 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. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections.
Also, 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 compounds of the instant invention are metallo-(3-lactamase inhibitors, which are intended for use in pharmaceutical compositions.
Accordingly, it is preferable that the metallo-(3-lactamase inhibitors are provided in substantially pure form, for example at least about 60% to about 75% pure, preferably about 85%
to about 95% pure and most preferably about 98% or more pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in pharmaceutical compositions.
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.
The compositions for human delivery per unit dosage, whether liquid or solid, 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.
In parenteral administration, 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 conjunction with a (3-lactam antibiotic such as a carbapenem, penicillin or cephalosporin in an effective combination.
The preferred methods of administration of the Formula I compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m.
injection.
The compounds of formula I may suitably be administered to the patient at a daily dosage of from 0.7 to 50 mg/kg of body weight. For an adult human (of approximately 70 kg body weight), from 50 to 3000 mg, preferably from 100 to 1000 mg, of a compound according to the invention may be administered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice.
The compounds may be used in combination with antibiotic agents for the treatment of infections caused by metallo-(3-lactamase producing strains, in addition to those infections which are subsumed within the antibacterial spectrum of the antibiotic agent. Metallo-~3-lactamase producing strains include: Bacillus cereus, Bacteroides fragilis, Aeromonas hydrophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia, Shigella flexneri, Legionella gormanii, Chryseobacterium meningosepticum, Chryseobacterium indologenes, Acinetobacter baumannii, Citrobacter freundii, and Aeromonas veronii.
In accordance with the instant invention, it is generally advantageous to use a compound of formula I in admixture or conjuction with a carbapenem, penicillin, cephalosporin or other (3-lactam antibiotic or prodrug. It also advantageous to use a compound of formula I in combination with one or more (3-lactam antibiotics 1 S because of the metallo-(3-lactamase inhibitory properties of the compounds. In this case, the compound of formula I and the (3-lactam antibiotic can be administered separately or in the form of a single composition containing both active ingredients.
Carbapenems, penicillins, cephalosporins and other (3-lactam antibiotics suitable for co-administration with the compounds of Formula I, whether by separate administration or by inclusion in the compositions according to the invention, include both those known to show instability to or to be otherwise susceptible to metallo-(3-lactamases and also known to have a degree of resistance to metallo-/3-lactamase.
When the compounds of Formula I are combined with a carbapenem antibiotic, a dehydropeptidase (DHP) inhibitor may also be combined. Many carbapenems are susceptible to attack by a renal enzyme known as DHP. This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent.
Inhibitors of DHP and their use with carbapenems are disclosed in, e.g., (European Patent 0007614, filed July 24, 1979 and application number 82107174.3, Fled August 9, 1982. A preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof.
Thus, compounds of the present invention in combination with a carbapenem such as imipenem and a DHP inhibitor such as, cilastatin is contemplated within the scope of this invention.

A serine (3-lactamase inhibitor such as clavulanic acid, sulbactam or tazobactam may also be co-administered with the compound of the invention and (3-lactam antibiotics, either by separate administration, or co-formulation with one, other or both of the compounds of the invention and the (3-lactam antibiotic.
Examples of carbapenems that may be co-administered with the compounds of formula I include imipenem, meropenem, biapenem, (4R, SS, 6S)-3-[3S, SS)-5-(3-carboxyphenyl-carbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (1S, SR, 6S)-2-(4-(2-(((carbamoylmethyl)-1,4-diazoniabicyclo[2.2.2]oct-1-yl)-ethyl(1,8-naphthosultam)methyl)-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate chloride, BMS181139 ([4R-[4alpha,5beta,6beta(R*)]]-4-[2-[(aminoiminomethyl)amino] ethyl]-3-[(2-cyanoethyl)thio]-6-( 1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), B02727 ([4R-3[3S*,SS*(R*)], 4alpha,Sbeta,6beta(R*)]]-6-( 1-hydroxyethyl)-3-[ [5-[ 1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]
hept-2-ene-2-carboxylic acid monohydrochloride), E 1 O 10 (( 1 R, S S, 6S)-6-[ 1 (R)-hydroxymethyl]-2-[2(S)-[1(R)-hydroxy-1-[pyrrolidin-3(R)-yl] methyl]pyrrolidin-4(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid hydrochloride) and ((1R,SS,6S)-2-[(3S,SS)-5-(sulfamoylaminomethyl) pyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid), (1S,SR,6S)-1-methyl-2-f 7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1 yl]-methyl-fluoren-9-on-3-yl}-6-(1R-hydroxyethyl)-carbapen-2-em-3 carboxylate chloride.
Examples of penicillins suitable for co-administration with the compounds according to the invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azloccillin, mezlocillin, sulbenicillin, piperacillin, and other known penicillins. The penicillins may be used in the form of pro-drugs thereof; for example as in vivo hydrolysable esters, for example the acetoxymethyl, pivaloyloxymethyl, a-ethoxycarbonyloxy-ethyl and phthalidyl esters of ampicillin, benzylpenicillin and amoxycillin; as aldehyde or ketone adducts of penicillins containing a 6-a-aminoacetamido side chain (for example hetacillin, metampicillin and analogous derivatives of amoxycillin);
and as a-estsers of carbenicillin and ticarcillin, for example the phenyl and indanyl a-esters.

Examples of cephalosporins that may be co-administered with the compounds according to the invention include, cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin, cephaloglycin, cefoperazone, cefsulodin, ceftazidime, cefuroxime, cefinetazole, cefotaxime, ceftriaxone, and other known cephalosporins, all of which may be used in the form of pro-drugs thereof.
Examples of (3-lactam antibiotics other than penicillins and cephalosporins that may be co-administered with the compounds according to the invention include aztreonam, latamoxef (Moxalactam-trade mark), and other known (3-lactam antibiotics such as carbapenems like imipenem, meropenem or (4R, SS, 6S)-3-[(3 S,5 S)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-( 1 R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]kept-2-ene-2-carboxylic acid, all of which may be used in the form of pro-drugs thereof.
Preferred carbapenems are imipenem, meropenem and (4R, SS, 6S)-3-[(3S,SS)-5-(3-carboxyphenylcarbamoyl)pyrrolidin-3-ylthio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]kept-2-ene-2-carboxylic acid.
Particularly suitable penicillins for co-administration with the compounds according to the invention include ampicillin, amoxycillin, carbenicillin, piperacillin, azlocillin, mezlocillin, and ticarcillin. Such penicillins may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts.
Alternatively, ampicillin or amoxycillin may be used in the form of fine particles of the zwitterionic form (generally as ampicillin trihydrate or amoxycillin trihydrate) for use in an injectable or infusable suspension, for example, in the manner described herein in relation to the compounds of formula I. Amoxycillin, for example in the form of its sodium salt or the trihydrate, is particularly preferred for use in compositions according to the invention.
Particularly suitable cephalosporins for co-administration with the compounds according to the invention include cefotaxime, ceftriaxone and ceftazidime, which may be used in the form of their pharmaceutically acceptable salts, for example their sodium salts.
When the compositions according to this invention are presented in unit dosage form, each unit dose may suitably comprise from about 25 to about mg, preferably about from 50 to about 500 mg, of a compound according to the invention. Each unit dose may, for example, be 62.5, 100, 125, 150, 200 or 250 mg of a compound according to the invention.

When the compounds of formula I are co-administered with a penicillin, cephalosporin, carbapenem or other (3-lactam antibiotic, the ratio of the amount of the compounds of formula I to the amount of the other (3-lactam antibiotic may vary within a wide range. The said ratio may, for example, be from 100:1 to 1:100; more particularly, it may for example, be from 2:1 to 1:30. The amount of carbapenem, penicillin, cephalosporin or other (3-lactam antibiotic according to the invention will normally be approximately similar to the amount in which it is conventionally used.
The claimed invention also includes the use of a compound of formula I, a pharmaceutically acceptable salt, ester, prodrug, anhydride or solvate thereof, in the manufacture of a medicament for the treatment of bacterial infections.
The claimed invention also includes the use of a compound of formula I as a metallo-~3-lactamase inhibitor.
The claimed invention further includes a method of treating bacterial infections in humans or animals which comprises administering, in combination with a (3-lactam antibiotic, a therapeutically effective amount of a metallo-(3-lactamase inhibitor of formula I.
The claimed invention further includes a method of treating bacterial infections in humans or animals which comprises administering, in combination with a carbapenem antibiotic, a therapeutically effective amount of a metallo-~i-lactamase inhibitor of formula I.
The claimed invention also includes a composition comprising a metallo-~3-lactamase inhibitor of formula I together with a ~3-lactam antibiotic and a pharmaceutically acceptable carrier.
The claimed invention also includes a composition comprising a metallo-(3-lactamase inhibitor of formula I together with a carbapenem antibiotic and a pharmaceutically acceptable carrier.
The compositions discussed above may optionally include a serine (3-lactamase inhibitor as described above as well as a DHP inhibitor.
The compounds of the present invention are synthesized using the general conditions shown in the accompanying flow charts (A through E).

