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EP1578898A2 - Inhibiteurs de nad synthetase, et utilisations correspondantes - Google Patents

Inhibiteurs de nad synthetase, et utilisations correspondantes

Info

Publication number
EP1578898A2
EP1578898A2 EP02723209A EP02723209A EP1578898A2 EP 1578898 A2 EP1578898 A2 EP 1578898A2 EP 02723209 A EP02723209 A EP 02723209A EP 02723209 A EP02723209 A EP 02723209A EP 1578898 A2 EP1578898 A2 EP 1578898A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
group
alkylamino
optionally
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02723209A
Other languages
German (de)
English (en)
Inventor
Wayne J. Brouillette
Lawrence J. Delucas
Christie G. Brouillette
Sadanandan E. Velu
Yong-Chul Kim
Liyuan Mou
R. Stephen Porter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UAB Research Foundation
Virtual Drug Development Inc
Original Assignee
UAB Research Foundation
Virtual Drug Development Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2001/022203 external-priority patent/WO2002007516A2/fr
Application filed by UAB Research Foundation, Virtual Drug Development Inc filed Critical UAB Research Foundation
Publication of EP1578898A2 publication Critical patent/EP1578898A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention in general relates to antimicrobial agents, and in particular, to inhibitors of the nicotinamide adenine dinucleotide (NAD) synthetase enzyme of microbes such as bacteria and fungi.
  • the present invention also relates to the various uses of these antimicrobial agents, including in a method of treating or preventing a microbial infection in a mammal, in a method of treating the environment against microbial contamination, in agriculture, e.g., in raising foodcrops and food animals, in medicine, e.g., to disinfect, sterilize, or decontaminate equipment, devices, rooms, and/or people, and in combating bioterrorism, e.g., agroterrorism.
  • bioterrorism e.g., agroterrorism.
  • Drug-resistant infectious bacteria that is, bacteria that are not killed or inhibited by existing antibacterial and antimicrobial compounds, have become an alarmingly serious worldwide health problem. Rubenstein, Science, 264, 360 (1994). It is believed that a number of bacterial infections may soon be untreatable unless alternative drug treatments are identified.
  • VRE vancomycin-resistant enterococci
  • Streptococcus pneumoniae causes thousands of cases of meningitis and pneumonia, as well as 7 million cases of ear infection in the United States each year. Currently, about 30 percent of S. pneumoniae isolates are resistant to penicillin, the primary drug used to treat this infection. Many penicillin-resistant strains are also resistant to other antimicrobial or antibacterial drugs.
  • MDR-TB multi-drug resistant tuberculosis
  • spore-forming bacteria can be lethal.
  • Bacillus anthracis causes the deadly disease, anthrax.
  • anthrax There exists an uncertainty relating to the efficacy of currently available vaccines against B. anthracis.
  • terrorists could employ antibiotic-resistant strains, e.g., engineered strains that are not recognized by B. anthracis antibodies or common bacteria engineered to carry the virulence gene (see, e.g., T. C. Dixon et al., "Anthrax," New England Journal of Medicine, 341 (11), 815-826, Sept. 1999).
  • antibiotic-resistant strains e.g., engineered strains that are not recognized by B. anthracis antibodies or common bacteria engineered to carry the virulence gene (see, e.g., T. C. Dixon et al., "Anthrax," New England Journal of Medicine, 341 (11), 815-826, Sept. 1999).
  • T. C. Dixon et al. "An
  • anthracis or bacteria carrying the virulence gene of B. anthracis.
  • Fungi are plant-like eukaryotes that grow in colonies of single cells, called yeasts, or in filamentous multicellular aggregates, called molds. While many fungi are common in the environment and not harmful to plants or mammals, some are parasites of terrestrial plants and others can produce disease in humans and animals. When present in humans, mycotic (fungal) diseases can include contagious skin and hair infections, noncontagious systemic infections, and noncontagious foodborne toxemias. The incidence of such infections is not insignificant; in the U.S.
  • Bioterrorism especially agricultural bioterrorism (or agroterrorism), is presently of great concern in this country as well as in many countries throughout the world. See, e.g., Joseph W. Foxell, Jr., "Current Trends in Agroterrorism (Antilivestock, Anticrop, and Antisoil Bioagricultural Terrorism) and Their Potential Impact on Food Security", in Studies in Conflict & Terrorism, 24, 107-129 (2001); Mark Wheelis, "Agricultural Biowarfare and Bioterrorism - An Analytical Framework and Recommendations for the Fifth BTWC Review Conference", 14 th Workshop of the Pugwash Study Group on the Implementation of the Chemical Biological Weapons Conventions, Geneva, Switzerland, November 2000; Radford G.
  • the present invention ameliorates some of the disadvantages of previously known antimicrobial agents.
  • the present invention provides antimicrobial agents comprising two aryl moieties linked by a suitable linker, and the antimicrobial agents inhibit the NAD synthetase enzyme of a microbe.
  • the present invention provides a compound of the formula (I):
  • the present invention further provides a compound of the formula A-B-(CH ) n -O- CO-CH -Ph (NMe 3 ) + 1 " , wherein A is a phenyl or indole, optionally substituted with a benzyloxy group; B is a covalent bond or oxygen atom; n is 1-15; and T is a pharmaceutically acceptable anion.
  • the invention provides a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal a treatment effective or treatment preventive amount of a microbial NAD synthetase enzyme inhibitor compound.
  • a method is provided of killing a prokaryote with an amount of prokaryotic NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the prokaryote is killed.
  • a method is provided of decreasing prokaryotic growth, comprising contacting the prokaryote with an amount of prokaryotic NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby prokaryotic growth is decreased.
  • a disinfecting composition comprising a microbial NAD synthetase enzyme inhibitor.
  • the invention provides a method of disinfecting a material contaminated by a microbe, comprising contacting a contaminated material with a microbial NAD synthetase enzyme inhibitor compound in an amount sufficient to kill or deactivate the microbe.
  • the present invention provides a method for treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound that inhibits the enzymatic activity of the microbial NAD synthetase.
  • the present invention in an embodiment, is based in part on the discovery that NAD synthetase inhibitors are highly effective in inhibiting the growth of a fungus such as yeast, yet exhibit only moderate toxicity in animals.
  • the present invention includes the use of NAD synthetase inhibitors as antifungal agents for preventing or controlling fungal infections such as parasitic yeast and mold infections in plants, and for the prophylactic or therapeutic treatment, topically and systemically, of fungal infections in humans and animals.
  • the present invention provides a method of killing a fungus with an amount of NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the fungus is killed.
  • the present invention also provides a method of decreasing fungus growth, comprising contacting the yeast with an amount of a NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby fungus growth is decreased.
  • the present invention also provides a method for increasing production of food animals comprising administering to the food animal an effective amount of at least one inhibitor of NAD synthetase of a microbe capable of infecting the food animal.
  • the present invention further provides a method for the treatment or prevention of infection by a spore- forming bacterium in an animal comprising treating an environment of the animal with an effective amount of at least one inhibitor of NAD synthetase of the spore-forming bacterium.
