EP1194135A2 - Methods of treating fungal infections with inhibitors of nad synthetase enzyme - Google Patents

Methods of treating fungal infections with inhibitors of nad synthetase enzyme

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Publication number
EP1194135A2
EP1194135A2 EP00943322A EP00943322A EP1194135A2 EP 1194135 A2 EP1194135 A2 EP 1194135A2 EP 00943322 A EP00943322 A EP 00943322A EP 00943322 A EP00943322 A EP 00943322A EP 1194135 A2 EP1194135 A2 EP 1194135A2
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European Patent Office
Prior art keywords
integer
och
compound
compounds
compound administered
Prior art date
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EP00943322A
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German (de)
French (fr)
Inventor
Wayne J. Brouillette
Christie G. Brouillette
Lawrence J. Delucas
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UAB Research Foundation
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UAB Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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 relates to methods of treating fungal infections. More particularly, the present invention relates to methods of treating yeast infections with compounds that selectively target the NAD synthetase enzyme of yeast, with little or no attendant targeting of the NAD synthetase enzyme of the host.
  • Fungi are plant-like eukaryotes that grow in colonies of single cells, called yeasts, or in filamentous mutlicellular 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. approximately 10% of the population suffers from contagious skin and hair infections.
  • Ergosterol is very similar to the mammalian steroid cholesterol, and there is a closely related mammalian C-14 demethylase enzyme for which fluconazole is a much poorer inhibitor. This selectivity for inhibition of the fungal form of the enzyme over the mammalian form has resulted in the clinical utility of fluconazole. 4
  • preclinical studies on new antifungal agents that select for the yeast form over the mammalian form of a biochemical target include development of inhibitors for the plasma membrane ATPase 5 and for topoisomerase I. 6
  • NAD synthetase an essential enzyme found in nearly all prokaryotic and eukaryotic cells. This enzyme is essential for the biosynthesis of nicotinamide adenine dinucleotide (NAD 4 ), an essential cofactor in numerous enzymatic reactions. NAD synthetase 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 nicotinic acid adenine dinucleotide (NaAD) in the presence of ATP and Mg . The overall reaction is illustrated in Scheme 1.
  • Prokaryotic NAD synthetase is an ammonia-dependent amidotransferase that belongs to a family of "N-type" ATP pyrophosphatases; this family also includes asparagine synthetase and argininosuccinate synthetase. Unlike eukaryotic NAD synthetase found in yeast and mammals that can use glutamine as a source of nitrogen, the prokaryotic NAD synthetase of bacteria requires ammonia as the only nitrogen source. Furthermore, B. subtilis NAD synthetase, which was previously crystallized and used for drug design by the inventors, is a dimer with molecular weight around
  • the present invention is based in part on the surprising discovery that NAD synthetase inhibitors are highly effective in inhibiting the growth of yeast, yet exhibited only moderate toxicity in animals.
  • the present invention includes the use of NAD synthetase inhibitors as new antifungal agents for preventing or controlling 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 treating or preventing an antifungal infection in a host comprising administering to a host a treatment effective or treatment preventive amount of a yeast NAD synthetase enzyme inhibitor compound.
  • the method of killing yeast with an amount of yeast NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the yeast is killed provides a method of decreasing yeast growth, comprising contacting the yeast with an amount of a yeast NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby yeast growth is decreased.
  • 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.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, «-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 (-CH2-), ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), 2-methylpropylene [-CH2-CH(CH3)-CH2-], hexylene [-(CH2)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 cyclic compounds discussed herein may be saturated or unsaturated and may be heterocychc.
  • heterocychc 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 heterocychc.
  • 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 adenine dinucleotide (NaAD), NAD, adenosine triphosphate (ATP), adenosine monophosphate (AMP), pyrophosphate, magnesium and ammonia in yeast.
  • receptor site or "receptor subsite” relates tp those portions of the yeast NAD synthetase enzyme in which the yeast NAD synthetase enzyme inhibitors disclosed herein are believed to bind.
  • the terms "catalytic site,” “receptor site” and “receptor subsite” may be used interchangeably.
  • 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 in Figure 1 below.
  • the antifungal agent comprises one or more of the compounds set forth in Figure 2 below.
  • the compounds administered comprise one or more of the compounds of Structure 2, Structure 4, Structure 6, Structure 7, Structure 8, Structure 10, or Structure 12.
  • the antifungal agent comprises one or more of the compounds denoted 1 to 1106 below.
  • the invention herein is preferably a method of killing yeast with an amount of yeast NAD synthetase enzyme inhibitor compound to reduce or eliminate the production of NAD whereby the yeast is killed.
  • 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 compound comprises one or more compounds of Figure 1 below.
  • the compound comprises one or more compounds of Figure 2 below.
  • the compound administered is a compound of Structure 2, Structure 4, Structure 6, or Structure 7.
  • the compounds administered comprise one or more of the compounds of Structure 8, Structure 10, or Structure 12.
  • the compounds administered comprise one or more compounds denoted 1-1106 below.
  • FIGURE 1 LEAD I COMPOUNDS
  • the compound comprises one or more compounds re 2 below ("Lead II Compounds").
  • FIGURE 2 LEAD II COMPOUNDS
  • the methods of the invention comprise administering a compound having the general structure of Structure 2:
  • n is an integer of from 1 to 12
  • Ri - R7 each, independently, is an H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group
  • 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.
  • heteroatoms it is meant that one or more atoms is an element other than carbon.
  • R1-R7 may also be one of the following groups: an H, alkyl, alkenyl, alknyl, or an aryl.
  • R1-R7 may further 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 preferably 5 to 9 and, still more preferably 6 to 9.
  • the tethered active molecule, e.g., in this example denoted "aryl,” moieties may be the same or different.
  • the invention comprises administering a compound of Structure 4:
  • 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
  • R ⁇ -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
  • 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 R 7 may also be one of the following groups: an H, alkyl, alkenyl, alkynyl, or an aryl group.
  • R]-R 7 may also be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups.
  • One of skill in the art would know what moieties are considered to constitute 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 methods of the invention comprise administering a compound of Structure 6:
  • X is C, N, O or S
  • Y is C, N, O, S, carboxy, ester, amide, or ketone
  • a and B represent the respective sites of attachment for a linker
  • n is an integer of from 1 to 12
  • RrR 7 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group
  • the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
  • R ⁇ -R 7 may also be one of the following groups: an H, alkyl, alkenyl, alknyl, or an aryl.
  • Ri-R may further 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 preferably 5 to 9 and, still more preferably 6 to 9.
  • the tethered active molecule, e.g., in this example denoted "aryl,” moieties may be the same or different.
  • the methods of the invention comprise administering a compound of Structure 7:
  • X is C, N, O or S
  • Y is C, N, O, S, carboxy, ester, amide, or ketone
  • a and B represent the respective sites of attachment for a linker
  • n is an integer of from 1 to 12
  • R t -Re each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group
  • the linker is a saturated or unsaturated cychc or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
  • Ri-R ⁇ may also be one of the following groups: an H, alkyl, alkenyl, or alkynyl, or an aryl group.
  • R R ⁇ may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen and the common derivatives of these groups.
  • One of skill in the art would know what moieties are considered to constitute 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 methods of the invention comprise administering a compound of Structure 8:
  • n is an integer of from 1 to 12
  • Ri is an H, methoxy, benzyloxy, or nitro
  • R 2 is 3- pyridyl, N-methyl-3-pyridyl, 3-quinolinyl, N-methyl-3-quinolinyl, 3- (dimethylamino)phenyl, 3-(trimethylammonio)phenyl, 4-(dimethylamino)phenyl, 4- (trimethylammonio)phenyl, 4-(dimethylamino)phenylmethyl, or 4- (trimethylammonio)phenylmethyl.
  • N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the methods of the invention comprise administering a compound of Structure 10:
  • n is an integer of from 1 to 12
  • Ri is an H, CO 2 H, -OCH 3 , or -OCH2PI1
  • R3 is H or CO 2 H
  • Y is N-linked pyridine-3 -carboxylic acid, N- linked pyridine, N-linked quinoline, or N-linked isoquinoline.
  • N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the methods of the invention comprise administering a compound of Structure 12 :
  • n is an integer of from 1 to 12
  • Ri is H, F, or NO2
  • R2 is H, CH3, CF3, NO2
  • R is H or CF 3
  • Y is N-linked pyridine-3 -carboxylic acid, N- linked pyridine, N-linked quinoline, or N-linked isoquinoline.