FLOW SHEET A
/C02P' ~

1.
NaN(TMS~, THF
1.
tBuCOCI, Et3N

HO~R~ O
~ R~
N~R~ ~
-.
~
' 2. O
O 2.
BrCH2COzP

~N'u~

~/

-Ph Remove Chlral Auxilliary 1.
Strong Base (2-3 eq) R R~
THF, low temp P'OZC P'OZC
COzH COZH
2.
Alkylating agent (R2X) Remove carboxyl protecting group 02 Pt = carboxyl R, protecting group X = displaceablegroup HOZC leaving COzH

FLOW SHEET B
1. Strong Base OH
R~ THF, low temp Ar~~~R~
P~02 C02H 2. Ar~CHO P~02C~C02H

cyclize Are O O
Ar~~R~ reduction P~02C~'C02H P~OzC R' Remove carboxyl protecting group Ar~~R~ P' = carboxyl protecting group H02C C02H Ari = optionally substituted B4 aryl or heteroaryl group FLOW SHEET C
R~ 1. Strong base, THF Y-Ar2-(CH2)n \R~
PLO C CO H PLO ~ O H
2 2 2. Alkylating agent 2 2 A4 [ Y-Arz-(CH2)r; X J C1 Protect carboxyl group R3- Ar2- (CH2)n 3 Y-Ar2- (CH2)n ~\R~ R -Met ~~R
PLO C CO P2 ~ Palladium catalyst P~02C~---~C02P2 C3 solvent, 0 C2 Remove carboxyl protecting groups X = displaceable leaving group Ar optionally substituted aryl = or heteroaryl R3-Ar2-(CH2)n group R~

Y = iodide, bromide, chloride H02C C02H or protected hydroxy C4 n = 1, 2, 3 or 4 _ 3 R optionally substituted alkenyl, = alkynyl, aryl or heteroaryl group Met boronic acid or trialkyltin = moiety P1 carboxyl protecting group =

P2 carboxyl protecting group =

FLOW SHEET D
(~ 1. Strong ~R~
~R~ base ' ~
THF, low tem p MO~ HOZC COZH

D1 2. Oxidizing D2 agent 3. Acidic work-up 4. Remove ester group if present M = H or esterifying group FLOW SHEET E
R 1. Strong base HO~R~ 1. tBuCOCI, Et3N ~R~ THF, low temp E1 2, '-', 2. Oxidizing agent ~Li E2 =Ph '' =Ph R' ~t~ Remove R' .ft~ O
Chiral Auxilliary ~ X* - p~N~~
X* ~X* ' HOzC COZH
d~O
E4 -Ph The 2,3-disubstituted succinic acid compounds of the present invention can be prepared by the general methods described in Flow Sheets A-E. When one or more Rx substituents are present in a compound synthesized according to the Flow Sheets, it is sometimes advantageous that they be carried through the syntheses in protected or precursory form and then be deprotected or elaborated at or near the end of the synthesis. For example, if a desired Rx group is incompatible with the reaction conditions of the synthesis being employed, said Rx group may be introduced initially in a protected form and then be deprotected at the end of the synthesis.
The synthesis of Flow Sheet A is based on a known literature procedure (M. J. Crimmin et. al., SynLett 1993, 137). Referring to Flow Sheet A, the R1-substituted acetic acid starting materials A1 are readily available from commercial sources or are readily prepared by a variety of methods known in the art.
Briefly, the starting material A1 is alkylated with an ester derivative of bromoacetic acid, employing a chiral auxiliary group to achieve stereoselectivity in the reaction. After removal of the chiral auxiliary to give A4, the R2-alkyl group is introduced stereoselectively by an alkylation reaction to give A5. Removal of the carboxyl protecting group of AS provides the final compound A6.
The first step of Flow Sheet A is introduction of the chiral auxiliary. A
suggested method is as follows. A mixed anhydride is formed between the starting carboxylic acid A1 and pivalic acid by treating A1 with a tertiary amine base such as triethylamine and pivaloyl chloride in a suitable ethereal solvent such as tetrahydrofuran at reduced temperature such as between -78°C and 0°C. After a suitable reaction time, such as from 30 min to 3 hours, the resulting activated intermediate is then reacted with a freshly prepared solution of lithio-(4R)-benzyl-2-oxazolidinone in tetrahydrofuran at reduced temperature such as between -78°C and 0°C. After conventional isolation and purification, intermediate A2 is obtained.
Intermediate A2 is deprotonated with a strong base such as sodium hexamethyldisilazide in a solvent such as tetrahydrofuran at reduced temperature such as between -78°C and -70°C. The resulting enolate is alkylated by addition of BrCH2C02P1, where P1 is a removable carboxyl protecting group. After an appropriate reaction period, such as from 1 to 3 hours, compound A3 is obtained by conventional isolation and purification techniques. Suitable removable ester derivatives of bromoacetic acid for this alkylation reaction are t-butyl bromoacetate, allyl bromoacetate or benzyl bromoacetate.
The oxazolidinone chiral auxiliary group of A3 is removed by a hydrolysis reaction. Aqueous lithium hydroxide and aqueous hydrogen peroxide are employed for this reaction along with an organic co-solvent such as tetrahydrofuran.
The reaction is carried-out at a temperature of from 0°C to 30°C
for a reaction time of from 30 min to 4 hours. After acidification, conventional isolation and purification provides intermediate A4.