  • the present invention further provides a method for killing the vegetative cell of a spore-forming bacterium in an environment comprising treating the environment with an effective amount of at least one inhibitor of NAD synthetase of the bacterium.
  • the present invention also provides a method for treating a fungal or bacterial disease in a plant comprising treating the plant or the environment of the plant with an effective amount of at least one inhibitor of NAD synthetase of the fungus or bacterium.
  • the present invention further provides a method for treating or preventing harm to a plant due to a pest comprising contacting the plant, or an environment thereof, with a pesticidal effective amount of a NAD synthetase enzyme inhibitor of the pest.
  • the present invention further provides a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable carrier.
  • the present invention further provides a method for treating or preventing a microbial infection in a mammal comprising administering to said mammal an effective amount of a compound that binds to the interface of the NAD synthetase enzyme dimer of the microbe.
  • the present invention further provides a method for combating agroterrorism involving an infective agent on an object comprising treating the object with an amount of a compound effective to inhibit the NAD synthetase of the infective agent.
  • Fig. 1 depicts a reaction scheme wherein the NAD synthetase enzyme catalyzes the final step in the biosynthesis of NAD.
  • Fig. 2 schematically illustrates catalytic sites on a bacterial NAD synthetase enzyme.
  • Fig. 3 schematically illustrates the blocking of catalytic sites of a bacterial NAD synthetase enzyme.
  • the present invention provides a microbial NAD synthetase enzyme inhibitor, having the formula 1 :
  • R ⁇ .-R each, independently, is H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or unbranched group, wherein the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group and wherein the linker may also contain heteroatoms.
  • R ⁇ -R may also be one of the following groups: H, alkyl, alkenyl, alkynyl, or an aryl.
  • R ⁇ -R may further be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or a common derivatives of these groups.
  • n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the "aryl,” moieties may be the same or different.
  • the present invention provides a microbial NAD synthetase enzyme inhibitor, having formula 2:
  • X is a C, N, O or S within a monocyclic or bicyclic moiety
  • a and B represent the respective sites of attachment for the linker
  • n is an integer of from 1 to 12
  • Ri-R 7 each, independently, is an H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, wherein the linker is a saturated or unsaturated cyclic group or an aliphatic branched or unbranched alkyl, alkenyl or alkynyl group, and wherein the linker may also contain heteroatoms.
  • R 1 -R 7 may also be one of the following groups: H, alkyl, alkenyl, alkynyl, or an aryl group.
  • Rj-R may also be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups.
  • n may also be an integer of from 3 to 10, more preferable 5 to 9 and, still more preferably 6 to 9.
  • the linker has the formula A-(C, Heteroatom)n-B.
  • the linker may be an amide, ester, ether, or combinations thereof.
  • the present invention in an embodiment, provides a compound of formula (I): -X- -Y-L-Z-Q (I) wherein Q is Q Ar 3 or Ar 3 Qj . ;
  • Ar 2 , and Ar 3 are independently aryl or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of C ⁇ -C 6 alkyl, Ci- alkoxy, C ⁇ -C 6 haloalkyl, C ⁇ -C 6 hydroxyalkyl, C ⁇ -C 6 alkoxy Ci-C ⁇ alkyl, halo, amino, C ⁇ -C 6 alkylamino, C ⁇ -C 6 dialkylamino, C C 6 trialkylamino, C ⁇ . -C 6 alkylamino C ⁇ -C 6 alkyl, C ⁇ -C 6 dialkylamino C ⁇ .
  • -C 6 alkyl C ⁇ -C 6 trialkylamino C ⁇ -C 6 alkyl, azido, amine oxide, hydroxy, carboxyl, C ⁇ -C 6 alkylcarbonyl, C C ⁇ alkylcarbonyl C ⁇ -C 6 alkyl, Ci-Ce alkylcarbonyloxy, C C ⁇ alkylcarbonyloxy CrC 6 alkyl, C C 6 alkyloxycarbonyl C C 6 alkyl, -C ⁇ alkyloxycarbonyl, C ⁇ -C 6 alkylthio, nitro, nitrosyl, cyano, hydroxylamino, sulfonamido, Ci- C 6 dialkyl sulfonamido, C !
  • W is a moiety selected from the group consisting of alicyclic ring, aromatic ring, heterocyclic ring, combinations of alicyclic, heterocyclic, and/or aromatic rings, C 2 -C 6 alkenyl, dienyl, C 2 -C 6 alkynyl, Q-C ⁇ alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, anhydrido, enol, ketene, amino, imino, hydrazinyl, epoxy, episulfide, amido, amine oxide, urea, urethane, ester, thioester, carbonate, carbonyl, thiocarbony
  • Qi is (i) a C ⁇ -C 6 alkylenyl, C ⁇ -C 6 alkylenyl carbonyloxy C ⁇ -C 6 alkyl, or C ⁇ -C 6 alkylenyl carbonylamino C ⁇ -C 6 alkyl group, optionally having a substituent selected from the group consisting of amino, Ci-C ⁇ alkylamino, C ⁇ -C 6 haloalkylamino, d-C 6 haloalkyl d-C ⁇ alkyl amino, C ⁇ -C 6 hydroxyalkylamino, d-C ⁇ hydroxyalkyl d-C 6 alkylamino, C ⁇ -C 6 dialkylamino, d-C 6 trialkylamino, and heterocyclic containing a nitrogen atom which may be optionally quaternized, (ii) a C 2 -C 6 alkylenyl; (iii) methylenyl with the proviso that Z is other than covalent bond or O(
  • the aryl of Ar t , Ar 2 , and Ar 3 includes 1-3 aromatic rings, for example, phenyl, naphthyl, or anthracenyl, preferably phenyl.
  • the heteroaryl of Ari, Ar 2 , and Ar 3 include 1-3 rings, one or more of which include O, N, or S, preferably N. Examples of heteroaryls include indole, benzopyranone, benzoxazole, benzothiazole,
  • a ⁇ is phenyl or phenyl substituted with one or more substituents selected from the group consisting of d-C 6 alkyl, d-C ⁇ alkoxy, d-C 6 haloalkyl, hydroxyalkyl, Ci-Ce alkoxy d-C 6 alkyl, halo, amino, d-C 6 alkylamino, d-C ⁇ dialkylamino, C ⁇ -C 6 trialkylamino, d-C 6 alkylamino C ⁇ -C 6 alkyl, C ⁇ -C 6 dialkylamino C ⁇ -C 6 alkyl, d-C 6 trialkylamino Ci-Ce alkyl, azido, amine oxide, hydroxy, carboxyl, d-C 6 alkylcarbonyl, C ⁇ -C 6 alkylcarbonyl C ⁇ -C 6 alkyl, C ⁇ -C 6 alkylcarbonyloxy, C ⁇ -C 6 alkylcarbon
  • Ari is phenyl or phenyl substituted with one or more substituents selected from the group consisting of C ⁇ -C 6 alkoxy, halo, amino, C ⁇ -C 6 alkylamino, d-C 6 dialkylamino, azido, C ⁇ -C 6 alkylcarbonyloxy, C ⁇ -C 6 alkylthio, nitro, cyano, sulfonamido, d-C 6 dialkyl sulfonamido, C ⁇ -C 6 alkylcarbonylamino, and heterocyclyl.