  • N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the methods of the invention comprise administering a compound of Structure 14:
  • n is an integer of from 1 to 12
  • Rj is H, phenyloxy, isopropyl, acetyl, or benzoyl
  • R is H or CF 3
  • Y is 3-(dimethylamino)phenyl, 3-(trimelthylammonio)phenyl, 4- (dimethylamino)phenyl, 4-(trimethylammonio)phenyl, 2-(phenyl)phenyl, diphenylmethyl, 3-pyridyl, 4-pyridyl, or pyridine-3 -methyl.
  • N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the invention comprises administering compounds of the structures denoted in Tables 102-128 as Compounds 1-274 were synthesized utilizing the methods disclosed previously in co-pending patent application PCT US99/00810.
  • Fragments I-X each represent an active molecule, as defined previously herein, which can be included in the compounds of the present invention as further described in the respective Tables.
  • the point of attachment for the linker compound is at the nitrogen.
  • the symbol or X designates generally the presence of an anion.
  • the type of anion in the compounds of this invention is not critical.
  • the compounds of this invention may be comprised of any such moieties known generally to one of skill in the art or that follow from the synthesis methods disclosed in co-pending patent application PCT US99/00810.
  • the methods of the invention comprise administering a compound corresponding to Structure 100:
  • R' is as defined below in Figure 6:
  • N is an integer of from 1 to 12.
  • N may also be from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 100 and as further defined in Table 100.
  • n may also be an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9.
  • R' corresponds to a Fragment as previously defined in Figure 6 and n indicates the number of linker groups separating the two tethered active molecule groups in the compound.
  • Fragments A - G are set out in Figure 8.
  • the group denoted R in A-G of Figure 8 can be a benzyl group, a methyl group or a hydrogen.
  • the point of attachment of the linker group to Fragments A-G is at the nitrogen group.
  • the methods of the invention comprise administering a compound corresponding to compounds of Structure 101.
  • n is an integer of from 1 to 12, more preferably from 3 to 10, more preferably from 5 to 9 and, still more preferably from 6 to 9.
  • the point of attachment of the linker group for both RI and R' is at the respective nitrogen groups of each illustrated fragment.
  • RI is:
  • R group in Fragments A-G is a benzyl group, a methyl group or a hydrogen.
  • the compounds may include the Fragments illustrated below in Figure 8.
  • FIGURE 8 FRAGMENTS A-G IN COMPOUNDS 25-274
  • the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 102.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein correspond to Structure 102, as further set out in Table 102.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • A corresponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and A in the respective compounds.
  • Groups I, ⁇ , VII, VIE each have a benzyl group and Groups I*, in*, VII*, VTH* each have a hydrogen, respectively, in the position designated R in Fragment A of Figure 8.
  • the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 104.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein correspond to Structure 104, as further set out in Table 104.
  • R' corresponds to a Fragment as previously defined in
  • Figure 6 B corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and B in the respective compounds.
  • Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment B of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 106.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 106 as further set out in Table 106.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 108.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 108 as further set out in Table 108.
  • R' conesponds to a Fragment as previously defined in Figure 6 D conesponds to a fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and D in the compound.
  • Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment D of Figure 8.
  • the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 110.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 110 as further set out in Table 110.
  • R' conesponds to a Fragment as previously defined in Figure 6 E conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and E in the respective compounds.
  • Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment E of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 112.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein correspond to Structure 112, as further set out in Table 112.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • F conesponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and F in the respective compounds.
  • Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment F of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 114.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 114 as further set out in Table 114.
  • R' conesponds to a Fragment as previously defined in Figure 6 corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and G in the respective compounds.
  • Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment G of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 116.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 116 as further set out in Table 116.
  • R' conesponds to a Fragment as previously defined in Figure 6 corresponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and A in the respective compounds.
  • Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment A of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 118.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • R' corresponds to a Fragment as previously defined in
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 120.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 120 as further set out in Table 120.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • n indicates the number of linker groups separating Groups R' and C in the respective compounds.
  • Groups I, II each have a methyl group and Groups I*, II* each have a hydrogen, respectively, in the position designated R in Fragment C of Figure 8.
  • the methods of the invention comprise administering a compound corresponding n Structure 122.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 122 as further set out in Table 122.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • D conesponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and D in the respective compounds.
  • Groups I, II each have a methyl group and Groups I, III each have a hydrogen, respectively, in the position designated R in Fragment D of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 124.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 124 as further set out in Table 124.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • E corresponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and E in the respective compounds.
  • Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment E of Figure 8.
  • the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 126.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • the compounds herein conespond to Structure 126 as further set out in Table 126.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • F conesponds to a Fragment as previously defined in Figure 8
  • n indicates the number of linker groups separating Groups R' and F in the respective compounds.
  • Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment F of Figure 8.
  • the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 128.
  • n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9.
  • R' corresponds to a Fragment as previously defined in Figure 6
  • n indicates the number of linker groups separating Groups R' and G in the respective compounds.
  • Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment G of Figure 8.
  • Ph phenyl
  • I- propyl isopropyl
  • OPh O-Phenyl
  • the compounds administered in the methods of the present invention conespond to compounds of the Structure 130 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds conesponding to Structure 130 are set out in Table 130.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 132 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 5-H, 6-CF 3; 5-CH 3 , 5,7-diF, 5,7-diNO 2 , 5-Butyl, 5- iPropyl, 5-Phenyl, 5-NO 2 , 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF 3 , 5-COCH 3 , 5-OCH 3 , 5- COOCH 3 or 5-COOH.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 134 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF 3 , 5-CH 3 , 5,7-diF, 5,7-diNO 2 , 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO 2 , 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF 3 , 5-COCH 3 , 5-OCH 3 , 5- COOCH3, or 5-COOH.
  • STRUCTURE 134 is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF 3 , 5-CH 3 , 5,7-diF, 5,7-diNO 2 , 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO 2 , 5-Trityl
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 136 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF 3 , 5-CH 3 , 5,7-diF, 5,7-diNO 2 , 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO 2 , 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF 3 , 5-COCH 3 , 5-OCH 3 , 5- COOCH 3 , or 5-COOH.
  • Further embodiments of the compounds corresponding to Structure 136 are set out in Table 136.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 138 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF 3 , 5-OPh, 5-iPropyl, 5-COCH 3 , or 5-COPh and Y is 3-N,N-dimethylarninophenyl (3-N,N-diCH 3 ), 4-N,N-dimethylaminophenyl (4-N,N- diCH 3 ), or 2-Ph.
  • STRUCTURE 138 is set out in Table 138.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 140 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF 3 , 5-OPh, 5-iPropyl, 5-COCH 3 or 5-COPh, and Z is CH(Ph) 2 or 3-Pyridyl. Further embodiments of the compounds corresponding to Structure 140 are set out in Table 140.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 142 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF 3 , 5-OPh, 5-iPropyl, 5-COCH 3 , or 5-COPh. Further embodiments of the compounds corresponding to Structure 142 are set out in Table 142. STRUCTURE 142:
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 144 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF 3 , 5-OPh, 5-iPropyl, 5-COCH 3 , or 5-COPh. Further embodiments of the compounds corresponding to Structure 144 are set out in Table 144.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 146 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 146 are set out in Table 146.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 148, as further defined in Table 148.
  • STRUCTURE 148 :
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 150 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 150 are set out in Table 150.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 152 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 152 are set out in Table 152.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 154 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is CH(DiPh), 4-(N,N-dimethylamino)phenyl, CH 2 CH 2 -(3- pyridyl), or (2-phenyl)-phenyl.
  • n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is CH(DiPh), 4-(N,N-dimethylamino)phenyl, CH 2 CH 2 -(3- pyridyl), or (2-phenyl)-phenyl.
  • Z is CH(DiPh), 4-(N,N-dimethylamino)phenyl, CH 2 CH 2 -(3- pyridyl), or (2-phenyl)-phen
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 156 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds conesponding to Structure 156 are set out in Table 156.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 158 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 158 are set out in Table 158.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 160 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 160 are set out in Table 160.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 162 wherein n is an mteger of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 162 are set out in Table 162.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 164 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds conesponding to Structure 164 are set out in Table 164.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 166 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 166 are set out in Table 166.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 168 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 168 are set out in Table 168.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 170 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 or -OCH Ph. Further embodiments of the compounds corresponding to Structure 170 are set out in Table 170.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 172 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 and -OCH 2 Ph. Further embodiments of the compounds corresponding to Structure 172 are set out in Table 172.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 174 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH 3 and -OCH 2 Ph. Further embodiments of the compounds-corresponding to Structure 174 are set out in Table 174.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 176 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is 3 -quinoline, 3-(N,N-dimethylamino)phenyl, or 4-(N,N- dimethylamino)phenyl.