An alternative method of removing the chiral auxilliary consists of reacting A3 with lithium benzyloxide (LiOCH2Ph) followed by cleavage of the resulting benzyl ester to give A4. The reaction of A3 with lithium benzyloxide is carried-out in tetrahydrofuran as solvent at a temperature of from -78°C to 30°C for a reaction time of from 30 min to 4 hours. Cleavage of the resulting benzyl ester is accomplished in conventional fashion, eg by hydrogenolysis employing a suitable catalyst such as palladium on carbon in an appropriate solvent such as ethanol at 1-2 atmospheres pressure of hydrogen. After conventional isolation and purification, compound A4 is obtained.
Alkylation of A4 to give AS is accomplished by deprotonating A4 with >2 equivalents of a strong hindered base to give a dianion, which is then reacted with an alkylating agent R2X to give A5, where R2 is as defined above and X is a displaceable leaving group such as iodide, bromide or trifluoromethanesulfonate. The reaction proceeds with high stereoselectivity to give predominately the stereoisomer 1 S shown in Flow Sheet A. The deprotonation reaction is carried-out in a suitable solvent such as tetrahydrofuran at a temperature of from -78°C to -70°C for a reaction time of from 30 min to 3 hours. Preferred bases for this reaction are lithium bis(trimethylsilyl)amide and lithium diisopropylamide. After addition of the alkylating agent, the reaction is allowed to proceed at a temperature of from -78°C to 25°C for a reaction time of from 1 to 12 hours. Progress of the reaction can be monitored by conventional analytical methods, eg HPLC and TLC. Preferred alkylating agents for this reaction are alkyl iodides and alkyl bromides.
Other suitable alkylating agents are well known in the art and include alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl tosylates. After conventional isolation and purification, intermediate AS is obtained. The minor stereoisomer produced in this reaction can often be separated from AS at this stage by conventional chromatographic techniques. However, it is often preferable to carry-out this separation at the stage of A6, after removal of the carboxyl protecting group as described below.
Removal of the carboxyl protecting group of AS by standard methods gives the final compound A6. When P 1 is t-butyl, this is accomplished by treating AS
with a strong acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane. The reaction is carried-out at a temperature of from 0°C to 30°C for a reaction time of from 1 to 8 hours. The final compound A6 is then isolated by conventional techniques. Other methods of removing tert-butyl ester groups are known in the art and may also be employed (see e.g. Greene, T. W., et al.
Protective Groins in Or anic S tin hesis, John Wiley & Sons. Inc., 1991).
It will be apparent to one skilled in the art that employing a chiral auxiliary of the opposite absolute configuration [eg. lithio-(4S)-benzyl-2-oxazolidinone] in the first step of Flow Sheet A will make possible the synthesis of compound A3 with the alternative stereochemistry at the newly created stereocenter.
This will in turn make possible the synthesis of the final compounds A6 of Flow Sheet A, with the opposite absolute configuration. Other chiral auxiliary groups are also known in the art and may also be employed.
Flow Sheet B illustrates a variation of Flow Sheet A which is preferred in certain cases, for example when Arl is a heteroaryl group such as pyridyl.
1n this synthesis the second substituent on the succinic acid is introduced by an aldol reaction instead of an alkylation reaction. The synthesis begins with compound A4, which is prepared as described in Flow Sheet A. Compound A4 is deprotonated with >2 equivalents of a strong hindered base to give a dianion which is then reacted with an aldehyde ArlCHO to give B15, where Arl is an optionally substituted aryl or heteroaryl group, terms which are defined above. The deprotonation reaction is carried-out in a suitable solvent such as tetrahydrofuran at a temperature of from -78°C to -70°C for a reaction time of from 30 min to 3 hours.
Preferred bases for this reaction are lithium bis(trimethylsilyl)amide and lithium diisopropylamide.
After addition of the aldehyde, the reaction is allowed to proceed at a temperature of from -78°C to 25°C for a reaction time of from 1 to 12 hours. After conventional isolation and purification, intermediate B 1 is obtained.
Compound B 1 is next cyclized to the lactone B2. Suitable conditions for this cyclization reaction would be exposure of B 1 to acetic anhydride and triethylamine in an inert solvent such as dichloromethane. Reductive opening of lactone B2, such as by hydrogenolysis over palladium on carbon in a suitable solvent such as methanol, provides compound B3. Removal of the carboxyl protecting group of B3 by conventional methods then gives the final compound B4.
Flow Sheet C illustrates an extension of the synthesis of Flow Sheet A
which makes possible the introduction of a variety of preferred biaryl-type R2 substituents. Briefly, starting with compound A4 from Flow Sheet A, alkylation with Y-Ar2-(CH2)n-X by the method described in Flow Sheet A gives intermediate C1;
where X is a displaceable leaving group such as iodide, bromide or trifluoromethanesulfonate, n is 1,2,3 or 4, Ar2 is an optionally substituted aryl or heteroaryl group as defined above, and Y is iodide, bromide, chloride or a protected hydroxyl group which can be converted to a trifluoromethanesulfonate group by known methods. Protection of the free carboxyl group of C 1 with a removable protecting group P2 gives C2. When Y is a protected hydroxyl group it is deprotected and converted to a trifluoromethanesulfonate group at this point. A palladium catalyzed organometallic cross-coupling reaction between C2 and an organometallic reagent R3-Met gives compound C3; where Met is a boronic acid or trialkyltin moiety and R3 is an optionally substituted alkenyl, alkynyl, aryl or heteroaryl group as defined above Removal of the two carboxyl protecting groups of C3 then provides the final compound C4.
The P2 carboxyl protecting group is introduced in conventional fashion. A preferred P2 group is p-methoxybenzyl which can be introduced employing p-methoxybenzyl alcohol, a carbodiimide reagent such as 1,3-diisopropylcarbodiimide and N,N-dimethylaminopyridine catalyst in a suitable inert solvent such as dichloromethane. Other suitable ester protecting groups known in the art could also be employed (see e.g. Greene, T. W., et al. Protective Groups in Organic Synthesis, John Wiley & Sons. Inc., 1991).
The palladium catalyzed cross-coupling reaction between C2 and R3-Met is carned-out by procedures known in the scientific and patent literature.
When Met is a boronic acid moiety [-B(OH)2] the reaction is commonly known as a Suzuki reaction (see Suzuki, Chem. Rev. 1995, 95, 2457). Compound C2 is combined with the boronic acid R3-B(OH)2 in a coupling solvent such as 1,2-dimethoxyethane, N,N-dimethylformamide or toluene, optionally with water as a co-solvent, with a base such as sodium carbonate and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0). The reaction is carried-out at a temperature of from 20 °C to 125 °C for a reaction time of from 1 to 48 hours. The coupled product C3 is then isolated by conventional techniques. When Met is a trialkyltin moiety, the reaction is commonly known as a Stille reaction and the cross-coupling is carried-out by procedures well known in the literature (T. N. Mitchell, Synthesis 1992, 803).
Removal of the carboxyl protecting groups of C3 by standaxd methods provides the final compound C4. It is often convenient for the protecting groups P1 and P2 to be selected such that they can both be removed under the same reaction conditions. For example, when P1 is tert-butyl and P2 is p-methoxybenzyl, both esters of C3 can be removed in a single step by treating C3 with a strong acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane. It is sometimes advantageous to include a trapping agent such as triethylsilane or anisole in the reaction mixture. The reaction is carned-out at a temperature of from 0 °C to 30 °C
for a reaction time of from 1 to 8 hours. The final compound C4 is then isolated by conventional techniques. Other methods of removing tert-butyl and p-methoxybenzyl ester groups are known in the art and may also be employed (see e.g. Greene, T. W., et al. Protective Groups in Organic Synthesis, John Wiley & Sons. Inc., 1991).
Flow Sheet D illustrates an alternative synthesis of compounds of the present invention. The R1-substituted acetic acid starting materials D1 (M = H) and the esterified derivatives thereof (M = esterifying group) are readily available from commercial sources or are readily prepared by a variety of methods known in the art.
The synthesis of Flow Sheet D is based on known literature procedures (see for example J. L. Belletire and D. F. Fry, J. Org. Chem. 1987, 52, 2549). Briefly, starting material D1 is deprotonated with a strong base and the resulting dianion (M =
H) or anion (M = esterifying group) is oxidatively coupled with a suitable oxidizing reagent.
In the case of M = H, acidic work-up and conventional isolation and purification gives the final compound D2. In the case of M = esterifying group, an additional deprotection step is also needed. A preferred strong base for the deprotonation reaction is lithium diisopropylamide. Suitable oxidizing agents for the synthesis of Flow Sheet D include iodine, copper(II) salts such as CuBr2, and titanium tetrachloride.
Since the synthesis of Flow Sheet D is based on a dimerization-type reaction, it is best suited for the synthesis of symmetrically 2,3-disubstituted succinic acids. For this reason, it is generally less preferred than the syntheses of Flow Sheets A, B and C. The synthesis of Flow Sheet D also generally produces a racemic mixture of stereoisomers. However, it is possible to employ a chiral auxiliary in the synthesis of Flow Sheet D in order to achieve high stereoselectivity and optical purity (see for example N. Kise et. al. J. Org. Chem. 1995, 60, 1100). Such use of a chiral auxiliary is illustrated in Flow Sheet E.
The invention is further described in connection with the following non-limiting examples.

THF
LiN O -7p °C P
PhJ
CI I / O N I /

Compound 1 A solution of (4R)-benzyl-2-oxazolidinone (2.44 g, 13.77 mmol) in 100 mL of THF
was cooled to -70°C and metalated by the dropwise addition of a 2.5M
solution of n-butyllithium in hexanes (5.52 mL, 13.77 mmol). After 20 min, neat hydrocinnamoyl chloride (2.05 ml, 13.79 mmol) was added. After 15 min, the reaction mixture was warmed by placing in an ice bath and kept at 0°C for 1 hr. The reaction was hydrolyzed by the addition of sat. aqueous NH4C1 and most of the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and sat.
aqueous NH4Cl and the organic phase was washed with sat. aqueous NaHC03, water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a solid. Flash chromatography through 500 g of silica gel (50:40:10 hexane/CH2C12 /EtOAc) yielded 3.89 g of the title compound as a white solid.
1H-NMR (S00 Mz, CDC13): 8 2.79 (dd, J = 13.5, 9.4 Hz, 1H), 3.02-3.13 (m, 2H), 3.24-3.41 (m, 3H), 4.16-4.21 (m, 2H), 4.65-4.74 (m, 1H), 7.16-7.40 (m, 10H).
MS (CI): m/z = 385.2 (MH+).

1. NaN(TMS~ P t-BuO, ~O
THF, 78 °C
2. BrCH2C02t-Bu 1 O v 2 Compound 2 A stirred solution of compound 1 (3.283 g, 10.612 mmol) in 35 mL of THF was cooled to -78°C and a 1.0M solution of NaN(TMS)2 in THF
(11.67 mL, 11.67 mmol) was added dropwise during 15 min. After 30 min, a solution of t-butyl bromoacetate (2.04 mL, 13.82 mmol) in 2 mL of THF was added dropwise during 5 min. The solution was stirred at -78°C for 1 h and then the ice bath was removed and stirnng was continued for 1 h. The reaction was hydrolyzed by the addition of sat.
aqueous NH4C1 and most of the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and sat. aqueous NH4C1 and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a solid. Flash chromatography through 410 g of silica gel (35:60:5 hexane/CH2C12/EtOAc) yielded 2.86 g of the title compound as a white foam.
1H-NMR (500 Mz, CDC13): 8 1.43 (s, 9H), 2.41 (dd, J = 17.0, 4.1 Hz, 1H), 2.64-2.80 (m, 2H), 2.88 (dd, J = 17.0, 11.0 Hz, 1H), 3.04 (dd, J = 13.0, 6.3 Hz, 1H), 3.34 (dd, J
= 13.5, 3.2 Hz, 1 H), 3 .95 (t, J = 8.4 Hz, 1 H), 4.08-4.12 (m, 1 H), 4.5-4.6 (m, 2H), 7.21-7.40 (m, 10H).
MS (ESI): m/z = 441.3 (M+NH4+) Ph t-Bu0 ~O
\ LiOH / HOOH
THF, H20, 0 °C t-Bu0 CO H