  • Embodiments of the compounds of the present invention include compounds wherein Ari is phenyl, phenyl substituted with one or more C ⁇ -C 6 alkoxy, particularly phenyl substituted with one or more methoxy or propoxy.
  • Embodiments of the compounds of the present invention also include compounds wherein Ar t is phenyl substituted with one or more halo, particularly, one, two, or three chloro or fluoro.
  • Embodiments of the compounds of the present invention also include compounds wherein Ari is phenyl substituted with one or more C ⁇ -C 6 dialkylamino, particularly N,N-dimethylamino.
  • Embodiments of the compounds of the present invention further include compounds wherein Ari is phenyl substituted with one or more azido, nitro, and cyano.
  • Embodiments of the compounds of the present invention also include compounds wherein Ari. is phenyl substituted with one or more C ⁇ -C 6 dialkyl sulfonamido, particularly N,N-dimethyl sulfonamido.
  • Embodiments of the compounds of the present invention also include compounds wherein Ari is phenyl substituted with one or more C ⁇ -C 6 alkylcarbonyloxy, particularly acetoxy.
  • Embodiments of the compounds of the present invention also include compounds wherein Arj is phenyl substituted with one or more Ci-C ⁇ alkylcarbonylamino, particularly acetylamino.
  • Embodiments of the compounds of the present invention also include compounds wherein Ari is phenyl substituted with one or more C ⁇ -C 6 alkylthio, particularly methylthio.
  • Embodiments of the compounds of the present invention also include compounds wherein is phenyl substituted with one or more heterocyclyl, particularly diazolyl.
  • embodiments include compounds wherein Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of Ci-C ⁇ alkyl, C ⁇ -C 6 alkoxy, and C ⁇ -C 6 alkyloxycarbonyl.
  • Ar is phenyl.
  • embodiments also include compounds wherein Ar 2 is indolyl or indolyl substituted with one or more substituents selected from the group consisting of C ⁇ -C 6 alkyl, Ci-C ⁇ alkoxy, and C ⁇ -C 6 alkyloxycarbonyl.
  • Ar is indolyl, particularly indolyl substituted with one or more d-C 6 alkylcarbonyloxy.
  • Ar 2 is benzopyranonyl.
  • embodiments include compounds wherein Ar 3 is phenyl, indolyl, or pyridyl, optionally substituted with one or more substituents selected from the group consisting of C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, amino, C ⁇ -C 6 alkylamino, C ⁇ -C 6 dialkylamino, C ⁇ -C 6 trialkylamino, and nitro.
  • Ar 3 is phenyl, optionally substituted with one or more d-C ⁇ trialkylamino, preferably N,N,N- trimethylamino.
  • Ar 3 is indolyl.
  • Q is Ar 3 Q ⁇ and Q is Ci-Ce alkylenyl carbonyloxy C ⁇ -C 6 alkyl, optionally having a d-C 6 trialkylamino, for example, Qi is trimethylamino ethylenyl carbonyloxy t-butyl.
  • Q is Q ⁇ Ar 3 , wherein Qi is d-C 6 alkylenyl, optionally having a d ⁇ C 6 trialkylamino or a heterocyclic containing a quaternized nitrogen atom.
  • Qi examples include methylenyl and trimethylarnino ethylenyl, and ethylenyl having a N-alkyl pyrrolidinyl, N-alkyl piperidinyl, or N,N-dialkyl-N-tetrahydropyranyl substituent.
  • Qi is a zwitterion, for example, an internal salt of a natural or synthetic amino acid.
  • Qi is a group containing amidine or guanidine function wherein the amidine or guanidine may be optionally N-substituted with a d-C 6 alkyl.
  • t is 0.
  • Ri ⁇ are H.
  • q and r are independently 1-7.
  • p is 1-4.
  • Still further preferred embodiments include compounds wherein q and r are 1, q and r are 2, and one of q and r is 1 and the other of q and r is 2.
  • Y is selected from the group consisting of covalent bond and O.
  • An example of a covalent bond is a single bond.
  • Specific compounds of the present invention include compounds wherein Art is phenyl or a phenyl substituted with chloro, fluoro, methylthio, methoxy, isopropoxy, N,N- dimethylamino, azido, nitro, acetoxy, cyano, acetylamino, sulfonamido, or diazolyl;
  • Ar 2 is phenyl, indolyl, or benzopyranonyl, each of the Ar 2 may be substituted with methoxycarbonyl;
  • L is (CH 2 ) n wherein n is 7-11 ;
  • Qi is single bond, CH 2 -CH(GU)-CH 2 , (
  • Ari is dichlorophenyl wherein the chlorine atoms may be in the 2,3; 2,4; 2,5; 2,6; 3,4; 3,5; or 3,6-position;
  • Ar 2 is phenyl;
  • Y is O;
  • L is (CH 2 ) 8 ;
  • Qi is single bond, CH 2 , CH(NMe 3 )CH 2 ;
  • Ar 3 is phenyl, N- methyl pyridinyl, or N,N,N-lj methylaminophenyl.
  • Additional embodiments include compounds wherein Ar !
  • Ar 2 is phenyl
  • Y is O
  • L is (CH 2 ) 8
  • Qi. is CH 2 , CH(NMe 3 )CH 2
  • Ar 3 is phenyl or N,N,N- Mmemylaminophenyl.
  • Ari is o-, m-, oxp- fluorophenyl
  • Ar 2 is phenyl
  • Y is O
  • L is (CH 2 ) 8
  • Qi is CH(NMe 3 )CH 2
  • Ar 3 is phenyl.
  • Ari is difluorophenyl wherein the fluorine atoms may be in the 2,3; 2,4; 2,5; 2,6; 3,4; 3,5; or 3,6- position;
  • Ar 2 is phenyl;
  • Y is O;
  • L is (CH 2 ) 8 ;
  • Qi is CH(NMe 3 )CH 2 ; and
  • Ar 3 is phenyl.
  • Additional embodiments include compounds wherein Ari is methoxy phenyl or isopropoxy phenyl, wherein the methoxy or isopropoxy group may be present in the o-, m-, o ⁇ p- position;
  • Ar 2 is phenyl;
  • Y is O;
  • L is (CH 2 ) 8 ;
  • Qi is single bond, CH 2 , or CH(NMe 3 )CH 2 ; and
  • Ar 3 is phenyl or N-methyl pyridinyl, or N,N,N-trimethylaminophenyl.
  • Q is preferably Q ⁇ .Ar 3 .
  • Particular examples of compounds of the present invention include:
  • T is a pharmaceutically acceptable anion
  • the compounds described above can have a suitable configuration if an asymmetric center is present.
  • the compounds may be in R, S, or a mixture of R and S forms.
  • the amino acids employed may be the natural (L) form or the unnatural (D) form.
  • Embodiments of the above compounds of formula (I) include:
  • the present invention provides in another embodiment, a compound of the formula A-B-(CH 2 ) n -O-CO-CH 2 -Ph (NMe 3 ) + 1 " , wherein A is a phenyl or indole, optionally substituted with a benzyloxy group; B is a covalent bond or oxygen atom, and I " is a pharmaceutically acceptable anion.