  • n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is 3 -quinoline, 3-(N,N-dimethylamino)phenyl, or 4-(N,N- dimethylamino)phenyl.
  • STRUCTURE 176 is set out in Table 176.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 178 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 178 are set out in Table
  • the compounds aclrninistered according to the methods of the present invention conespond to compounds of the Structure 180 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 180 are set out in Table 180.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 182 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 182 are set out in Table 182.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 184 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF 3 , 5-OPh, 5-CH(CH 3 ) 2 , 5-COCH 3 or 5-COPh. Further embodiments of the compounds corresponding to Structure 184 are set out in Table 184.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 186 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF3, 5-OPh, 5-CH(CH 3 )2, 5-COCH3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 186 are set out in Table 186.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 188 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF3, 5-OPh, 5-CH(CH 3 ) 2 , 5-COCH 3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 188 are set out in Table 188.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 190 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF 3 , 5-OPh, 5-CH(CH 3 ) 2 , 5-COCH 3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 190 are set out in Table 190.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 192 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF 3 , 5-OPh, 5-CH(CH 3 ) 2 , 5-COCH 3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 192 are set out in Table 192.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 194 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and R 1 is an H or -OCH 2 Ph and R 2 is H or COOCH 3 . Further embodiments of the compounds corresponding to Structure 194 are set out in Table 194.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 196 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R 1 is an H or a -OCH 2 Ph and R 2 is H or COOCH 3 . Further embodiments of the compounds corresponding to Structure 196 are set out in Table 196.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 198 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R 1 is an H or a -OCH 2 Ph and R 2 is H, or COOCH 3 .
  • STRUCTURE 198 is set out in Table 198.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 200 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R 1 is H or a -OCH 2 Ph and R 2 is H or COOCH 3 .
  • n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R 1 is H or a -OCH 2 Ph and R 2 is H or COOCH 3 .
  • Further embodiments of the compounds conesponding to Structure 200 are set out in Table 200.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 202 A.
  • Further embodiments of the compounds corresponding to Structure 206 are set out in Table 206.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 210 wherein R is NH 2 ; NMe 2 ; NMe 3 .I; NH 2 .HC1; NMe 2 .HCl . Further embodiments of the compounds corresponding to Structure 210 are set out in Table 210.
  • the compounds administered according to the methods of the present invention correspond to compounds of the Structure 212 wherein R' is PhCONH or Ph 3 C and R" is H or COOCH 3 . Further embodiments of the compounds corresponding to Structure 212 are set out in Table 212.
  • the compounds administered according to the methods of the present invention conespond to compounds of the Structure 214 wherein R is 4- hydroxyphenyl or 3-hydroxy-4-methylphenyl. Further embodiments of the compounds corresponding to Structure 214 are set out in Table 214.
  • STRUCTURE 214 :
  • 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
  • R R 5 each, independently, is an 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.
  • R R 2 may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group.
  • the (CH 2 ) n linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents and wherein the linker may also contain heteroatoms.
  • the aryl group is an aromatic grouping which may contain one or more rings, and the quaternary nitrogen may be part of the ring (as, for example, in pyridines and quinolines) or outside the ring (as, for example, in anilines and aminonaphthalenes).
  • the value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
  • 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 Rs each, independently, is an 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.
  • R R 2 may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group.
  • the (CH 2 ) n linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents, and wherein the linker may also contain heteroatoms.
  • the value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. Specific examples include Structure 1230:
  • the NAD synthetase enzyme inhibitor 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.
  • the host is a mammal. In a further embodiment, the host is a plant.
  • 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. See e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein.
  • 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.
  • the yeast NAD synthetase enzyme inhibitor compounds of the invention 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 preferred 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 compounds 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 admmistration 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 s ⁇ bject'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.
  • EXAMPLE 1 NAD synthetase enzyme inhibition assay- Determination of test compound concentrations providing 50% inhibition (ICgfl) of the maximum enzyme rate.
  • the potential inhibitory activity of the synthetic compounds was determined by the use of a coupled enzymatic assay.
  • the coupled assay involves two steps as summarized below.
  • the final reaction mixture includes 0.2 ml of 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl 2 , 19 mM NH 4 CL 2 , 20 mM KCL, O.lmM NaAD, 0.3% n-octyl- ⁇ -D- glucopyranoside, 1% ethanol, 1 g/ml NAD synthetase, 62.5 ⁇ g/ml yeast alcohol dehydrogenase, 0.2 mM ATP and 2.5% DMSO.
  • the measurement of inhibitory activities of the test compounds was facilitated by the use of a high through-put screening system (HTS system).
  • HTS system utilizes an integrated Sagian 2M ORCA robotic system coordinating the functions of a Beckman Biomek 2000 liquid handler and a Molecular Devices SpectraMax Plus spectrophotometer.
  • the 2M ORCA robotic station is responsible for the movement of all hardware and the integration of multiple stations on the worksurface.
  • the Biomek 2000 is programmed to perform all phases of liquid dispensing and mixing.
  • the SpectraMax Plus spectrophotometer is equipped to monitor absorbance in a 96- well plate format.
  • the current assay is designed for a 96-well plate format and begins with the dispensing of 0.170 mL of reaction buffer containing 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl 2 , 19 mM NH 4 CL2, 20 mM KCL, 0.118 mM NaAD, 0.3% n-octyl- ⁇ -D- glucopyranoside, 1.18% ethanol, 1.18 ⁇ g/ml NAD synthetase (recombinant protein from B. subtilis; purified), and 73.75 ⁇ g/ml yeast alcohol dehydrogenase.
  • reaction buffer containing 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl 2 , 19 mM NH 4 CL2, 20 mM KCL, 0.118 mM NaAD, 0.3% n-octyl- ⁇ -D- glucopyranoside, 1.18% ethanol, 1.18 ⁇ g/ml NAD synth
  • the Biomek 2000 mixes these components utilizing a predefined mixing program.
  • the reaction is initiated by the addition of 0.025ml of a solution of 1.6 mM ATP dissolved in 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl 2 , 19 mM NILCL ⁇ 20 mM KCL, 2.5% DMSO, and 0.3% n-Octyl- ⁇ -D-Glucopyranoside.
  • the reaction is monitored by measuring the increase in absorbance at 340 nm (NADH).
  • the linear portion of the reaction is monitored for 180 sec.
  • the initial velocity is determined using Softmax Pro, the software supplied with the Molecular Devices SpectrMax Plus spectrophotometer.
  • test compounds were supplied as a stock solution with a concentration of 50mM dissolved in 100% dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • An initial screen was conducted on all compounds using a 2 or 3 concentration screen.
  • the 2 panel screen used concentrations of 0.2mM and O.lmM for the compounds.
  • the 3 panel screen used concentrations of 0.2mM, O.lmM, and 0.05 mM. From the initial screen, compounds which indicated the greatest inhibitory capacity were then subjected to a wider screen of concentrations (O.lmM to 0.005mM).
  • the IC 50 values for each compound were determined graphically from a plot of % inhibition versus rate. Table 1.
  • Enzyme Inhibition Data for Selected Compounds Concentration of Test Compounds Producing 50% Inhibition (ICso) of the NAD Synthetase Enzyme Rate
  • Example 2 Determination of minimum inhibitory concentration (MIC) against yeast.
  • Candida albicans ATCC 10231
  • Candida tropicalis ATCC 28707- amphotericin B-resistant
  • Candida tropicalis ATCC 750
  • MIC minimum inhibitory concentration
  • Test compounds were prepared as 5 mg/mL stock solutions in 100% dimethyl sulfoxide. This was diluted 1:100 into 4 mL of diluted broth media for a starting concentration of 50 ⁇ g/mL. An additional 9 tubes were prepared with each containing 2 mL of the appropriate broth medium. Serial doubling dilutions were performed for each set of 10 tubes by transferring 2 mL of test material from the first tube to the second tube, mixing thoroughly, then transferring 2 mL to the next tube and mixing, until the tenth tube. From the tenth tube, 2 mL of mixture was discarded. Each tube is then inoculated with 0.01 mL of the yeast suspension in broth.
  • Tubes were incubated for 37 °C for 20 hours and then scored for visible growth or no visible growth.
  • the MIC is defined as the concentration of test compound ( ⁇ g/mL) that completely inhibits growth of yeast.
  • a positive control without test compound in broth containing 1% DMSO inoculated with 0.01 mL of the suspension in broth) and a sterility control (only broth containing 1% DMSO) were incubated and evaluated under the same conditions.