O O

Compound 3 A stirred solution of compound 2 (2.860 g, 6.753 mmol) in 70 mL of 4:1 THF/H20 was cooled to 0°C and 30% aq. hydrogen peroxide (2.8 mL, 27.01 mmol) was added dropwise during 5 min. After 5 min, a 1.0M solution of LiOH~H20 in H20 (13.51 ml, 13.51 mmol) was added dropwise during 10 min. The reaction was kept at 0°C for 1.75 hr. and then a 1.5M solution of Na2S03 in H20 (18.0 ml, 27.01 mmol) was added. The ice bath was removed and the reaction mixture was allowed to warm towards room temperature over 30 min. A solution of 1.0N

NaHC03 in H20 was added until the reaction mixture had a pH=9 by pH paper (~S
ml). Most of the THF was removed by rotary evaporation and the residue was partitioned between CH2C12 and H20. The aqueous layer was washed 3 x CH2C12 and then acidified with 2N HCl until pH=3 by pH paper. The aqueous layer was extracted 4 x CH2Cl2 and the combined organic extracts were dried over Na2S04 and evaporated in vacuo to give an oil. Flash chromatography through 100 g of silica gel (94:6 CH2C12/MeOH + 0.5% HOAc) yielded 1.74 g of the title compound as a white solid.
1H-NMR (500 Mz, CDC13): 8 1.45 (s, 9H), 2.38 (dd, J = 16.6, 4.4 Hz, 1H), 2.58 (dd, J = 16.6, 8.5 Hz, 1H), 2.80 (dd, J = 15.3, 10.3 Hz, 1H), 3.10-3.20 (m, 2H), 7.20-7.40 (m, SH), 11.99 (bs, 1H).
MS (ESI): m/z = 430.2 (M+NH4+) 1. CICOt-Bu, Et~N P
THF, -70 °C
HOzC I ~ O N
THF
Li ~ _7p °C O O 4 Ph-' Compound 4 To a stirred solution of 3-(4-biphenyl)-propionic acid ( 1.805 g, 7.977 mmol) in 40 mL of THF was added Et3N (1.28 mL, 9.17 mmol) and the solution was cooled to -70°C. Neat pivaloyl chloride (1.0 ml, 8.1 mmol) was added and a thick white suspension resulted. After 15 min, the reaction mixture was warmed by placing in an ice bath and kept at 0°C for 40 min. The mixture was then re-cooled to -70°C.
In a separate flask, a solution of (4R)-benzyl-2-oxazolidinone (1.44 g, 8.13 mmol) in mL of THF was cooled to -70°C and metalated by the dropwise addition of a 2.5M
solution of n-butyllithium in hexanes (3.25 mL, 8.13 mmol). The resulting anion solution was added to the re-cooled suspension via a cannula, rinsing with an additional 3 mL of THF. After 1 S min, the reaction mixture was warmed by placing 30 in an ice bath and kept at 0°C for 30 min. The reaction was hydrolyzed by the addition of sat. aqueous NH4Cl and most of the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and sat.
aqueous NH4Cl and the organic phase was washed with sat. aqueous NaHC03, water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a solid. Flash chromatography through 240 g of silica gel (CH2C12) yielded 2.45 g of the title compound as a white solid.
1H-NMR (500 Mz, CDCl3): b 2.79 (dd, J = 13.3, 9.4 Hz, 1H), 3.05-3.15 (m, 2H), 3.25-3.41 (m, 3H), 4.15-4.25 (m, 2H), 4.65-4.75 (m, 1H), 7.15-7.65 (m, 14H).
MS (E1): m/z = 385.2 (M+).

P / I 1. NaN(TMS)2 P t-Bu~
O
THF, -78 °C ~ _ O N I / O N I /
2. BrCHzCOzt-Bu Compound 5 A stirred solution of compound 4 (1.000 g, 2.594 mmol) in 40 mL of THF was cooled to -78°C and a 1.0M solution of NaN(TMS)2 in THF (2.85 mL, 2.85 mmol) was added dropwise during 5 min. After 30 min, a solution of t-butyl bromoacetate (0.500 mL, 3.37 mmol) in 4 mL of THF was added dropwise during 5 min. The solution was stirred at -78°C for 1 h and then the reaction was hydrolyzed by the addition of sat. aqueous NH4Cl. The reaction mixture was partitioned between ethyl acetate and sat. aqueous NH4Cl and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a solid. Flash chromatography through 150 g of silica gel (65:30:5 hexane/CH2C12/EtOAc) yielded 1.12 g of the title compound as a white solid.
1H-NMR (500 Mz, CDCl3): b 1.43 (s, 9H), 2.45 (dd, J = 16.9, 4.1 Hz, 1H), 2.65-2.80 (m, 2H), 2.89 (dd, J =16.9, 10.8 Hz, 1H), 3.07 (dd, J = 13.0, 6.1 Hz, 1H), 3.34 (dd, J
= 13.5, 3.0 Hz, 1H), 3.94 (t, J = 8.4 Hz, 1H), 4.08-4.11 (m, 1H), 4.5-4.6 (m, 2H), 7.25-7.60 (m, 14H).
MS (ESI): m/z = 517.5 (M+NH4+).

t-Bu / t-Bu LiOBn \ ~ \
THF, -78 °C Bn0 I /
O O

Compound 6 S
A stirred solution of compound 5 (0.907 g, 1.815 mmol) in 10 mL of THF was cooled to -70°C and a freshly prepared 0.27 M solution of LiOBn in THF
(10 mL, 2.7 mmol) was added dropwise during 10 min. The reaction was allowed to warm gradually to -10°C during 2h and was then placed in an ice bath and kept at 0°C
for 50 min. The reaction mixture was partitioned between ethyl acetate and sat.
aqueous NH4Cl and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give an oil. Flash chromatography through 125 g of silica gel (75:20:5 hexane/CH2C12/EtOAc) yielded 0.696 g of the title compound as a white solid.
1H-NMR (500 Mz, CDC13): b 1.42 (s, 9H), 2.43 (dd, J = 16.6, 5.1 Hz, 1H), 2.67 (dd, J = 16.6, 9.1 Hz, 1 H), 2.85 (dd, J = 13.6, 7.9 Hz, 1 H), 3.07 (dd, J = 13.5, 6.9 Hz, 1 H), 3.15-3.25 (m, 1 H), 5.09 (d, J = 12.4 Hz, 1 H), 5.1 S (d, J = 12.4 Hz, 1 H), 7.20-7.65 (m, 14H).
MS (El): m/z = 430.2 (M+).

t-BuQ
\ ~ H2, Pd/C
Bn0 EtOH, THF t-Bu02C COzH
O

Compound 7 A solution of compound 6 (0.696 g, 1.617 mmol) in 10 mL of EtOH
and 5 mL of THF was hydrogenated at atmospheric pressure at room temperature over 70 mg of 10% PdIC. After 20 h, the mixture was filtered and evaporated to give a solid. Flash chromatography through 50 g of silica gel (5:2:2:1 hexane/CH2Cl2/EtOAc/MeOH + 0.05% HOAc) yielded 0.540 g of the title compound as a white solid.
1H-NMR (500 Mz, CDCl3): 8 1.45 (s, 9H), 2.43 (dd, J = 16.6, 5.1 Hz, 1H), 2.62 (dd, J = 16.8, 8.6 Hz, 1H), 2.84 (dd, J = 15.5, 10.4 Hz, 1H), 3.1-3.2 (m, 2H), 7.25-7.60 (m, 9H).
MS (E)]: m/z = 340.2 (M+).