  • A is a phenyl group substituted with benzyloxy, chlorobenzyloxy, or methoxybenzyloxy group.
  • the chloro or methoxy group can be in any of ortho, para, or meta positions. In embodiments, the chloro or methoxy group is in the ortho or para position.
  • a further example includes a compound where A is an indole substituted with benzyloxy.
  • the inhibitor of NAD synthetase has the Structure 2' :
  • Aryl 1 is indolyl or phenyl
  • Aryl 2 is phenyl, pyridinyl, indolyl, or quinolinyl
  • R ⁇ -R 3 are independently selected from the group consisting of H, aryloxy, hydroxyaryl, aryl d-Ce alkoxy, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkoxycarbonyl, Ci-C ⁇ alkyl, C ⁇ -C 6 alkylcarbonyl, arylcarbonyl, nitro, halo, carboxy, halo C ⁇ -C 6 alkyl, perhalo C ⁇ -C 6 alkyl, triphenylmethoxy, phenylcarbonylamino, C ⁇ -C 6 alkoxycarbonyl C 2 -C 6 alkenyl, arylcarbonyl C 2 -C 6 alkenyl, benzof ⁇ ranyl carbonyl, Ci-C 6 alkylbenzylfuranyl carbonyl, arylaminocarbonyl, arylcarbonyloxy, aminocarbonyl, C ⁇ -C 6 alkoxycarbonylamino, phthal
  • Aryl 1 is indolyl. In some other embodiments, Aryl 1 is phenyl. In certain embodiments, Aryl 2 is phenyl. In certain other embodiments, Aryl 2 is pyridinyl. In further embodiments, Aryl 2 is quinolinyl. In other embodiments, Aryl 2 is indolyl.
  • R 1 -R3 are independently selected from the group consisting of H, phenoxy, hydroxyphenyl, benzyloxy, methoxy, methoxycarbonyl, isopropyl, butyl, acetyl, phenylcarbonyl, nitro, fluoro, carboxy, trifluoromethyl, triphenylmethoxy, phenylcarbonylamino, methoxycarbonyl ethenyl, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, memoxycarbonylamino, phthalidimido, morpholino, pyrrolidinyl, phenylhydantoinyl, and acetylpiperaz
  • R 1 -R 3 are independently selected from the group consisting of H, phenoxy, hydroxyphenyl, benzyloxy, acetyl, phenylcarbonyl, nitro, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, and memoxycarbonylamino.
  • Other examples of inhibitors of NAD synthetase has the Stoicture 300:
  • Y is C, N, O, S, ester, amide, or ketone
  • n is an integer of from 1 to 12
  • a is an integer from 1-3
  • R1-R5 each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, or alkynyl, or an aryl group.
  • a further example of the inhibitor of NAD synthetase has the Structure 400:
  • Y is C, N, O, S, ester, amide, or ketone
  • Z is C, N, O, or S
  • AA is a natural or unnatural stereoisomer of an .-, ⁇ -, ⁇ -, or ⁇ -amino acid in which the carboxyl carbonyl is attached to Z, and the amino grouping may be a primary, secondary, tertiary, or quaternary ammonium compound
  • n is an integer of from 1 to 12
  • R 1 -R 5 each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, alkynyl, aryl, aryl alkyl, or aryl alkoxy group.
  • R1.-R 2 may also be H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group.
  • inhibitors of NAD synthetase are 5940, 5949, 5951, 5409, 5948, 5270, 5939, 5947, 5953, and 5274:
  • the present invention further provides a method for treating or preventing a microbial (e.g., bacterial or fungal) infection in a mammal comprising administering to said mammal an effective amount of a compound that binds to the dimer interface of the NAD synthetase enzyme of the microbe (bacterium or fungus).
  • a microbial e.g., bacterial or fungal
  • the NAD synthetase enzyme inMbitor is a compound that selectively binds with catalytic sites or subsites on a yeast NAD synthetase enzyme to reduce or eliminate the production of NAD by the yeast.
  • it is particularly preferably that there is little or no inhibitory activity on the host cell.
  • the host is a mammal. In a further embodiment, the host is a plant.
  • the invention provides administering an antifungal agent to a mammal in need of such treatment or prevention.
  • the fungal agent that causes the infection is yeast.
  • the antifungal agent comprises one or more compounds disclosed herein.
  • the present invention further provides a method of decreasing yeast growth, comprising contacting the yeast with an amount of yeast NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of
  • NAD whereby yeast growth is decreased is also provided.
  • the present invention provides, in an embodiment, a method for increasing production of a food animal comprising administering to the food animal an effective amount of at least one inhibitor of NADs of a microbe capable of infecting the food animal.
  • the present invention provides a method for the treatment or prevention of infection by a spore-forming bacterium in an animal comprising freating an environment of the animal with an effective amount of at least one inhibitor of NADs of the spore-forming bacterium.
  • the present invention provides a method for killing the vegetative cell of a spore-forming bacterium in an environment comprising treating the environment with an effective amount of at least one inhibitor of
  • NADs of the bacterium NADs of the bacterium.
  • An example of a spore-forming bacterium is a biological warfare agent, e.g., Bacillus anthracis.
  • the present invention provides a method for freating a fungal or bacterial disease in a plant comprising treating the plant or an environment of the plant with an effective amount of at least one inhibitor of NADs of the fungus or bacterium.
  • the present invention provides a method for a treating plant comprising the treating the plant, or an environment thereof, with a pesticidal effective amount of at least one inhibitor of NADs of a pest.
  • a pesticidal effective amount of at least one inhibitor of NADs of a pest An example of the plant is a food crop.
  • the present invention provides a method for dismfecting, sterilizing, or decontaminating an object comprising treating the object with an effective amount of at least one inhibitor of NADs of a microbe.
  • the microbe is a microorganism, e.g., bacterium or fungus.
  • An example of a fungus is mold or yeast.
  • Any suitable object can be disinfected, sterilized, or decontaminated.
  • suitable objects include an article of clothing, an animal, an organ of an animal, a structure, an equipment, a furniture, an environment, a food crop, a chicken, a chicken skin, and an egg, e.g., egg shell.
  • the environment being disinfected, sterilized, or decontaminated can be land, air, or water, or a combination thereof.
  • An example of the environment includes a medical environment.
  • a medical device, medical equipment, hospital, or surgical room can be disinfected. Medical personnel also can be disinfected or decontaminated.
  • medical devices such as implantable medical devices, e.g., catheters can be disinfected, sterilized, or decontaminated.
  • Medical equipment such as a surgical equipment may also be disinfected, sterilized, or decontaminated.
  • the organs of ammals, including human can be disinfected or decontaminated.
  • An example of an organ is the digestive tract.
  • the present invention provides a method for controlling insect population in an environment comprising treating the environment with an effective amount of at least one inhibitor of NADs of the insect.
  • Any suitable environment can be treated.
  • a household environment or an agricultural environment can be treated.