  • the MIC determinations and controls were performed in duplicate.
  • the MIC values reported in Table 2 are the mean of duplicate results.
  • IP intraperitoneal
  • LDso 50% lethality
  • mice Male CD-I mice (Charles River Labs) at age 4-6 weeks with a body weight of about 25 g were divided into groups of 5 mice each. Animals were fed with commecial diet and water ad lib. Each group of 5 mice received, intraperitoneally (IP), a single dosage of 0, 31.25, 62.5, 125, 250, 500, and 1,000 mg/kg compound. Test compounds were provided as 400 mg/mL stock solutions in 100% dimethyl sulfoxide (DMSO). An equivalent volume was injected into each animal. Animals were observed for 14 days following injection, and body weight was measured every other day. The LD50 was determined from a plot of death rate (%) versus log dose (mg/kg).
  • IP intraperitoneally
  • Test compounds were provided as 400 mg/mL stock solutions in 100% dimethyl sulfoxide (DMSO). An equivalent volume was injected into each animal. Animals were observed for 14 days following injection, and body weight was measured every other day. The LD50 was determined from a plot of death rate (%) versus log

Abstract

The present invention provides methods of treating or preventing fungal infections in a host comprising administering a treatment effective or treatment effective amount of a yeast NAD synthetase inhibitor compound. The invention further provides a method of killing yeast comprising administring a yeast NAD synthetase compound that selectively binds to catalytic sites in yeast whereby the yeast is killed.

Description

METHODS OF TREATING FUNGAL INFECTIONS WITH INHIBITORS OF NAD SYNTHETASE ENZYME
CROSS REFERENCE TO RELATED APPLICATIONS
This application is related to copending provisional application Serial No. 60/141,436, filed June 29, 1999, which is incorporated by reference, and claims the benefit of its earlier filing date under 35 USC Section 119(e).
FIELD OF THE INVENTION
The present invention relates to methods of treating fungal infections. More particularly, the present invention relates to methods of treating yeast infections with compounds that selectively target the NAD synthetase enzyme of yeast, with little or no attendant targeting of the NAD synthetase enzyme of the host.
BACKGROUND OF THE INVENTION
The incidence of serious fungal infections, either systemic or topical, continues to increase for plants, animals, and humans. Fungi are plant-like eukaryotes that grow in colonies of single cells, called yeasts, or in filamentous mutlicellular 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. approximately 10% of the population suffers from contagious skin and hair infections. While few healthy persons develop life-threatening systemic fungal infections, immunocompromised individuals, such as found in pregnancy, congenital thymic defects, or acquired immune deficiency syndrome (AIDS), can become seriously ill. This is further illustrated by the fact that fungal infections have become a major cause of death in organ transplant recipients and cancer patients.1 Numerous antifungal agents have been developed for topical use against nonsystemic fungal infections. However, the treatment of systemic fungal infections, particularly in immunocrompromised hosts, continues to be a major objective in infectious disease chemotherapy. The organisms most commonly implicated in systemic infections include Candida spp., Cryptococcus neoformans, and Aspergillus spp., although there are a number of emerging pathogens. The major classes of systemic drugs in use currently are the polyenes (e.g., amphotericin B) and the azoles (e.g., fluconazole). While somewhat effective in otherwise healthy patients, these agents are inadequate in severely immunocompromised individuals. Furthermore, drug resistance has become a serious problem, rendering these antifungal agents ineffective in some individuals.2'3
One reason for the limited number of systemic antifungal agents relates to the fact that, unlike bacteria, which are prokaryotes, yeast and molds are eukaryotes. Thus the biochemical make-up of yeast and molds more closely resembles eukaryotic human and animal cells. In general, this has made it difficult to develop antifungal drugs which selectively target in yeast an essential enzyme or biochemical pathway that has a close analog in humans and animals.
The ability to selectively inhibit the yeast form of a biochemical target with rriinimal effect on the mammalian form would provide a number of new approaches to the development of systemic antifungal drugs. In a few cases, this type of approach has already been proven to provide clinically useful systemic antifungal agents. For example, the mechanism of action for fluconazole, a widely used systemic antifungal drug, involves inhibition of a fungal C-14 demethylase, a cytochrome P450 enzyme that is essential for the production of the principal fungal sterol ergosterol. Ergosterol is very similar to the mammalian steroid cholesterol, and there is a closely related mammalian C-14 demethylase enzyme for which fluconazole is a much poorer inhibitor. This selectivity for inhibition of the fungal form of the enzyme over the mammalian form has resulted in the clinical utility of fluconazole.4 In a further example, preclinical studies on new antifungal agents that select for the yeast form over the mammalian form of a biochemical target include development of inhibitors for the plasma membrane ATPase5 and for topoisomerase I.6
The inventors herein previously were part of a group that developed a number of antibacterial and antimicrobial agents that were targeted to NAD synthetase, an essential enzyme found in nearly all prokaryotic and eukaryotic cells. This enzyme is essential for the biosynthesis of nicotinamide adenine dinucleotide (NAD4), an essential cofactor in numerous enzymatic reactions. NAD synthetase 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 nicotinic acid adenine dinucleotide (NaAD) in the presence of ATP and Mg . The overall reaction is illustrated in Scheme 1.
Scheme 1
Prokaryotic NAD synthetase is an ammonia-dependent amidotransferase that belongs to a family of "N-type" ATP pyrophosphatases; this family also includes asparagine synthetase and argininosuccinate synthetase. Unlike eukaryotic NAD synthetase found in yeast and mammals that can use glutamine as a source of nitrogen, the prokaryotic NAD synthetase of bacteria requires ammonia as the only nitrogen source. Furthermore, B. subtilis NAD synthetase, which was previously crystallized and used for drug design by the inventors, is a dimer with molecular weight around
65,000, while the yeast enzyme is multimeric and has at least 10 times larger molecular weight.8 These differences between eukaryotic and prokaryotic forms of NAD synthetase enzyme suggested that drugs specific for the prokaryotic enzyme could be designed, and the inventors subsequently developed inhibitors of this enzyme that are effective antibacterial and antimicrobial agents.9 Given these marked differences between prokaryotic and eukaryotic NAD synthetase, the inventors fully expected that the compounds would be selective for the prokaryotic NAD synthetase and would show little to no effect on eukaryotic NAD synthetase.
SUMMARY OF THE INVENTION
The present invention is based in part on the surprising discovery that NAD synthetase inhibitors are highly effective in inhibiting the growth of yeast, yet exhibited only moderate toxicity in animals. Thus, the present invention includes the use of NAD synthetase inhibitors as new antifungal agents for preventing or controlling parasitic yeast and mold infections in plants, and for the prophylactic or therapeutic treatment, topically and systemically, of fungal infections in humans and animals.
In a major aspect, the present invention provides a method of treating or preventing an antifungal infection in a host comprising administering to a host a treatment effective or treatment preventive amount of a yeast NAD synthetase enzyme inhibitor compound.
In a further aspect, the method of killing yeast with an amount of yeast NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the yeast is killed. In yet another aspect, the invention provides a method of decreasing yeast growth, comprising contacting the yeast with an amount of a yeast NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby yeast growth is decreased.
Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included herein.
Before the present methods, compounds, compositions and apparatuses are disclosed and described it is to be understood that this invention is not limited to the specific synthetic methods described herein. It is to be further understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.
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.
Throughout this application, where a chemical diagram has a straight line emanating from a chemical structure, such a line represents a CH3 group. For example, in the following diagram:
0-methyIbenzoic acid is represented.
The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. The term "cycloalkyl" intends a cyclic alkyl group of from three to eight, preferably five or six carbon atoms.
The term "alkoxy" as used herein 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.
The term "alkylene" as used herein refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-CH2-CH2-CH2-), 2-methylpropylene [-CH2-CH(CH3)-CH2-], hexylene [-(CH2)6-] and the like. The term "cycloalkylene" as used herein refers to a cyclic alkylene group, typically a 5- or 6-membered ring.
The term "alkene" as used herein intends a mono-unsaturated or di-unsaturated hydrocarbon group of 2 to 24 carbon atoms. Asymmetric structures such as (AB)C=C(CD) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present.
The term "alkynyl" as used herein refers to a branched or unbranched unsaturated hydrocarbon group of 1 to 24 carbon atoms wherein the group has at least one triple bond.
The term "cyclic" as used herein intends a structure that is characterized by one or more closed rings. As further used herein, the cyclic compounds discussed herein may be saturated or unsaturated and may be heterocychc. By heterocychc, 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.