STEP A
1. LiN(TMSh THF, -70 °C
/ 2. / \ ~ /
t-BuOZC COZH I \ / t-BuOZC COZH

TFA

/
HOZC COzH

Compound 9 STEP A:
A stirred solution of compound 3 from Preparation 3 (1.011 g, 3.825 mmol) in 15.5 mL of THF was cooled to -70°C and a 1.0M solution of LiN(TMS)2 in hexane (8.42 mL, 8.42 mmol) was added dropwise. After 1 h, a freshly prepared 1.14M solution of p-iodobenzyl iodide in THF (6.0 mL, 6.84 mmol) was added dropwise. The solution was stirred at -70°C for 30 min and was then allowed to warm gradually to 10°C during 90 min. The reaction was hydrolyzed by the addition of sat.
aqueous NH4Cl and most of the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and sat. aqueous NH4C1 and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a solid. Flash chromatography through 450 g of silica gel (98:2 CH2C12/MeOH + 0.1 % HOAc) yielded 1.78 g of compound 8 as a ~6:1 mixture of (S,S:R,S) diastereomers (major isomer depicted).
1H-NMR (500 Mz, CDC13): 8 1.32 (s, 9H), 2.74-3.05 (m, 6H), 6.89 (d, J = 8.2 Hz, 2H), 7.12-7.28 (m, SH), 7.56 (d, J = 8.4 Hz, 2H).
S MS (E>]: m/z = 480.4 (M+).
STEP B:
To a solution of compound 8 (182.0 mg, 0.3789 mmol) in 0.6 mL of CH2Cl2 was added neat trifluoroacetic acid (0.2 mL). The solution was stirred at room temperature for 4 h, and was then evaporated in vacuo to give an oil.
Separation by reverse phase medium pressure chromatography on RP-18 (40:60 MeCN/0.1%
aqueous TFA) gave after lyophilization 103.7 mg of the title compound as a white solid.
1H-NMR (500 Mz, CD30D): b 2.84-2.91 (m, 2H), 2.96-3.06 (m, 4H), 6.89 (d, J =
8.2 Hz, 2H), 7.11-7.25 (m, SH), 7.55 (d, J = 8.2 Hz, 2H).
MS (E>]: m/z = 424.2 (M+).

STEP A
1. LiN(i-Pr)z THF, -70 °C
> / ~ : \ / ~ /
t-BuOz COZH 2. BrCH2Ph t_guOzC , COZH
7 10 (S,S):(R,S)-8:1 TFA STEP B
CHZCiz / ~ ;: \ / \ / + / ~ .; \ / ~ /
HOz COZH HOZC COZH

Compounds 11 & 12 STEP A:
A stirred solution of compound 7 (26.2 mg, 0.0770 mmol) in 0.7 mL of THF was cooled to -70°C and a freshly prepared l .OM solution of LiN(i-Pr)2 in THF
(0.17 mL, 0.17 mmol) was added dropwise. After 1 h, neat benzyl bromide (0.015 mL, 0.12 mmol) was added dropwise. The solution was stirred at -70°C
for 20 min and was then allowed to warm gradually to 10 °C during 90 min. The reaction was hydrolyzed by the addition of sat. aqueous NH4C1. The reaction mixture was partitioned between ethyl acetate and sat. aqueous NH4C1 and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give an oil. Purification by preparative layer chromatography on silica gel (93:7 CH2Cl2/MeOH + 0.1 % HOAc) yielded 28 mg of compound 10 as an ~8:1 mixture of (S,S:R,S) diastereomers (major isomer depicted).
1H-NMR (500 Mz, CDCl3): b 1.33 (s, 9H, isomer B, minor), 1.37 (s, 9H, isomer A, major), 2.85-3.20 (m, 6H, isomers A & B), 7.10-7.65 (m, 14H, isomers A & B).
1 S MS (E~: m/z = 430.3 (M+) STEP B:
To a solution of compound 10 from Step A (10.3 mg, 0.0239 mmol) in 0.3 mL of CH2C12 was added neat trifluoroacetic acid (0.1 mL). The solution was stirred at room temperature for 4 h, and was then evaporated in vacuo to give an oil.
Separation by reverse phase medium pressure liquid chromatography on RP-18 (45:55 MeCN/0.1 % aqueous TFA) gave after lyophilization 5.0 mg of compound 11 and 0.7 mg of compound 12 as white solids.
Compound 11:
1H-NMR (500 Mz, CD30D): 8 2.90-2.97 (m, 2H), 3.0-3.1 (m, 4H), 7.14 (d, J = 7.1 Hz, 3H), 7.15-7.25 (m, SH), 7.41 (t, J = 7.7 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H).
MS (En: m/z = 374.2 (M+).
Compound 12:
1H-NMR (500 Mz, CD30D): 8 2.85-3.00 (m, 6H), 7.19 (d, J = 6.8 Hz, 3H), 7.24-7.32 (m, SH), 7.30 (t, J = 7.4 Hz, 1H), 7.41 (dd, J = 7.5, 8.0 Hz, 2H), 7.49 (d, J
= 8.0 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H).

MS (E1): m/z = 374.2 (M+) STEP A
PMB-OH
CHzCiz, 0 °C T
/ DMAP, DIC
t-BuO2C COZH t-BuO2C COZPMB

STEP B
Pd(PPh 3)a NazC03, H20 Me0 ~ ~ B(OH)Z DME, 100 °C
STEP C
Me0 ~ ~ ~ ~ ~ ~ Me0 CHZCIZ ~ /
HOZC CO2H t-BuO2C C02PMB

Compound 15 STEP A:
A stirred solution of compound 8 (830.1 mg, 1.728 mmol) and p-methoxybenzyl alcohol (0.54 ml, 4.33 mmol) in 14 mL of CH2C12 was cooled to 0°C, and a 1.0M solution of N,N-dimethylaminopyridine in CH2C12 (0.259 ml, 0.259 mmol) was added, followed by neat 1,3-diisopropylcarbodiimide (0.541 ml, 3.46 mmol). After 1 hr, the cooling bath was removed. The reaction mixture was stirred an additional 180 min, and was then hydrolyzed by the addition of sat. aqueous NH4C1.
The reaction mixture was partitioned between ethyl acetate and sat. aqueoues and the organic phase was washed with water and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give a semi-solid. This crude material was triturated with 10 ml CH2Cl2 and filtered through a sintered-glass funnel.
Evaporation of the filtrate in vacuo gave an oil. Flash chromatography through 160 g of silica gel (73:20:7 hexane/CH2C12/EtOAc) yielded 921.6 mg of compound 13 as a white solid.
1H-NMR (500 Mz, CDCl3): b 1.37 (s, 9H), 2.8-3.1 (m, 6H), 3.83 (s, 3H), 4.98 (dd, J
= 43.5, 11.9 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 7.07 (d, J =
6.6 Hz, 2H), 7.16-7.27 (m, 5H), 7.53 (d, J = 8.1 Hz, 2H).
MS (ESI): m/z = 623.2 (M+Na+).

STEP B:
To a stirred solution of compound 13 (76.6 mg, 0.1276 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.4 mg, 0.0064 mmol) in 1.1 ml DME
was added a solution of 4-methoxybenzeneboronic acid (29.1 mg, 0.192 mmol) in 0.2 ml DME. After 10 min, a 2.0M solution of Na2C03 in H20 (0.130 ml, 0.260 mmol) was added and the reaction mixture was heated to 100°C for 3.5 hr. The reaction mixture was allowed to cool to RT and then hydrolyzed by the addition of sat.
aqueous NH4C1. The reaction mixture was partitioned between ethyl acetate and sat.
aqueous NH4C1 and the organic phase was washed with sat. aqueous NaS2O3, water, and brine. The organic layer was dried over Na2S04 and evaporated in vacuo to give an oil. Flash chromatography through 18 g of silica gel (73:20:7 hexane/CH2C12BtOAc) yielded 37.1 mg of compound 14 as a white solid.
1H-NMR (500 Mz, CDC13): 8 1.36 (s, 9H), 2.90-3.07 (m, 6H), 3.82 (s, 3H), 3.87 (s, 3H), 4.98 (dd, J = 34.8, 11.9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.99 (d, J =
8.7 Hz, 2H), 7.09 (d, J = 7.8 Hz, 4H), 7.16-7.26 (m, SH), 7.42 (d, J = 8.0 Hz, 2H), 7.52 (d, J =
8.5 Hz, 2H).
MS (ES)]: m/z = 603.3 (M+Na+) STEP C:
To a solution of compound 14 (37.1 mg, 0.064 mmol) in 0.6 mL of CH2Cl2 was added neat trifluoroacetic acid (0.2 mL). The solution was stirred at room temperature for 4 h, and was then evaporated in vacuo to give an oil.
Separation by reverse phase medium pressure chromatography on RP-18 (45:55 MeCN/0.1 aqueous TFA) gave after lyophilization 9.3 mg of the title compound as a white solid.
1H-NMR (500 Mz, CD30D): 8 2.89-2.96 (m, 2H), 3.01-3.07 (m, 4H), 3.81 (s, 3H), 6.97 (d, J = 8.9 Hz, 2H), 7.11-7.25 (m, 7H), 7.43 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H).
MS (ESn: m/z = 427.1 (M+Na+).