  • the inhibitor or antimicrobial agent may be mixed with animal feed at a typical concentration of 1-500 mg per kg of feed. Alternatively, similar concentrations may be added to the animals' drinking water. Further alternatively, the antimicrobial agent may be administered as an oral pill or may be injected, either intramuscularly or intravenously.
  • the method of the present invention in an embodiment is useful in the prophylaxis or therapy of biological warfare agents, including, but not limited to, the spore-forming bacterium such as Bacillus anthracis or a microorganism carrying the virulent gene of a spore-forming bacteria such as Bacillus anthracis.
  • the spore-forming bacterium such as Bacillus anthracis or a microorganism carrying the virulent gene of a spore-forming bacteria such as Bacillus anthracis.
  • NADs is required for outgrowth of the germinated spore. Since inhibitors of NADs also prevent vegetative growth, this represents two different points of attack on the life cycle of these bacteria and should provide extremely effective prophylaxis and/or therapy.
  • the antimicrobial agent in a suitable vehicle is sprayed onto growing plants to either prevent or treat fungal and/or bacterial diseases.
  • application may be made by deposition of solutions or solid preparations on the soil near growing plants.
  • NADs inhibitors as pesticides for controlling pests and insects in the household and/or for agricultural uses
  • NADs inhibitors with pesticidal or insecticidal activities and in a suitable vehicle are sprayed in areas of homes that are commonly treated with existing insecticidal preparations.
  • the pesticidal or insecticidal agent in a suitable vehicle is sprayed onto growing plants to either prevent or treat infestation by insects.
  • pesticidal or insecticidal application to plants may be made by deposition on the soil near growing plants.
  • a solution of the microbicidal compound in a suitable vehicle would be painted, sprayed, or soaked (by immersion into a solution) onto the surface of the object.
  • a solution of the microbicidal agent in a suitable vehicle may be sprayed onto or soaked into the ground, or a solid form may be mixed with the soil.
  • the microbicidal agent may also be added to contaminated water supplies in sufficient concentration (1-100 micromolar) to cause sterilization.
  • a solution of the microbicidal compound in a suitable vehicle may be painted, sprayed, or soaked (by immersion into a solution) onto the surface of the food.
  • a solution of the microbicidal compound in a suitable vehicle may be painted, sprayed, or soaked (by immersion into a solution) onto the surface of the food.
  • Numerous related beneficial applications are possible, including decontamination of chicken skins, e.g., to reduce Salmonella typhimurium, egg shells (carriers of Salmonella), and disinfection of other foods.
  • disinfecting and decontamination including, microbicidal concentrations of NADs inhibitors have the potential for use in a variety of situations benefiting from sterilization or decontamination, including the treatment of clothing, surfaces of structures, equipment, furniture, and natural environmental surfaces such as the ground and water supplies.
  • a typical application for disinfection of implantable devices would involve soaking the device in a solution of the microbicidal compound.
  • the implantable device may be manufactured to contain a releasable or bioactive form of the microbicidal compound, either by mechanical entrapment in the polymeric material composing the surface of the device or by covalent chemical attachment to the polymeric material composing the surface of the device.
  • the organ may be immersed in a solution of the microbicidal agent contained in a suitable vehicle.
  • Whole body washing can be accomplished by thoroughly wiping the body with a solution of the microbicidal agent, or by immersion of the body in a suitable solution.
  • Control of dental caries and/or gum disease may be accomplished by washing of the oral cavity with a suitable solution of the microbicidal agent, or by incorporation into a toothpaste used in brushing the teeth.
  • Numerous medical applications and devices requiring disinfection or decontamination are possible such as pacemakers, defibrillators, artificial hearts or parts thereof, whole body washing of infected patients, treatment of transplantable organs for transplantation, decontamination of surgical rooms and surgical equipment, and control of dental caries or gum disease.
  • inhibitors of germination may cause damage to the spore and should be bactericidal to the vegetative cell.
  • these inhibitors may be used ( to decontaminate a variety of environments including, but not limited to, environmental surfaces and drinking water.
  • the inhibitor in the treatment, prevention, or control of fungal and bacterial diseases in plants and foodcrops, can be carried in a suitable vehicle and sprayed onto the plants to either prevent or treat fungal and/or bacterial diseases.
  • application may be made by deposition of solutions or solid preparations on the soil near growing plants.
  • Numerous medical applications requiring disinfection or decontamination are possible. These include digestive tract decontamination in humans related to surgery (see G. Ramsay and R. H. van Saene, "Selective gut decontamination in intensive care and surgical practice: where are we [Review]," World Journal of Surgery, 22(2): 164-70, Feb 1998; and G.
  • Ranges may be expressed herein as from “about” one particular value, and or to "about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
  • ⁇ -methylbenzoic acid is represented.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, «-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • cycloalkyl intends a cyclic alkyl group of from three to eight, preferably five or six carbon atoms.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be defined as -OR where R is alkyl as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing from one to six, more preferably from one to four, carbon atoms.
  • alkylene refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), 2-methylpro ⁇ ylene [-CH 2 -CH(CH 3 )-CH 2 -], hexylene [-(CH 2 )6-] and the like.
  • cycloalkylene refers to a cyclic alkylene group, typically a 5- or 6-membered ring.
  • alkene intends a mono-unsaturated or di-unsaturated hydrocarbon group of 2 to 24 carbon atoms.
  • alkynyl refers to a branched or unbranched unsaturated hydrocarbon group of 1 to 24 carbon atoms wherein the group has at least one triple bond.
  • cyclic intends a structure that is characterized by one or more closed rings.
  • the cychc compounds discussed herein may be saturated or unsaturated and may be heterocyclic.
  • heterocyclic it is meant a closed-ring structure, preferably of 5 or 6 members, in which one or more atoms in the ring is an element other than carbon, for example, sulfur, nitrogen, etc.
  • bicyclic intends a structure with two closed rings. As further used herein, the two rings in a bicyclic structure can be the same or different. Either of the rings in a bicyclic structure may be heterocyclic.
  • an effective amount of a compound as provided herein is meant a sufficient amount of the compound to provide the desired treatment or preventive effect.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact "effective amount.” However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation. It is preferred that the effective amount be essentially non- toxic to the subject, but it is contemplated that some toxicity will be acceptable in some circumstances where higher dosages are required.
  • pharmaceutically acceptable carrier a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the compounds of the invention without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • NAD synthetase enzyme is defined as the enzyme that catalyzes the final reaction in the biosynthesis of NAD, namely, the transformation of NaAD into NAD.
  • catalytic sites are defined as those portions of the NAD synthetase enzyme that bind to substrates, and cofactors, including nicotinic acid dinucleotide (NaAD), NAD, adenosine triphosphate (ATP), adenosine monophosphate (AMP), pyrophosphate, magnesium and ammonia in bacteria or microbes.
  • receptor site or "receptor subsite” relates to those portions of the bacterial NAD synthetase enzyme in which the bacterial NAD synthetase enzyme inhibitors disclosed herein are believed to bind.
  • the terms “catalytic site,” “receptor site” and “receptor subsite” may be used interchangeably.