The term "bicyclic" as used herein 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 heterocychc.
By the term "effective amount" of a compound as provided herein is meant a sufficient amount of the compound to provide the desired treatment or preventive effect. As will be pointed out below, 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.
By "pharmaceutically acceptable carrier" is meant 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.
As used herein, "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. As used herein, the term "catalytic sites" are defined as those portions of the NAD synthetase enzyme that bind to substrates, and cofactors, including nicotinic acid adenine dinucleotide (NaAD), NAD, adenosine triphosphate (ATP), adenosine monophosphate (AMP), pyrophosphate, magnesium and ammonia in yeast. The term "receptor site" or "receptor subsite" relates tp those portions of the yeast NAD synthetase enzyme in which the yeast NAD synthetase enzyme inhibitors disclosed herein are believed to bind. For the purposes of this disclosure, the terms "catalytic site," "receptor site" and "receptor subsite" may be used interchangeably.
In one embodiment, the invention provides administering an antifungal agent to a mammal in need of such treatment or prevention. In one embodiment, the fungal agent that causes the infection is yeast. In separate embodiments of the methods of administering, the antifungal agent comprises one or more compounds in Figure 1 below. In further separate preferred embodiments of the methods of administering, the antifungal agent comprises one or more of the compounds set forth in Figure 2 below. In still further separate embodiments, the compounds administered comprise one or more of the compounds of Structure 2, Structure 4, Structure 6, Structure 7, Structure 8, Structure 10, or Structure 12. In yet further separate embodiments of the methods of administering, the antifungal agent comprises one or more of the compounds denoted 1 to 1106 below.
Further provided by the invention herein is preferably a method of killing yeast with an amount of yeast NAD synthetase enzyme inhibitor compound to reduce or eliminate the production of NAD whereby the yeast is killed. 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. With respect to the method of killing yeast, as well as in the method of decreasing yeast growth, in separate embodiments of the methods the compound comprises one or more compounds of Figure 1 below. In further separate embodiments, the compound comprises one or more compounds of Figure 2 below. In a further embodiment, the compound administered is a compound of Structure 2, Structure 4, Structure 6, or Structure 7. In still further embodiments, the compounds administered comprise one or more of the compounds of Structure 8, Structure 10, or Structure 12. In yet further separate embodiments, the compounds administered comprise one or more compounds denoted 1-1106 below.
FIGURE 1: LEAD I COMPOUNDS
In yet a further embodiment, the compound comprises one or more compounds re 2 below ("Lead II Compounds"). FIGURE 2: LEAD II COMPOUNDS
174
745
769
832
884
886
887 889
894
906
909
921
917
924 936
939
941
942
970 972
975 976
977
981 982
983 984
985 986
988
990
1072
1090
In the above Figures 1 and 2, X" = F", Cl", Br", I", acetate, or any pharmaceutically acceptable anion.
In one embodiment, the methods of the invention comprise administering a compound having the general structure of Structure 2:
STRUCTURE 2:
wherein: n is an integer of from 1 to 12, Ri - R7 each, independently, is an H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group, and 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. By heteroatoms, it is meant that one or more atoms is an element other than carbon.
R1-R7 may also be one of the following groups: an H, alkyl, alkenyl, alknyl, or an aryl. R1-R7, may further be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. Note that n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. The tethered active molecule, e.g., in this example denoted "aryl," moieties may be the same or different.
In a further embodiment, the invention comprises administering a compound of Structure 4:
STRUCTURE 4:
DIMERS
wherein:
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, Rι-R7 each, independently, is an H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, and 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 R7 may also be one of the following groups: an H, alkyl, alkenyl, alkynyl, or an aryl group. R]-R7 may also be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. One of skill in the art would know what moieties are considered to constitute 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.
In a further embodiment, the methods of the invention comprise administering a compound of Structure 6:
STRUCTURE 6:
wherein:
X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and RrR7 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
Rι-R7 may also be one of the following groups: an H, alkyl, alkenyl, alknyl, or an aryl. Ri-R , may further be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. Note that n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. The tethered active molecule, e.g., in this example denoted "aryl," moieties may be the same or different.
In a further embodiment, the methods of the invention comprise administering a compound of Structure 7:
STRUCTURE 7
wherein:
X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and Rt-Re each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cychc or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
Ri-Rδ may also be one of the following groups: an H, alkyl, alkenyl, or alkynyl, or an aryl group. R Rβ may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen and the common derivatives of these groups. One of skill in the art would know what moieties are considered to constitute 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.
In a further embodiment, the methods of the invention comprise administering a compound of Structure 8:
STRUCTURE 8:
wherein: n is an integer of from 1 to 12, Ri is an H, methoxy, benzyloxy, or nitro and R2 is 3- pyridyl, N-methyl-3-pyridyl, 3-quinolinyl, N-methyl-3-quinolinyl, 3- (dimethylamino)phenyl, 3-(trimethylammonio)phenyl, 4-(dimethylamino)phenyl, 4- (trimethylammonio)phenyl, 4-(dimethylamino)phenylmethyl, or 4- (trimethylammonio)phenylmethyl.
N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. In a further embodiment, the methods of the invention comprise administering a compound of Structure 10:
STRUCTURE 10:
Y
wherein: n is an integer of from 1 to 12, Ri is an H, CO2H, -OCH3, or -OCH2PI1, R2 is H, CO2H, or CH=CHCO2H, R3 is H or CO2H, and Y is N-linked pyridine-3 -carboxylic acid, N- linked pyridine, N-linked quinoline, or N-linked isoquinoline. N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
In a further embodiment, the methods of the invention comprise administering a compound of Structure 12 :
STRUCTURE 12:
wherein: n is an integer of from 1 to 12, Ri is H, F, or NO2, R2 is H, CH3, CF3, NO2, phenyl, n- butyl, isopropyl, F, phenyloxy, triphenylmethyl, methoxycarbonyl, methoxy, carboxy, acetyl, or benzoyl, R is H or CF3 and Y is N-linked pyridine-3 -carboxylic acid, N- linked pyridine, N-linked quinoline, or N-linked isoquinoline. N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
In a further embodiment, the methods of the invention comprise administering a compound of Structure 14:
STRUCTURE 14:
wherein: n is an integer of from 1 to 12, Rj. is H, phenyloxy, isopropyl, acetyl, or benzoyl, R is H or CF3, and Y is 3-(dimethylamino)phenyl, 3-(trimelthylammonio)phenyl, 4- (dimethylamino)phenyl, 4-(trimethylammonio)phenyl, 2-(phenyl)phenyl, diphenylmethyl, 3-pyridyl, 4-pyridyl, or pyridine-3 -methyl. N may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
In further embodiments of the invention herein, the invention comprises administering compounds of the structures denoted in Tables 102-128 as Compounds 1-274 were synthesized utilizing the methods disclosed previously in co-pending patent application PCT US99/00810.
For Compounds 1-274, structures denoted in Figure 6 as Fragments I-X each represent an active molecule, as defined previously herein, which can be included in the compounds of the present invention as further described in the respective Tables. In Fragments I-X of Figure 6, the point of attachment for the linker compound is at the nitrogen.
In the chemical structures that follow, and as intended for the compounds of this invention, the symbol or X" designates generally the presence of an anion. As contemplated by the present invention, the type of anion in the compounds of this invention is not critical. The compounds of this invention may be comprised of any such moieties known generally to one of skill in the art or that follow from the synthesis methods disclosed in co-pending patent application PCT US99/00810.
In separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to Structure 100:
Structure 100
wherein R' is as defined below in Figure 6:
IX X
FIGURE 6
and n is an integer of from 1 to 12. N may also be from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 100 and as further defined in Table 100. For those compounds that correspond to Structure 100, n may also be an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9.
STRUCTURE 100:
TABLE 100: SUBSTITUENT GROUPS FOR COMPOUNDS 1-24
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6 and n indicates the number of linker groups separating the two tethered active molecule groups in the compound.
As set out below in relation to Compounds 25 - 274, Fragments A - G are set out in Figure 8. The group denoted R in A-G of Figure 8 can be a benzyl group, a methyl group or a hydrogen. The point of attachment of the linker group to Fragments A-G is at the nitrogen group.
In one embodiment, the methods of the invention comprise administering a compound corresponding to compounds of Structure 101. For those compounds that correspond to Structure 101, n is an integer of from 1 to 12, more preferably from 3 to 10, more preferably from 5 to 9 and, still more preferably from 6 to 9. The point of attachment of the linker group for both RI and R' is at the respective nitrogen groups of each illustrated fragment.