Employing the procedures described herein, additional compounds of the present invention were prepared. Additional examples of representative compounds of the present invention are described in Tables 1-5, which include characterizing data.
Table 1 R

Example No. R m/z 4 499.1 (M-H+); ESI-Neg OMe 499.1 (M-H+); ESI-Neg Me0 6 ~ ~ ~ ~ 404.2 (M+); EI
H O ~.r Me 7 ~ ~ ~ ~ 387.2 (M-H+); ESI-Neg R
Table 1 (Cont'd) Example No. R m/z \ ~ ~ w 353.1 (M-H+); ESI-Neg 322.2 (M+-H20); EI

Ph--~

O
Phi 13 ~ I 312.3 (M+); EI

/ \ / ~ ~ 399.6 (M-H+); ESI-Neg R ~ \ /
Table 1 (Cont'd) Example No. R m/z 16 HO ~ 345.4 (M-Na+); ESI
17 HO \ / 312.3 (M+ - H20); EI
HO
18 \ / 328.1 (M+); EI
Me0 / \ \ / ~ 401.5 (M-H+); ESI-Neg 20 / \ O \ / 404.2 (M+); EI
21 ~. 315.05 (M+Na+); ESI
22 \ / 406.0 (M+-H20); EI
I
\ \
23 ~ / / '~ 387.4 (M-H+); ESI-Neg O

R
Table 1 (Cont'd) Example No. R m/z 371.20 (M+Na+); ESI

,,.,~' 298.2 (M+); EI

348.1 (M+); EI

342.1 (M+); EI
O
308.1 (M+-H20); EI

R
Table 1 (Cont'd) Example No. R m/z 31 ~ ~ 355.1 (M-H+); ESI-Neg Me02C
32 ~ ~ 366.3 (M+); EI

33 ~~ 306.1 (M+-H20); EI
34 HO ~ ~ 314.1 (M+); EI
35 ~ ~ 348.1 (M+); EI
36 Me-(CH2)~ ~-CH2-37 ~ ~ 316.3 (M+); EI
F
38 ~~ 299.0 (M+Na+); ESI

R
Table 1 (Cont'd) Example No. R m/z 40 287.15 (M+Na+); ESI
HO
41 ~ / 357.2 (M+H+); ESI
42 Me ~ ~ 312.2 (M+); EI
43 HO ~ ~ 346.2 (M+NH4+); ESI

374.2 (M+); EI

R
Table 1 (Cont'd) Example No. R m/z Me0 357.0 (M-H+); ESI-Neg Me0 F

334.2 (M+); EI
F
323.2 (M+); EI
NC

323.2 (M+); EI

R
Table 1 (Cont'd) Example No. R m/z 52 MeO
O

56 Me-C=C
283.05 (M+Na+); ESI

Me~ 236.2 (M+); EI
5$ Me02C
279.0 (M-H+); ESI-Neg Me 222.1 (M+); EI

R '~ \
Tabie 1 (Cont'd) Example No. R m/z O ~
61 N \
300.1 (M+H+); ESI
62 N ~
300.1 (M+H+); ESI
63 ~ N 300.1 M+H+ ' ESI
( ), Table 2 H02C 02H
Example No. R m/z 66 ~ ~ 353.1 (M-H+); ESI-Neg Ph--~

O
Phi 348.1 (M+); EI

F
69 ~ ~ 334.4 (M+); EI
F
~ ~ ~ ~ ~ 400.5 (M+); EI

Table 2 (Cont'd) Ho2 co2H
Example No. R m/z 71 ~~ 323.1 (M-H+); ESI-Neg /
72 ~ 294.2 (M+-H20); EI
73 ~ ~ 258.3 (M++NH4+); EI
74 ,.r 356.2 (M+-H20); EI
75 355.1 (M-H+); ESI-Neg Me02C
76 348.1 (M+); EI

328.1 (M+); EI
Me0 R v Table 2 (Cont'd) Ho2 co2H
Example No. R m/z 342.2 (M+); EI
O

316.3 (M+); EI
F
80 ~ ~ O
~ 404.2 (M+); EI

366.5 (M+); EI

323.2 (M+); EI
NC

298.2 (M+); EI
84 Me 235.1 (M-H+); ESI-Neg 323.2 (M+); EI

Table 3 Example No. Compound m/z 86 ~ \ ~ \ Me \ ~ 388.2 (M+); EI
H02C ~C02H
87 ~ \
391.5 (M+Na+); ESI

~O O
88 O ~ \ ~ \ ~ O

89 ~ \
\ ~ 362.2 (M+-2H20); EI
OH

90 / \ Me \ ~ 294.1 (M+-H20); EI
H02C '~~C02H
91 ~ \ ~ \
\ ~ \ ~ 450.2 (M+); EI

Table 3 (Cont'd) Example No. Compound m/z 92 ~ \
\ ~ 298.1 (M+); EI

~O O
93 O ~ \ ; \ ~ O 387.2 (M+H+); CI

94 Me ', \ / \ ~ 298.2 (M+); EI

95 ~ \ Me' \ ~ 312.2 (M+); EI
H02C .~COzH
96 ~ 337.2 (M+Na+); ESI

Table 3 (Cont'd) Example No. Compound m/z 97 / \ / \ \ / \ / 432.2 (M+-H20); EI
':
H02C COzH
98 / \ Me \ / 294.1 (M+-H20); EI
H02C~' .~C02H
/ \
99 ~ 349.1 (M+Na+); ESI

100 / \ Me;
\ / 312.2 (M+); EI
H02C~ ~C02H

R '~ ~
Table 4 Example No. R

S f,.r S ~
103 N ~
N-O r,r O ~

R
Table 4 (Cont'd) Example No. R
/

S
108 \ I S
-N

N-//
S

S

R
Table 4 (Cont'd) Example No. R
S

O

/ O

H
/ N

OS O

R
Table 4 (Cont'd) Example No. R

O
O

F

F
124 Me02C ~ ~ ~

R
Table 4 (Cont'd) Example No. R

HO
127 ACC~

O

HO

Table 5 Example No. R

Me0 137 SL=

R '~ ~ / ~
Table 5 (Cont'd) Example No. R

F

O

BIOLOGICAL ACTIVITY
IMP-1 metallo-13-lactamase lacking the N-terminal 18 hydrophobic amino acids which encode the putative periplasmic signal sequence (EMBL access code PACATAAC6) was PCR amplified from plasmid DNA prepared from a carbapenem-resistant strain of Pseudomonas aeruginosa (CL5673). The PCR
product was cloned into pET30a+ (Novegen) and expressed in E.coli BL21(DE3) after induction with 0.5 mM IfTG for 20 hours at room temperature in minimal media supplemented with casamino acids and 348 ~.M ZnS04. Soluble IMP-1 was purified from cell extracts by SP-Sepharose (Pharmacia) ion exchange and Superdex 75 (Pharmacia) size-exclusion chromatography.
The ICSO of succinate derivatives of Formula I was determined following a 15 minute incubation at 37°C with IMP-1 (0.75nM in 50mM
MOPS, pH
7). Using initial velocity as a measure of activity, inhibition was monitored spectrophotometrically at 490nm in a Molecular Devices SPECTRAmaxTM 250 96-well plate reader employing nitrocefin as the reporter substrate at approximately Km concentration (60~M).
A laboratory strain of E.coli engineered to express IMP-1 was used to evaluate the ability of succinate derivatives of Formula I to reverse metallo-lactamase-mediated carbapenem resistance in bacteria. Native IMP-1, which included the N-terminal periplasmic signal sequence, was PCR amplified from CNA
isolated from a carbapenem resistant P. aeruginosa clinical isolate, CL56673, and cloned into the pET30a vector. The basal (uninduced) level of IMP-1 expressed when pET30a-IMP-1 was introduced into E. coli BL21(DE3) resulted in 4-, 64- or 500-fold reduced sensitivity to impenem, meropenem or (1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo (2.2.2)octan-1-yl] methyl-fluoren-9-on-3-yl}-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride (a carbapenem synthesized at Merck Research Laboratories) respectively. For example, the minimum inhibitory concentration (MIC) of (1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1-yl]methyl-fluoren-9-on-yl},-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride, was typically increased from 0.06-0.12 ~,g/ml to 16-32 ~g/ml by the expression of IMP-1. To evaluate IMP-1 inhibitors, an overnight culture of E. coli BL2(DE3)/pET30a-IMP-1, grown 35°C in LB broth (Difco) or Mueller Hinton broth (BBL) supplemented with kanamycin (50 ~M/ml), was diluted to a final concentration of 105 cells/ml in Mueller Hinton broth (BBL) containing a subinhibitory concentration (0.25x MIC) of the carbapenem, (1S,5R,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1-yl]methyl-fluoren-9-on-3-yl}-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride. Various concentrations of compounds of Formula I were added to the bacterial growth medium and their capacity to effect a four-fold or greater increase in sensitivity to the carbapenem was monitored.
The readout for antibacterial activity showed no visible growth after 20 hours incubation at 35°C.
Representative compounds of Formula I were tested as inhibitors against purified IMP-1 metallo-13-lactamase and found to be active in an ICSO
range of from about 0.2nM to about SOOpM. The ability of representative compounds of Formula I to potentiate the activity of the carbapenem antibiotic (1 S,SR,6S)-1-methyl-2- {7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1 yl]-methyl-fluoren-9-on-3-yl)-6-(1R-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride against an 1MP-1 producing laboratory strain E. coli BL21(DE3)/pET30a-IMP-1 was tested.
Compounds of Formula I in the concentration range of from about 0.002p,M to about 100pM. were found to produce 4-fold increase in sensitivity to the carbapenem antibiotic (1S,SR,6S)-1-methyl-2-{7-[4-(aminocarbonylmethyl)-1,4-diazoniabicyclo(2.2.2)octan-1-yl]-methyl-fluoren-9-on-3-yl) -6-( 1 R-hydroxyethyl)-carbapen-2-em-3-carboxylate chloride in an IMP-1 producing laboratory strain E. coli BL21(DE3)/pET30a-IMP-1.