  • the inhibitors may also inhibit the NAD synthetase enzyme by mechanisms not involving binding of the inhibitor to catalytic sites.
  • the term "antimicrobial compound” denotes a material that kills or deactivates microbes so as to reduce or eliminate the harmful effects of the bacteria on a subject or in a system.
  • Microbes are microorganisms which are too small to be seen by the naked eye, e.g., bacteria, fungi, viruses, and protozoa, preferably bacteria and fungi.
  • antibacterials are known in the art as “bacteriostatic agents” or "bateriocidal agents.”
  • the bacteria so affected can be gram positive, gram negative or a combination thereof.
  • antimicrobial compound and “broad spectrum antibiotic” denote a material that kills or deactivates a wide variety of microbes, including, but not limited to, one of more of, gram positive or gram negative bacteria, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, Enterococcus, anaerobic Streptococcus, Pneumococcus, Gonococcus, Meningococcus, Mima, Bacillus anthracis, C. diphtheriae, List, monocytogenes, Streptobacillus monohiliformis, Erysipelothrix insidiosa, E. coli, A.
  • aerogenes A. faecalis, Proteus mirabilis, Pseudomonas aeruginosa, K. pneumoniae, Salmonella, Shigella, H. influenzae, H. ducreyi, Brucella, Past, pestis, Past, tularensis, Past, multocida, V. comma, Actinobacillus mallei, Pseud, pseudomallei, CI. tetani, Bacteroides, Fusobacterium fusiforme, M. tuberculosis, atypical mycobacteria, Actinomyces israelii, Nocardia, T. pallidum, T. pemue, Borrelia recurrentis, Peptospira, Rickettsia, and Mycoplasma pneumoniae.
  • novel compounds have been identified that inhibit bacterial NAD synthetase enzymatic activity. Such activity translates into effectiveness as bacteriocidal agents, as well as effectiveness a broad spectrum antibiotic materials. Novel compounds have been developed that inhibit a previously unrecognized target in prokaryotic organisms, such as bacteria, to block essential biological function and thereby cause bacterial death or deactivation of the microbes.
  • the invention herein has identified an enzyme found in both gram positive and gram negative bacteria, NAD synthetase enzyme, which can be utilized as a target for drug design to provide protection from and/or treatment for bacterial and other microbial infections.
  • NAD synthetase enzyme catalyzes the final step in the biosynthesis of nicotmamide adenine dinucleotide (NAD).
  • Bacterial NAD synthetase is an ammonia- dependent amidotransferase belonging to a family of "N-type" ATP pyrophosphatases; this family also includes asparagine synthetase and argininosuccinate synthetase.
  • NAD synthetase enzyme catalyzes the last step in both the de novo and salvage pathways for NAD + biosynthesis, which involves the transfer of ammonia to the carboxylate of mcotinic acid adenine dinucleotide (NaAD) in the presence of ATP and Mg +2 .
  • the overall reaction is illustrated in Fig. 1.
  • eukaryotic NAD synthetase e.g. , that found in mammals, which can utilize glutamine as a source of nitrogen
  • prokaryotic NAD synthetase in bacteria utilizes ammonia as the sole nitrogen source.
  • the invention has identified marked differences in the structures of eukaryotic and prokaryotic forms of the NAD synthetase enzyme.
  • B. subtilis NAD synthetase enzyme which in the invention has been crystallized and used in the drug design methodologies herein, is a dimeric material with molecular weight around 60,50,0.
  • the eukaryotic form of NAD synthetase found in mammals is multimeric and has a molecular weight of at least 10 times larger.
  • the invention herein provides novel compounds that can be utilized as antimicrobial agents that specifically target the prokaryotic NAD synthetase enzyme without significantly affecting a mammalian host.
  • antibacterial drugs may be developed that preferentially attack the bacteria to kill or deactivate it so as to reduce or eliminate its harmful properties, without appreciably affecting mammalian NAD synthetase enzymatic activity at the same dosage.
  • the invention provides methods of treating microbial infections in a mammal, e.g., human. Because of the differences in structure between bacterial and mammalian NAD synthetase enzyme, it would not be expected that the compounds of the invention would inhibit or otherwise affect mammalian NAD synthetase enzyme in the same manner as the compounds act on bacteria.
  • Small molecules of the proper configuration may bind with a receptor site or sites on the microbial, e.g., bacterial NAD synthetase enzyme, thereby blocking the catalytic activity of the enzyme.
  • Figure 3 illustrates a bacterial NAD synthetase enzyme in which the catalytic sites are blocked by an example of a compound of the present invention.
  • the invention has found that compounds that exhibit inhibitory activity against the bacterial NAD synthetase enzyme will also exhibit therapeutic activity as antibacterial and antimicrobial compounds, as well as broad spectrum antibiotic materials.
  • tethered dimeric compounds that exhibit activity as microbial NAD synthetase enzyme inhibitors.
  • linker molecule By linking one or more active molecules through a linker molecule, one or more ends of the tethered dimer can bind in the respective receptor sites or subsites to thereby render the bacterial NAD synthetase enzyme inactive.
  • each active molecule can be the same or different.
  • active molecules refers to small molecules that may be used alone or tethered together through a linker (tether) fragment to form a tethered dimeric compound.
  • selective affinity means that the active molecule shows enhanced tendency to bind with one subsite with the receptor in the bacterial NAD synthetase enzyme because of a chemical complementarity between the receptor subsite and the active molecule.
  • a tethered dimer compound is illustrated below.
  • a dimeric inhibitor compound will bind with, for example, the sites of catalytic activity on the bacterial NAD synthetase enzyme, thereby preventing the production of NAD/NADH by the bacteria.
  • the affinity of the inhibitor compound for the NAD synthetase enzyme maybe varied.
  • a software program can be utilized which facilitates the prediction of the binding affinities of molecules to proteins so as to allow identification of commercially available small molecules with the ability to bind to at least one receptor subsite in the bacterial NAD synthetase enzyme.
  • An example of one such computer program is DOCK, available from the Department of Pharmaceutical Chemistry at the University of California, San Francisco. DOCK evaluates the chemical and geometric complementarity between a small molecule and a macromolecular binding site.
  • active molecules specifically disclosed herein may be used, as well as any pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable salts of the compounds set out herein below are also contemplated for use in this invention. Such salts are prepared by treating the free acid with an appropriate amount of a pharmaceutically acceptable base.
  • Representative pharmaceutically acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, and the like.
  • the reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about 0°C to about 100°C, preferably at room temperature.
  • the molar ratio of the compounds to base used are chosen to provide the ratio desired for any particular salts.
  • the ammonium salts of the free acid starting material-a particular preferred embodiment-the starting material can be treated with approximately one equivalent of pharmaceutically acceptable base to yield a neutral salt.
  • the starting material can be treated with approximately one equivalent of pharmaceutically acceptable base to yield a neutral salt.
  • approximately one-half a molar equivalent of base is used to yield a neutral salt
  • aluminum salts approximately one-third a molar equivalent of base will be used.
  • the invention provides administering a broad spectrum antibiotic to a mammal in need of such treatment or prevention.
  • the microbial infection is a bacterial infection.