Structure 101 wherein R' is:
IX
wherein RI is:
wherein the R group in Fragments A-G is a benzyl group, a methyl group or a hydrogen.
In one embodiment of the invention herein, the compounds may include the Fragments illustrated below in Figure 8.
FIGURE 8: FRAGMENTS A-G IN COMPOUNDS 25-274
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 102. For those compounds that correspond to Structure 102, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 102, as further set out in Table 102.
STRUCTURE 102:
TABLE 102: SUBSTITUENT GROUPS FOR COMPOUNDS 25-48
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, A corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and A in the respective compounds. Groups I, π, VII, VIE each have a benzyl group and Groups I*, in*, VII*, VTH* each have a hydrogen, respectively, in the position designated R in Fragment A of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 104. For those compounds that correspond to Structure 104, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 104, as further set out in Table 104.
STRUCTURE 104:
TABLE 104: SUBSTITUENT GROUPS FOR COMPOUNDS 49-66
In the above Table, R' corresponds to a Fragment as previously defined in
Figure 6, B corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and B in the respective compounds. Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment B of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 106. For those compounds that correspond to Structure 106, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 106, as further set out in Table 106. STRUCTURE 106:
TABLE 106: SUBSTITUENT GROUPS FOR COMPOUNDS 67-90
In the above Table, R' conesponds to a Fragment as previously defined in
Figure 6, C conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and C in the respective compounds. Groups I, II, VII, VIII each have a benzyl group and Groups I*, III*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment C of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 108. For those compounds that conespond to Structure 108, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 108, as further set out in Table 108.
STRUCTURE 108:
TABLE 108: SUBSTITUENT GROUPS FOR COMPOUNDS 91-108
In the above Table, R' conesponds to a Fragment as previously defined in Figure 6, D conesponds to a fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and D in the compound. Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment D of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 110. For those compounds that conespond to Structure 110, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 110, as further set out in Table 110.
STRUCTURE 110:
TABLE 110: SUBSTITUENT GROUPS FOR COMPOUNDS 109-126
In the above Table, R' conesponds to a Fragment as previously defined in Figure 6, E conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and E in the respective compounds. Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment E of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 112. For those compounds that correspond to Structure 112, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 112, as further set out in Table 112.
STRUCTURE 112:
TABLE 112: SUBSTITUENT GROUPS FOR COMPOUNDS 127-144
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, F conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and F in the respective compounds. Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment F of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 114. For those compounds that correspond to Structure 114, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 114, as further set out in Table 114.
STRUCTURE 114:
TABLE 114: SUBSTITUENT GROUPS FOR COMPOUNDS 145-162
In the above Table, R' conesponds to a Fragment as previously defined in Figure 6, G corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and G in the respective compounds. Groups I, VII, VIII each have a benzyl group and Groups I*, VII*, VIII* each have a hydrogen, respectively, in the position designated R in Fragment G of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 116. For those compounds that conespond to Structure 116, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 116, as further set out in Table 116.
STRUCTURE 116:
TABLE 116: SUBSTITUENT GROUPS FOR COMPOUNDS 163-178
In the above Table, R' conesponds to a Fragment as previously defined in Figure 6, A corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and A in the respective compounds. Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment A of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 118. For those compounds that conespond to Structure 118, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 118, as further set out in Table 118. STRUCTURE 118:
In the above Table, R' corresponds to a Fragment as previously defined in
Figure 6, B conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and B in the respective compounds. Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment B of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 120. For those compounds that correspond to Structure 120, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 120, as further set out in Table 120. STRUCTURE 120:
TABLE 120: SUBSTITUENT GROUPS FOR COMPOUNDS 195-210
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, C conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and C in the respective compounds. Groups I, II each have a methyl group and Groups I*, II* each have a hydrogen, respectively, in the position designated R in Fragment C of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding n Structure 122. For those compounds that conespond to Structure 122, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 122, as further set out in Table 122. STRUCTURE 122:
TABLE 122: SUBSTITUENT GROUPS FOR COMPOUNDS 211-226
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, D conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and D in the respective compounds. Groups I, II each have a methyl group and Groups I, III each have a hydrogen, respectively, in the position designated R in Fragment D of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 124. For those compounds that correspond to Structure 124, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 124, as further set out in Table 124. STRUCTURE 124:
TABLE 124: SUBSTITUENT GROUPS FOR COMPOUNDS 227-242
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, E corresponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and E in the respective compounds. Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment E of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 126. For those compounds that correspond to Structure 126, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 126, as further set out in Table 126. STRUCTURE 126:
TABLE 126: SUBSTITUENT GROUPS FOR COMPOUNDS 243-258
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, F conesponds to a Fragment as previously defined in Figure 8, and n indicates the number of linker groups separating Groups R' and F in the respective compounds. Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment F of Figure 8.
In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound conesponding to the structures set out in Structure 128. For those compounds that conespond to Structure 128, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein conespond to Structure 128, as further set out in Table 128. STRUCTURE 128:
TABLE 128: SUBSTITUENT GROUPS FOR COMPOUNDS 259-274
In the above Table, R' corresponds to a Fragment as previously defined in Figure 6, G conesponds to a Fragment as previously defined in Figure 6, and n indicates the number of linker groups separating Groups R' and G in the respective compounds. Groups I, II each have a methyl group and Groups I*, III* each have a hydrogen, respectively, in the position designated R in Fragment G of Figure 8.
As used herein, the following terms are defined as follows: Ph: phenyl; I- propyl= isopropyl; OPh =O-Phenyl; and
In further embodiments, the compounds administered in the methods of the present invention conespond to compounds of the Structure 130 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds conesponding to Structure 130 are set out in Table 130. STRUCTURE 130:
TABLE 130: COMPOUNDS CORRESPONDING TO STRUCTURE 130
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 132 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 5-H, 6-CF3; 5-CH3, 5,7-diF, 5,7-diNO2, 5-Butyl, 5- iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF3, 5-COCH3, 5-OCH3, 5- COOCH3 or 5-COOH.
Further embodiments of the compounds corresponding to Structure 132 are set out in Table 132.
STRUCTURE 132:
TABLE 132: COMPOUNDS 282-389 CORRESPONDING TO STRUCTURE 132
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 134 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF3, 5-CH3, 5,7-diF, 5,7-diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF3, 5-COCH3, 5-OCH3, 5- COOCH3, or 5-COOH. Further embodiments of the compounds corresponding to Structure 134 are set out in Table 134. STRUCTURE 134:
TABLE 134: COMPOUNDS 390-497 CORRESPONDING TO STRUCTURE 134
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 136 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF3, 5-CH3, 5,7-diF, 5,7-diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF3, 5-COCH3, 5-OCH3, 5- COOCH3, or 5-COOH. Further embodiments of the compounds corresponding to Structure 136 are set out in Table 136.
STRUCTURE 136:
TABLE 136: COMPOUNDS 498-605 CORRESPONDING TO STRUCTURE 136
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 138 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF3, 5-OPh, 5-iPropyl, 5-COCH3, or 5-COPh and Y is 3-N,N-dimethylarninophenyl (3-N,N-diCH3), 4-N,N-dimethylaminophenyl (4-N,N- diCH3), or 2-Ph. Further embodiments of the compounds corresponding to Structure 138 are set out in Table 138. STRUCTURE 138:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 140 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF3, 5-OPh, 5-iPropyl, 5-COCH3 or 5-COPh, and Z is CH(Ph)2 or 3-Pyridyl. Further embodiments of the compounds corresponding to Structure 140 are set out in Table 140.
STRUCTURE 140:
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 142 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF3, 5-OPh, 5-iPropyl, 5-COCH3, or 5-COPh. Further embodiments of the compounds corresponding to Structure 142 are set out in Table 142. STRUCTURE 142:
TABLE 142: COMPOUNDS 681-695 CORRESPONDING TO STRUCTURE 142
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 144 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF3, 5-OPh, 5-iPropyl, 5-COCH3, or 5-COPh. Further embodiments of the compounds corresponding to Structure 144 are set out in Table 144.
STRUCTURE 144:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 146 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 146 are set out in Table 146.
STRUCTURE 146:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 148, as further defined in Table 148. STRUCTURE 148:
TABLE 148: COMPOUND 715 CORRESPONDING TO STRUCTURE 148
715
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 150 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 150 are set out in Table 150.
STRUCTURE 150:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 152 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 152 are set out in Table 152.
STRUCTURE 152:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 154 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is CH(DiPh), 4-(N,N-dimethylamino)phenyl, CH2CH2-(3- pyridyl), or (2-phenyl)-phenyl. Further embodiments of the compounds corresponding to Structure 154 are set out in Table 154.