Claims (96)

WHAT IS CLAIMED IS:
1. A compound represented by formula I:
including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:
M1 and M2 are independently selected from:
(a) Hydrogen, (b) Pharmaceutically acceptable canon, and (c) Pharmaceutically acceptable esterifying group;
R1 and R2 are independently selected from the following:
(a) Hydrogen, provided that R1 and R2 are not hydrogen at the same time;
(c) a C1 to C16 straight, branched or unsaturated alkyl group optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
(c) a group of the formula:
wherein -A- represents a single bond, C1 to C8 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
(1) a C6 to C14 aryl group;
(2) a C3 to C10 alicyclic group;
(3) a C3 to C14 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C3 to C10 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
(d) a group of the formula:
wherein:
-A- is as defined above;
A' is a single bond, O, S, or a C1 to C6 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x groups and optionally interrupted by one of the following groups O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
are independently selected from:
(1) a C6 to C10 aryl group;
(2) a C3 to C8 alicyclic group;
(3) a C2 to C9 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C3 to C8 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;

where each R x is independently selected from the group consisting of:
(f) F, Cl, Br, I, (g) CF3 (h) OR b, (i) CN, (j) -C(O)-Rc , (f) -S(O2)-R f, (g) -C(O)-OR a (h) -O-C(O)-R c, (i) -S-R b, (j) -N(R a)-C(O)-R c, (q) -N(R a)-C(O)-OR f, (r) -S(O)-R f, (s) _N(R a)-S(O2)-R f, (t) NO2, and (u) C1 to C8 straight, branched or unsaturated alkyl optionally substituted with one of the substituents (a) through (t) above;
(v) -CH2-aryl wherein the aryl is optionally substituted with one of the substituents (a) through (t) above;

or two adjacent R x groups on an aromatic ring may consist of the following divalent moiety, -O-CH2-O-;
wherein:
R a is H, C1 to C6 alkyl optionally substituted with RY;
R b is H, C1 to C6 alkyl optionally substituted with RY, CH2-aryl, or aryl, said aryls optionally substituted with 1-2 RY groups;
R c is H, C1 to C6 alkyl optionally substituted with RY, CF3, or aryl, said aryl optionally substituted with 1 to 2 RY groups;
R d and R e are independently hydrogen, C1 to C4 alkyl optionally substituted with RY, or R d and R e taken together may represent a 3 to 5-membered alkyl radical to form a ring, or R d and R e taken together may represent a 2 to 4-membered alkyl radical interrupted by O, S, SO or SO2 to form a ring;
R f is C1 to C6 alkyl optionally substituted with RY, or aryl, said aryl optionally substituted with 1 to 2 RY groups; and RY is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
2. A compound in accordance with claim 1 where R1 and R2 cannot be hydrogen.
3. A compound in accordance to claim 2 where R1 and/or R2 represents a C1 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2- and all other variables are described as above.
4. A compound in accordance with claim 3 wherein the alkyl is C5 to C16, and R1 does not equal R2.
5. A compound in accordance with claim 4 wherein the alkyl is C7 to C16.
6. A compound in accordance with claim 2 wherein M1 and M2 are independently hydrogen, sodium or potassium and all other variables are as described above.
7. A compound in accordance with claim 2 where R1 and/or R2 represents and all other variables are described as above.
8. A compound in accordance with claim 7 wherein R1 and R2 cannot be the same.
9. A compound in accordance with claim 8 wherein R1 and R2 cannot both be substituted benzyl and all variables are as originally described.
10. A compound in accordance with claim 8 wherein R1 or R2 cannot both be a benzyl substituted with -OH, -OCH3, OCH2Phenyl, or OCH2O.
11. A compound in accordance with claim 8 wherein one of R1 or R2 is benzyl or substituted benzyl and the other of R1 and R2 is a C5 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-.
12. A compound in accordance with claim 11 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, OCH2Phenyl, OCH2O, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
13. A compound in accordance with claim 8 wherein one of R1 or R2 is a benzyl or substituted benzyl and the other of R1 and R2 is wherein all other variables are described as above.
14. A compound in accordance to claim 2 where R1 and/or R2 represents wherein all other variables are described as above.
15. A compound in accordance with claim 14 wherein R1 and R2 cannot be the same.
16. A compound in accordance with claim 15 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
17. A compound in accordance to claim 2 where the relative and absolute stereochemistry is:
18. A compound in accordance to claim 17 where R1 and/or R2 represents a C1 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2- and all other variables are described as above.
19. A compound in accordance with claim 18 wherein the alkyl is C5 to C16, and R1 does not equal R2.
20. A compound in accordance with claim 19 wherein the alkyl is C7 to C16.
21. A compound in accordance with claim 19 wherein M1 and M2 are independently hydrogen, sodium or potassium and all other variables are as described above.
22. A compound in accordance with claim 19 where R1 and/or R2 represents and all other variables are described as above.
23. A compound in accordance with claim 22 wherein R1 and R2 cannot be the same.
24. A compound in accordance with claim 22 wherein R1 or R2 cannot both be a substituted benzyl and all other variables are as originally described.
25. A compound in accordance with claim 23 wherein R1 and R2 cannot both be a benzyl substituted with -OH, -OCH3, OCH2Phenyl, or OCH2O.
26. A compound in accordance with claim 23 wherein one of R1 or R2 is benzyl or substituted benzyl and the other of R1 and R2 is a C5 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-.
27. A compound in accordance with claim 26 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, OCH2Phenyl, OCH2O, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
28. A compound in accordance with claim 23 wherein one of R1 or R2 is a benzyl or substituted benzyl and the other of R1 and R2 is wherein all other variables are described as above.
29. A compound in accordance to claim 17 where R1 and/or R2 represents wherein all other variables are described as above.
30. A compound in accordance with claim 29 wherein R1 and R2 cannot be the same.
31. A compound in accordance with claim 30 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
32. A compound in accordance with claim 17 where R1 and/or R2 represents a group of the formula:
wherein A is (CH2)1-5 and is phenyl, naphthyl, cyclohexyl or dibenzofuranyl and all other variables are as originally defined.
33. A compound in accordance with claim 32 wherein R1 and R2 cannot be the same.
34. A compound in accordance with claim 33 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
35. A compound in accordance with claim 32 wherein one of R1 and R2 is a benzyl or substituted benzyl and the other of R1 and R2 is wherein all other variables are described as above.
36. A compound in accordance with claim 35 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
37. A compound in accordance with claim 17 where R1 and/or R2 represents a group of the formula:
wherein A is (CH2)1-3, A' is a bond, -O- or (CH2)1-2 and independently represent phenyl, thienyl, pyridyl, furanyl or cyclohexyl.
38. A compound in accordance with claim 37 wherein R1 and R2 cannot be the same.
39. A compound in accordance with claim 17 wherein one of R1 or R2 is:
and all other variables are as originally defined
40. A compound in accordance with claim 17 where R1 or R2 is a group of the formula:
where A is (CH2)1-2 and is phenyl or cyclohexyl and the other of R1 or R2 is a group of the formula:
where A is (CH2)1-2, A' is a single bond, is phenyl or cyclohexyl and is phenyl, thienyl or pyridyl
41. A compound in accordance with claim 17 wherein R1 is C5-7 alkyl substituted with 0 to 2 R x groups, R2 is C7-10 alkyl substituted with 0 to 2 R x groups, and all other variables are as described above.
42. A compound according to claim 17 of the following structure:
wherein R x, M2, and M1 are as originally defined.
43. A compound of the structural formula:

44. A compound represented by Tables 1-5:
Table 1 Example No.
45. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
46. A pharmaceutical composition in accordance with claim 45 used in the manufacture of a medicament for the treatment of bacterial infections.
47. A pharmaceutical composition in accordance with claim 45 further comprising a .beta.-lactam antibiotic.
48. A pharmaceutical composition in accordance with claim 47 wherein the .beta.-lactam is a carbapenem antibiotic.
49. A composition according to claim 45, which further contains a serine .beta.-lactamase inhibitor.
50. A composition according to claim 48, which further contains a DHP inhibitor.
51. A method of treating a bacterial infection comprising administering to a mammalian patient in need of such treatment a metallo-.beta.-lactamase inhibitor compound as defined in claim 1 in combination with a pharmaceutically acceptable .beta.-lactam antibiotic in an amount which is effective for treating a bacterial infection.
52. A method according to claim 51 wherein the .beta.-lactam is a carbapenem antibiotic.
53. A method according to claim 52, which further contains a DHP
inhibitor.
54. A method according to claim 53 wherein the DHP inhibitor is cilastatin.
55. A method according to claim 51 which further contains a serine .beta.-lactamase inhibitor.
56. A method of treating a bacterial infection comprising administering an amount which is effective for treating a bacterial infection to a mammalian patient in need of such treatment an effective amount of a pharmaceutically acceptable .beta.-lactam antibiotic in combination with metallo-.beta.-lactamase inhibitor compound of the formula:

including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:

M1 and M2 are independently selected from:
(a) Hydrogen, (b) Pharmaceutically acceptable cation, and (c) Pharmaceutically acceptable esterifying group;
R1 and R2 are independently selected from the following:
(a) Hydrogen, provided that R1 and R2 are not hydrogen at the same time;
(d) a C1 to C16 straight, branched or unsaturated alkyl group optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
(c) a group of the formula:

wherein -A- represents a single bond, C1 to C8 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
~represents:
(1) a C6 to C14 aryl group;
(2) a C3 to C10 alicyclic group;
(3) a C3 to C14 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;

(4) a C3 to C10 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
(d) a group of the formula:
wherein:
-A- is as defined above;
A' is a single bond, O, S, or a C1 to C6 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x groups and optionally interrupted by one of the following groups O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-;
are independently selected from:
(1) a C6 to C10 aryl group;
(2) a C3 to C8 alicyclic group;
(3) a C2 to C9 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C3 to C8 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
where each R x is independently selected from the group consisting of (k) F, Cl, Br, I, (l) CF3, (m) OR b, (n) CN, (o) -C(O)-R c, (f) -S(O2)-R f, (g) -C(O)-OR a (h) -O-C(O)-R c, (i) -S-R b, (j) -N(R a)-C(O)-R c, (q) -N(R a)-C(O)-OR f, (r) -S(O)-R f, (s) -N(R a)-S(O2)-Rf, (t) NO2, and (u) C1 to C8 straight, branched or unsaturated alkyl optionally substituted with one of the substituents (a) through (t) above;
(v) -CH2-aryl wherein the aryl is optionally substituted with one of the substituents (a) through (t) above;
or two adjacent R x groups on an aromatic ring may consist of the following divalent moiety, -O-CH2-O-;
wherein:
R a is H, C1 to C6 alkyl optionally substituted with R y;
R b is H, C1 to C6 alkyl optionally substituted with R y, CH2-aryl, or aryl, said aryls optionally substituted with 1-2 R y groups;
R c is H, C1 to C6 alkyl optionally substituted with R y, CF3, or aryl, said aryl optionally substituted with 1 to 2 R y groups;
R d and R e are independently hydrogen, C1 to C4 alkyl optionally substituted with R y, or R d and R e taken together may represent a 3 to 5-membered alkyl radical to form a ring, or R d and R e taken together may represent a 2 to 4-membered alkyl radical interrupted by O, S, SO or SO2 to form a ring;
R f is C1 to C6 alkyl optionally substituted with R y, or aryl, said aryl optionally substituted with 1 to 2 R y groups; and R y is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
57. A method in accordance with claim 56 where R1 and R2 cannot be hydrogen.
58. A method in accordance to claim 56 where R1 and/or R2 represents a C1 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2- and all other variables are described as above.
59. A method in accordance with claim 58 wherein the alkyl is C5 to C16 and R1 does not equal R2.
60. A method in accordance with claim 59 wherein the alkyl is C7 to C16 and R1 does not equal R2.
61. A method in accordance with claim 57 wherein M1 and M2 are independently hydrogen, sodium or potassium and all other variables are as described above.
62. A method in accordance with claim 57 where R1 and/or R2 represents and all other variables are described as above.
63. A method in accordance with claim 62 wherein R1 and R2 cannot be the same.
64. A compound in accordance with claim 63 wherein R1 and R2 cannot both be substituted benzyl and all variables are as originally described.
65. A method in accordance with claim 63 wherein R1 or R2 cannot both be a benzyl substituted with -OH, -OCH3, OCH2Phenyl, or OCH2O.
66. A method in accordance with claim 62 wherein one of R1 or R2 is benzyl or substituted benzyl and the other of R1 and R2 is a C5 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-.
67. A method in accordance with claim 66 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, OCH2Phenyl, OCH2O, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
68. A method in accordance with claim 62 wherein one of R1 or R2 is a benzyl or substituted benzyl and the other of R1 or R2 is wherein all other variables are described as above.
69. A method in accordance to claim 57 where R1 and/or R2 represents wherein all other variables are described as above.
70. A method in accordance with claim 69 wherein R1 and R2 cannot be the same.
71. A method in accordance with claim 70 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
72. A method in accordance to claim 56 where the relative and absolute stereochemistry is:
73. A method in accordance to claim 72 where R1 and/or R2 represents a C1 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2- and all other variables are described as above.
74. A method in accordance with claim 74 wherein the alkyl is C5 to C16 and R1 does not equal R2.
75. A method in accordance with claim 74 wherein the alkyl is C7 to C16 and R1 does not equal R2.
76. A method in accordance with claim 72 wherein M1 and M2 are independently hydrogen, sodium or potassium and all other variables are as described above.
77. A method in accordance with claim 72 where R1 and/or R2 represents and all other variables are described as above.
78. A method in accordance with claim 77 wherein R1 and R2 cannot be the same.
79. A compound in accordance with claim 78 wherein R1 and R2 cannot both be substituted benzyl and all variables are as originally described.
80. A method in accordance with claim 79wherein R1 or R2 cannot both be a benzyl substituted with -OH, -OCH3, OCH2Phenyl, or OCH2O.
81. A method in accordance with claim 78 wherein one of R1 or R2 is benzyl or substituted benzyl and the other of R1 and R2 is a C5 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NRa-, -CO2-.
82. A method in accordance with claim 81 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, OCH2Phenyl, OCH2O, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
83. A method in accordance with claim 72 where R1 and/or R2 represents a group of the formula:
wherein A is (CH2)1-5 and ~~is phenyl, naphthyl, cyclohexyl or dibenzofuranyl and all other variables are as originally defined.
84. A method in accordance with claim 83 wherein R1 and R2 cannot be the same.
85. A method in accordance with claim 84 wherein one of R1 or R2 is a benzyl or substituted benzyl and the other of R1 and R2 is a C5 to C16 straight, branched or unsaturated alkyl optionally substituted with 1 to 3 R x groups and optionally interrupted by one of the following O, S, SO2, -C(O)-, -C(O)-NR a-, -CO2-.
86. A method in accordance with claim 85 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
87. A method in accordance with claim 84wherein one of R1 and R2 is a benzyl or substituted benzyl and the other of R1 and R2 is wherein all other variables are described as above.
88. A method in accordance with claim 87 wherein R x is -OH, -OCH3, OCONH2, OCOCH3, CHO, COCH3, CO2CH3, CONH2, CN, SOCH3, SO2CH3, SO2NH2, F, Cl, Br, I or CF3.
89. A method in accordance with claim 72 where R1 and/or R2 represents a group of the formula:

wherein A is (CH2)1-3, A' is a bond, -O- or (CH2)1-2 and ~ and ~ independently represent phenyl, thienyl, pyridyl, furanyl or cyclohexyl.
90. A method in accordance with claim 89 wherein R1 and R2 cannot be the same.
91. A method in accordance with claim 72 wherein one of R1 or R2 is:
(R x)0-2 and all other variables are as originally defined.
92. A method in accordance with claim 72where R1 or R2 is a group of the formula:
where A is (CH2)1-2 and ~ is phenyl or cyclohexyl and the other of R1 or R2 is a group of the formula:
where A is (CH2)1-2, A' is a single bond, ~ is phenyl or cyclohexyl and ~ is phenyl, thienyl or pyridyl.
93. A method in accordance with claim 72 wherein R1 is C5-7 alkyl substituted with 0 to 2 R x groups, R2 is C7-10 alkyl substituted with 0 to 2 R x groups, and all other variables are as described above.
94. A method according to claim 72 of the following structure:
wherein R x, M2, and M1 are as originally defined.
95. A method according to claim 72 wherein the compound is of the structural formula:

96. A method of claim 72 wherein the compound is represented by Tables 1-5:

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CA2952968A1 (en) 2014-07-01 2016-01-07 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
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