  • the bacterial infection is caused by a bacterium that is a gram negative or gram positive bacteria.
  • the bacterial infection may preferably be caused by an antibiotic resistant strain of bacteria.
  • a method of killing a prokaryote with an amount of prokaryotic NAD synthetase enzyme inhibitor compound to reduce or eliminate the production of NAD whereby the prokaryote is killed is also provided.
  • a method of decreasing prokaryotic growth comprising contacting the prokaryote with an amount of a prokaryotic NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby prokaryotic growth is decreased is also provided.
  • the compound comprises one or more compounds provided herein.
  • the prokaryote is a bacterium. Further preferably, the bacterium is a gram negative or a gram positive bacteria. Still preferably, the prokaryote is an antibiotic resistant strain of bacteria.
  • the NAD synthetase enzyme inhibitor is a compound that selectively binds with catalytic sites or subsites on a bacterial NAD synthetase enzyme to reduce or eliminate the production of NAD by the bacteria.
  • the compound is preferably administered by oral, rectal, intramuscular, intravenous, intravesicular or topical means of administration.
  • the compounds of this invention can be administered to a cell of a subject either in vivo or ex vivo.
  • the compounds of this invention can be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, subcutaneous injection, transdermally, extracorporeally, topically, mucosally or the like.
  • the compounds of the present invention can be in pharmaceutical compositions in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include, as noted above, an effective amount of the selected composition, possibly in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.
  • Parenteral administration of the compounds of the present invention is generally characterized by injection.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions.
  • parenteral administration includes intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous and intratracheal routes.
  • One approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.
  • These compounds can be present in a pharmaceutically acceptable carrier, which can also include a suitable adjuvant.
  • pharmaceutically acceptable it is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected compound without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Routes of administration for the compounds herein are preferably in a suitable and pharmacologically acceptable formulation.
  • the bacterial NAD synthetase enzyme inhibitor compounds of the libraries herein are preferably presented to animals or humans orally, rectally, intramuscularly, intravenously, intravesicularly or topically (including inhalation).
  • the dosage preferably comprises between about 0.1 to about 15g per day and wherein the dosage is administered from about 1 to about 4 times per day.
  • the prefened dosage may also comprise between 0.001 and 1 g per day, still preferably about 0.01, 0.05, 0.1, and 0.25, 0.5, 0.75 and 1.0 g per day.
  • the dosage may be administered in an amount of about 1, 2.5, 5.0, 7.5,10.0, 12.5 and 15.0 g per day.
  • the dosage may be administered at a still preferable rate of about 1, 2, 3, 4 or more times per day.
  • it may be preferable to administer the compound of the invention continuously, as with, for example, intravenous administration.
  • the exact amount of the compound required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the particular compound used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every compound. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.
  • cells or tissues can be removed and maintained outside the subject's body according to standard protocols well known in the art.
  • the compounds of this invention can be introduced into the cells via known mechanisms for uptake of small molecules into cells (e.g., phagocytosis, pulsing onto class I MHC- expressing cells, liposomes, etc.).
  • the cells can then be infused (e.g., in a pharmaceutically acceptable carrier) or transplanted back into the subject per standard methods for the cell or tissue type. Standard methods are known for transplantation or infusion of various cells into a subject.
  • a method of disinfecting a material contaminated by a microbe comprising contacting a contaminated material with a bacterial NAD synthetase enzyme inhibitor compound in an amount sufficient to kill or deactivate the microbe.
  • the compound utilized for contacting comprises one or more compounds provided herein.
  • the compounds of the present invention are effective as disinfectant materials for, for example, hard or soft surfaces, fabrics, and other contaminated materials such as those in hospitals, households, schools, nurseries, and any other location.
  • the invention provides a method for disinfecting comprising contacting a bacterial contaminated material with a bacterial NAD synthetase enzyme inhibitor compound.
  • the inhibitors of NAD synthetase according to the present invention can be employed in a variety of processes for the treatment of humans, animals and plants as well as decontamination, sterilization and or disinfectant techniques.
  • the present invention further provides a method for preventing germination of spore-forming bacteria and/or the vegetative growth of bacteria, fungi and/or molds comprising administering an effective amount of at least one inhibitor of NAD synthetase, e.g. prophylactically or therapeutically, e.g., to at least one of a human, a mammal, or an animal.
  • the present invention further provides a method for preparing a compound of the formula A:
  • Qi is (i) a d-C 6 alkylenyl, C ⁇ -C 6 alkylenyl carbonyloxy C ⁇ -C 6 alkyl, or C ⁇ -C 6 alkylenyl carbonylamino C ⁇ -C 6 alkyl group, optionally having a substituent selected from the group consisting of amino, C ⁇ -C 6 alkylamino, C ⁇ -C 6 haloalkylamino, C ⁇ -C 6 haloalkyl
  • n is from 1 to 15; comprising (i) providing a compound of the formula B: Ar 1 -X-Ar2-O-(CH 2 )n-NH2 (B) and (ii) reacting the compound of formula B with a compound of formula C:
  • the compound of formula B may be prepared by reacting a compound of formula D: Ari-X-Ar OH (D) with a compound of formula E: Hal-(CH 2 )n- NPhth (E); wherein "Hal” stands for a halogen atom and “NPhth” stands for phthalidimide linked to (CH )n at the nitrogen atom, to obtain a compound of formula F:
  • the present invention provides a method for preparing a compound of the formula G:
  • the compound of formula H may be prepared by reacting a compound of formula D: Ar ⁇ -X-Ar 2 -OH (D) with a compound of formula K:
  • the present invention provides a method for preparing the above compounds wherein n is from 7 to 13 relating to compounds of formulas A and G.
  • Ari, A ⁇ 2 , and Ar 3 are aryl, particularly phenyl.
  • X is CH 2 O.
  • Qi is a Ci- C 6 alkylenyl, optionally having a substituent selected from the group consisting of amino, Ci-C ⁇ alkylamino, C ⁇ -C 6 haloalkylamino, C ⁇ -C 6 haloalkyl C ⁇ -C 6 alkyl amino, C ⁇ -C 6 hydroxyalkylamino, C ⁇ -C 6 hydroxyalkyl d-C 6 alkylamino, Cj-C 6 dialkylamino, C]-C 6 trialkylamino, and a heterocyclic containing a nitrogen atom which may be optionally quaternized, preferably Qi is d-C 3 alkylenyl, having a substituent selected from the group consisting of amino, C ⁇ C 6 alkylamino. d-C 6 dialkylamino, and C ⁇ -C 6 trialkylamino.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds described along with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers described herein for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compound and one which has no detrimental side effects or toxicity under the conditions of use.
  • compositions of the present invention are merely exemplary and are in no way lin ⁇ ting.
  • Formulations suitable for oral administration can consist of (a) hquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • diluents such as water, saline, or orange juice
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols and polyethylene glycols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols and polyethylene glycols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the compounds of the present invention can be made into aerosol formulations to be administered via inhalation.
  • compositions may contain one or more nonionic surfactants having a hydrophile-Kpophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-Kpophile balance
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile Hquid carrier, for example, water, for inj ections, immediately prior to use.