STRUCTURE 154:
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 156 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds conesponding to Structure 156 are set out in Table 156.
STRUCTURE 156:
TABLE 156: COMPOUNDS 730-739 CORRESPONDING TO STRUCTURE 156
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 158 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds corresponding to Structure 158 are set out in Table 158.
STRUCTURE 158:
TABLE 158: COMPOUNDS 740-749 CORRESPONDING TO STRUCTURE 158
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 160 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds corresponding to Structure 160 are set out in Table 160.
STRUCTURE 160:
TABLE 160: COMPOUNDS 750-759 CORRESPONDING TO STRUCTURE 160
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 162 wherein n is an mteger of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds corresponding to Structure 162 are set out in Table 162.
STRUCTURE 162:
TABLE 162: COMPOUNDS 760-769 CORRESPONDING TO STRUCTURE 162
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 164 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds conesponding to Structure 164 are set out in Table 164.
STRUCTURE 164:
TABLE 164: COMPOUNDS 770-779 CORRESPONDING TO STRUCTURE 164
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 166 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds corresponding to Structure 166 are set out in Table 166.
STRUCTURE 166:
TABLE 166: COMPOUNDS 780-789 CORRESPONDING TO STRUCTURE 166
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 168 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH2Ph. Further embodiments of the compounds corresponding to Structure 168 are set out in Table 168.
STRUCTURE 168:
TABLE 168: COMPOUNDS 790-799 CORRESPONDING TO STRUCTURE 168
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 170 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 or -OCH Ph. Further embodiments of the compounds corresponding to Structure 170 are set out in Table 170.
STRUCTURE 170:
TABLE 170: COMPOUNDS 800-809 CORRESPONDING TO STRUCTURE 170
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 172 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 and -OCH2 Ph. Further embodiments of the compounds corresponding to Structure 172 are set out in Table 172.
TABLE 172: COMPOUNDS 810-819 CORRESPONDING TO STRUCTURE 172
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 174 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH3 and -OCH2 Ph. Further embodiments of the compounds-corresponding to Structure 174 are set out in Table 174.
STRUCTURE 174:
TABLE 174: COMPOUNDS 820-829 CORRESPONDING TO STRUCTURE 174
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 176 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is 3 -quinoline, 3-(N,N-dimethylamino)phenyl, or 4-(N,N- dimethylamino)phenyl. Further embodiments of the compounds corresponding to Structure 176 are set out in Table 176. STRUCTURE 176:
TABLE 176: COMPOUNDS 830-847 CORRESPONDING TO STRUCTURE 176
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 178 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 178 are set out in Table
178.
STRUCTURE 178:
TABLE 178: COMPOUNDS 848-853 CORRESPONDING TO STRUCTURE 178
In further embodiments, the compounds aclrninistered according to the methods of the present invention conespond to compounds of the Structure 180 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 180 are set out in Table 180.
STRUCTURE 180:
TABLE 180: COMPOUNDS 854-860 CORRESPONDING TO STRUCTURE 180
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 182 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 182 are set out in Table 182.
STRUCTURE 182:
TABLE 182: COMPOUNDS 861-867 CORRESPONDING TO STRUCTURE 182
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 184 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5-COCH3 or 5-COPh. Further embodiments of the compounds corresponding to Structure 184 are set out in Table 184.
STRUCTURE 184:
TABLE 184: COMPOUNDS 868-882 CORRESPONDING TO STRUCTURE 184
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 186 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5-COCH3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 186 are set out in Table 186.
STRUCTURE 186:
TABLE 186: COMPOUNDS 883-897 CORRESPONDING TO STRUCTURE 186
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 188 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5-COCH3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 188 are set out in Table 188.
STRUCTURE 188:
TABLE 188: COMPOUNDS 898-912 CORRESPONDING TO STRUCTURE 188
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 190 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5-COCH3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 190 are set out in Table 190.
STRUCTURE 190:
TABLE 190: COMPOUNDS 913-927 CORRESPONDING TO STRUCTURE 190
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 192 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5-COCH3 or 5-COPh. Further embodiments of the compounds conesponding to Structure 192 are set out in Table 192.
STRUCTURE 192:
TABLE 192: COMPOUNDS 928-942 CORRESPONDING TO STRUCTURE 192
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 194 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and R1 is an H or -OCH2Ph and R2 is H or COOCH3. Further embodiments of the compounds corresponding to Structure 194 are set out in Table 194.
STRUCTURE 194:
TABLE 194: COMPOUNDS 943-954 CORRESPONDING TO STRUCTURE 194
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 196 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R1 is an H or a -OCH2Ph and R2 is H or COOCH3. Further embodiments of the compounds corresponding to Structure 196 are set out in Table 196.
STRUCTURE 196:
TABLE 196: COMPOUNDS 955-966 CORRESPONDING TO STRUCTURE 196
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 198 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R1 is an H or a -OCH2Ph and R2 is H, or COOCH3. Further embodiments of the compounds corresponding to Structure 198 are set out in Table 198. STRUCTURE 198:
TABLE 198: COMPOUNDS 967-978 CORRESPONDING TO STRUCTURE 198
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 200 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R1 is H or a -OCH2Ph and R2 is H or COOCH3. Further embodiments of the compounds conesponding to Structure 200 are set out in Table 200.
STRUCTURE 200:
TABLE 200: COMPOUNDS 979-990 CORRESPONDING TO STRUCTURE 200
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 202 A.
STRUCTURE 202A:
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 202 A wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is H; 4-NO2; 2-CONHPh; 2-NO2; 4-[l,(4'-acetylpiperazine)]; 2-COCH3; 3-OCOCH3; 3-OCH3; 4-COCH3; 3-OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3,[2'-butylbenzo(b)furan]}; 3-NO2; 4-[5'-(5'- phenylhydantoin)]; 2-CH=CHCOPh; 2-OCH3; 4-COPh; 4-CONH2; 3-COCH3; 4-OPh; 4-(N-Phthalimide); 3-(N-Morpholine); 2-(N-pyrrolidine); 2-(N-Morpholine); or 4- OCH2Ph. Further embodiments of the compounds conesponding to Structure 202 are set out in Table 202. TABLE 202: COMPOUNDS 991-1021 CORRESPONDING To STRUCTURE 202A
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 204A wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 4-NO2; 2-CONHPh; 2-NO2; 4-[l'(4,-acetylpiperazine)]; 2-COCH3; 3- OCOCH3; 3-OCH3; 4-COCH3; 3-OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4- CH=CHCOPh; 4-{CO-3,[2,-butylbenzo(b)furan]}; 3-NO2; 4-[5,-(5,-phenylhydantoin)]; 2-CH=CHCOPh; 2-OCH3; 4-COPh; 4-CONH2; 3-COCH3; 4-OPh; 4-(N-phthalimide); 3-( -morpholine); 2-(N-pynolidine); 2-(N-morpholine); or 4-OCH2Ph. Further embodiments of the compounds conesponding to Structure 204 are set out in Table 204.
STRUCTURE 204A:
TABLE 204: COMPOUNDS 1022-1048 CORRESPONDING TO STRUCTURE 204A
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 206 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is H; 4-NO2; 2-CONHPh; 2-NO2; 2-COCH3; 3-OCH3; 4-COCH3; 3-OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3'[2'- butylbenzo(b)furan]}; 3-NO2; 2-CH=CHCOPh; 2-OCH3; 4-COPh; 3-COCH3; 4-OPh; 4-(N-phthalimide); or 4-OCH2Ph. Further embodiments of the compounds corresponding to Structure 206 are set out in Table 206.
STRUCTURE 206:
TABLE 206: COMPOUNDS 1049-1068 CORRESPONDING To STRUCTURE 206
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 208 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 4-NO2; 2-CONHPh; 2-NO2; 2-COCH3; 3-OCH3; 4-COCH3; 3-OCOPh; 2- CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3*[2'- butylbenzo(b)furan]}; 3-NO2; 2-CH=CHCOPh; 2-OCH3; 4-COPh; 3-COCH3; 4-OPh; 4-(N-mhthalimide); 3-(N-morpholine); 2-(N-morpholine); or 4-OCH2Ph. Further embodiments of the compounds conesponding to Structure 208 are set out in Table 208.
STRUCTURE 208:
TABLE 208: COMPOUNDS 1073-1094 CORRESPONDING TO STRUCTURE 208
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 210 wherein R is NH2; NMe2; NMe3.I; NH2.HC1; NMe2.HCl . Further embodiments of the compounds corresponding to Structure 210 are set out in Table 210.