  • sterile Hquid carrier for example, water
  • Extemporaneous inj ection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the compounds of the present invention maybe made into injectable formulations.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Iniectable Drugs. Toissel, 4th ed., pages 622-630 (1986).
  • the present invention further provides a method for treating or preventing a microbial (e.g., bacterial or fungal) infection in a mammal comprising administering to said mammal an effective amount of at least one of the compounds described above.
  • a microbial e.g., bacterial or fungal
  • the present invention also provides a method for treating or preventing tuberculosis.
  • the present invention further provides a method for combating agrotereorism involving an infective agent on an object comprising treating the object with an amount of a compound effective to inhibit the NAD synthetase of the infective agent.
  • Agrotenorism is defined as the intentional introduction of animal or plant pests or the cultivation or production of pathogenic bacteria, fungi, parasites, protozoans, viruses, or their toxic products for the purpose of causing poultry, livestock, crop, soil, or human disease, poisoning, or death.
  • This Example illustrates a method of preparing compounds of the present invention in accordance with an embodiment of the invention.
  • Triflate was then dissolved in CH 2 C1 2 (lOmL) and added in 10 minutes to a solution of N-Boc phenyl alaninol (1.53g, 6.095mmol) and NaH (0.305g, 60% in mineral oil, 7.625mmol) in CH 2 C1 2 (30mL) kept at 0°C. Reaction bubbled vigorously. It was stined for 5minutes and 18-crown-6 (0.081g, 0.307mmol) was added and the reaction mixture was allowed to attain room temperature and stined at room temp for 30 minutes. TLC (25%EtOAc in hexanes) showed that the reaction is complete.
  • NCCLS Committee for Clinical Laboratory Standards
  • test compounds were solubilized, diluted, and pipetted in duplicate into 10 mL sterile culture tubes and dried under vacuum. Challenge organisms, specified were grown overnight at 37°C in the appropriate medium (i.e., Mueller-Hinton Broth). These pure broth cultures were diluted 1:1,000 and 2.0 mL were added to the test compound tubes.
  • the cultures were incubated overnight at 37°C and MIC's in ⁇ g/mL were indicated by visual determination of the first clear tube.
  • the minimum inhibitory concentration (MIC) was defined as the concentration of test compound that completely inhibited growth of the challenge organism.
  • Ciprofloxacin ⁇ 5.0; ⁇ 0.5 ⁇ 5.0 ⁇ 5.0; ⁇ 0.25; 0.5 0.125
  • the initial solubilization of the test articles was in 50:50 methanohwater (v/v). (Note: Compound 1364 went into solution on day 1, but precipitated on day 2. The organic solvent was increased from 50% to 66%.(v/v)). Compound 1439 never went into solution at 50% organic.
  • Compound 1503b went into solution at 50% organic. Maximum concentration of methanol did not exceed 1.6% in the final assay. On day 1, compounds 1439 and 1364 required sonication before solubihty was reached). The cells plus compound were incubated overnight at 37°C, under a 5% CO 2 /95% O 2 atmosphere. On day 2, the cells in the positive control wells were lysed with 0.9% Triton X-100 for 45 minutes to establish maximum levels of LDH release. The plates were centrifuged at 250 x g for 5 minutes, the supematants transfened to a new assay plate, and the LDH was measured. The assay plates were read at OD 490 nm.
  • DMEM/Ham's F-12 without D-glucose, phenol red, or sodium pyruvate
  • Hydrocortisone 50 nM
  • selenium 5 ng/mL
  • human transferrin 5 ⁇ g/mL
  • bovine insulin 10 nM
  • L-ascorbic acid-2-phosphate 50 ⁇ M
  • RPRC phosphate-buffered saline
  • RPRC RPRC were washed three times in the binding buffer and were released from the monolayers by gentle scrapping with a rubber policeman.
  • Annexin V and PI staining were measured using a BectonDickson FacsCalibur flow cytometer (San Jose, CA). An equal number of cells (10,000) were counted for sample and apoptotic cells were defined as those that stained positive for annexin V-FITC only.
  • RPRC undergoing necrotic cell death stained for PI only. Late apoptotic cells RPRC dying initially by apoptosis and/or necrotic cell death that exhibited more extensive degradation of the plasma membrane over time) were defined as those that stained positive for both annexin V and PL
  • Reference value 1 ⁇ M approximately 0.6 to 0.7 ⁇ g/mL for compounds 1364, 1439, 1594 and 1617 contingent upon the molecular weight of the compound.
  • This Example illustrates the NAD synthetase enzyme inhibiting activity of some compounds of the present invention.
  • NADH The coupled assay - production of NAD was monitored through conversion to NADH by alcohol dehydrogenase.

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Abstract

L'invention concerne des composés, y compris leurs sels pharmaceutiquement acceptables, inhibant la NAD synthétase microbienne. Par exemple, l'invention concerne des composés de formule Ar1-X-Ar2-Y-L-Z-Q, sachant que Q est Q1Ar3 ou Ar3Q1; Ar1, Ar2, et Ar3 sont indépendamment aryle ou hétéroaryle, éventuellement substitués par un ou plusieurs substituants; X, Y, et Z peuvent être indépendamment une liaison covalente ou des groupes à un plusieurs atomes de C, H, N, O, S. L est un élément de liaison et Q1 est un groupe alkylényle, alkylényle carbonyloxy alkyle, ou alkylényle carbonylamino alkyle, éventuellement à un substituant; une liaison covalente; un groupe à fonction amidine ou guanidine, avec substitution éventuelle de N par un alkyle amidine ou guanidine; un zwittérion. L'invention concerne également des procédés faisant intervenir les composés décrits, par exemple dans le traitement ou la prévention d'une infection microbienne chez un mammifère ou sur une plante, l'élimination d'un procaryote ou la diminution de la croissance procaryotique, la désinfection d'un matériau ou d'un environnement contaminé par un microbe, l'augmentation de la production des animaux destinés à l'alimentation, la lutte contre les dégâts occasionnés aux plantes par les nuisibles ou les insectes, et la lutte contre l'agroterrorisme. On cite les bactéries et les champignons comme exemples de microbes affectés par les composés considérés.
EP02723209A 2001-07-13 2002-02-22 Inhibiteurs de nad synthetase, et utilisations correspondantes Withdrawn EP1578898A2 (fr)

Applications Claiming Priority (3)

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PCT/US2001/022203 WO2002007516A2 (fr) 2000-07-14 2001-07-13 Utilisation des inhibiteurs de la synthetase de nicotinamide-adenine-dinucleotide
WOPCT/US01/22203 2001-07-13
PCT/US2002/005172 WO2003006628A2 (fr) 2001-07-13 2002-02-22 Inhibiteurs de nad synthetase, et utilisations correspondantes

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WO2008136279A1 (fr) 2007-04-27 2008-11-13 Eisai R & D Management Co., Ltd. Sel d'un dérivé de pyridine substitué par hétérocycle ou cristaux dudit sel
TW200841879A (en) 2007-04-27 2008-11-01 Eisai R&D Man Co Ltd Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same
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