STRUCTURE 210:
TABLE 210: COMPOUNDS 1095-1099 CORRESPONDING TO STRUCTURES 210
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 212 wherein R' is PhCONH or Ph3C and R" is H or COOCH3 . Further embodiments of the compounds corresponding to Structure 212 are set out in Table 212.
STRUCTURE 212:
TABLE 212: COMPOUNDS 1100-1101 CORRESPONDING TO STRUCTURE 212
In further embodiments, the compounds administered according to the methods of the present invention conespond to compounds of the Structure 214 wherein R is 4- hydroxyphenyl or 3-hydroxy-4-methylphenyl. Further embodiments of the compounds corresponding to Structure 214 are set out in Table 214. STRUCTURE 214:
TABLE 214: COMPOUNDS 1102-1103 CORRESPONDING TO STRUCTURE 214
In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of Structure 216 wherein R' is PhCONH and and R" is H or COOCH3 and n= 7 or 8. Further preferred embodiments of the compounds corresponding to Structure 216 are set out in Table 216. STRUCTURE 216:
TABLE 216: COMPOUNDS 1104-1105 CORRESPONDING To STRUCTURE 216
Further embodiments of the invention include compounds having Structure 300:
R5
Structure 300
wherein 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, and R R5 each, independently, is an 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. R R2 may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group. The (CH2)n linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents and wherein the linker may also contain heteroatoms. The aryl group is an aromatic grouping which may contain one or more rings, and the quaternary nitrogen may be part of the ring (as, for example, in pyridines and quinolines) or outside the ring (as, for example, in anilines and aminonaphthalenes). The value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.
Specific examples include Structure 1300
1300
Yet another example of suitable compounds include those having Structure 400:
Structure 400
wherein 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 α-, β-, γ-, or δ-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; and R Rs each, independently, is an 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. R R2 may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group. The (CH2)n linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents, and wherein the linker may also contain heteroatoms. The value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. Specific examples include Structure 1230:
and Structure 1260:
In the method of killing yeast, as well as in the method of decreasing the growth of yeast, the NAD synthetase enzyme inhibitor 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. In such methods, it is particularly preferable that there is little or no inhibitory activity on the host cell. For example, when the method is utilized to inhibit yeast activity in a mammal, it is preferred that there is little or no attendant affect on the NAD synthetase activity of the host. In one embodiment, the host is a mammal. In a further embodiment, the host is a plant.
In the methods herein, 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. For administration to a cell of the subject in vivo, as well as for administration to the subject, 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. Depending on the intended mode of administration, 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, if used, 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. As used herein, "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. See e.g., U.S. Patent No. 3,610,795, which is incorporated by reference herein. These compounds can be present in a pharmaceutically acceptable carrier, which can also include a suitable adjuvant. By "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. When administered to a human or an animal subject, the yeast NAD synthetase enzyme inhibitor compounds of the invention 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 preferred 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. Further preferably, 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. Further, in some circumstances, it may be preferable to administer the compounds 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 admmistration 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.
If e vivo methods are employed, cells or tissues can be removed and maintained outside the sμbject'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.
EXAMPLES
The following examples are set forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compositions and methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g. , amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at room temperature, and pressure is at or near atmospheric.
EXAMPLE 1: NAD synthetase enzyme inhibition assay- Determination of test compound concentrations providing 50% inhibition (ICgfl) of the maximum enzyme rate.
The potential inhibitory activity of the synthetic compounds was determined by the use of a coupled enzymatic assay. The coupled assay involves two steps as summarized below.
Step l
Mg2+ + NH + + ATP NaAD ► NAD + AMP +PPi
NAD synthetase
Step 2
Ethanol .
NAD — ► NADH +Acetaldehyde + H
Alcohol Dehydrogenase
The final reaction mixture includes 0.2 ml of 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl2, 19 mM NH4CL2, 20 mM KCL, O.lmM NaAD, 0.3% n-octyl-α-D- glucopyranoside, 1% ethanol, 1 g/ml NAD synthetase, 62.5 ^g/ml yeast alcohol dehydrogenase, 0.2 mM ATP and 2.5% DMSO.
The measurement of inhibitory activities of the test compounds was facilitated by the use of a high through-put screening system (HTS system). The HTS system utilizes an integrated Sagian 2M ORCA robotic system coordinating the functions of a Beckman Biomek 2000 liquid handler and a Molecular Devices SpectraMax Plus spectrophotometer. The 2M ORCA robotic station is responsible for the movement of all hardware and the integration of multiple stations on the worksurface. The Biomek 2000 is programmed to perform all phases of liquid dispensing and mixing. The SpectraMax Plus spectrophotometer is equipped to monitor absorbance in a 96- well plate format.
The current assay is designed for a 96-well plate format and begins with the dispensing of 0.170 mL of reaction buffer containing 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl2, 19 mM NH4CL2, 20 mM KCL, 0.118 mM NaAD, 0.3% n-octyl-α-D- glucopyranoside, 1.18% ethanol, 1.18 μg/ml NAD synthetase (recombinant protein from B. subtilis; purified), and 73.75 μg/ml yeast alcohol dehydrogenase. Once the Biomek 2000 has completed this stage of the liquid handling, a 0.005ml volume of test compound in 100% DMSO or a 0.005ml of DMSO will be dispensed in the reaction well. The Biomek 2000 mixes these components utilizing a predefined mixing program. The reaction is initiated by the addition of 0.025ml of a solution of 1.6 mM ATP dissolved in 60 mM HEPPS buffer, pH 8.5, 10 mM MgCl2, 19 mM NILCL^ 20 mM KCL, 2.5% DMSO, and 0.3% n-Octyl-α-D-Glucopyranoside. The reaction is monitored by measuring the increase in absorbance at 340 nm (NADH). The linear portion of the reaction is monitored for 180 sec. The initial velocity is determined using Softmax Pro, the software supplied with the Molecular Devices SpectrMax Plus spectrophotometer.
The test compounds were supplied as a stock solution with a concentration of 50mM dissolved in 100% dimethyl sulfoxide (DMSO). An initial screen was conducted on all compounds using a 2 or 3 concentration screen. The 2 panel screen used concentrations of 0.2mM and O.lmM for the compounds. The 3 panel screen used concentrations of 0.2mM, O.lmM, and 0.05 mM. From the initial screen, compounds which indicated the greatest inhibitory capacity were then subjected to a wider screen of concentrations (O.lmM to 0.005mM). The IC50 values for each compound were determined graphically from a plot of % inhibition versus rate. Table 1. Enzyme Inhibition Data for Selected Compounds: Concentration of Test Compounds Producing 50% Inhibition (ICso) of the NAD Synthetase Enzyme Rate
Example 2: Determination of minimum inhibitory concentration (MIC) against yeast. Candida albicans (ATCC 10231), Candida tropicalis (ATCC 28707- amphotericin B-resistant) and Candida tropicalis (ATCC 750) from stock culture were subcultured on Sabouraud dextrose agar plates for 2 days at 37 °C in ambient air. At least 5 colonies from each of the cultures were inoculated into 3 mL of an approriate broth and thoroughly mixed. One-tenth mL of this suspension was transferred into 10 mL of the appropriate broth and incubated on a shaking incubator at 37 °C for 5-6 hours. Each suspension of the yeast was then adjusted with sterile saline to contain approximately 5xl08 CFU/mL. Test compounds (antifungal agents) were prepared as 5 mg/mL stock solutions in 100% dimethyl sulfoxide. This was diluted 1:100 into 4 mL of diluted broth media for a starting concentration of 50 μg/mL. An additional 9 tubes were prepared with each containing 2 mL of the appropriate broth medium. Serial doubling dilutions were performed for each set of 10 tubes by transferring 2 mL of test material from the first tube to the second tube, mixing thoroughly, then transferring 2 mL to the next tube and mixing, until the tenth tube. From the tenth tube, 2 mL of mixture was discarded. Each tube is then inoculated with 0.01 mL of the yeast suspension in broth. Tubes were incubated for 37 °C for 20 hours and then scored for visible growth or no visible growth. The MIC is defined as the concentration of test compound (μg/mL) that completely inhibits growth of yeast. A positive control (without test compound in broth containing 1% DMSO inoculated with 0.01 mL of the suspension in broth) and a sterility control (only broth containing 1% DMSO) were incubated and evaluated under the same conditions. The MIC determinations and controls were performed in duplicate. The MIC values reported in Table 2 are the mean of duplicate results.
Table 2. Minimum Inhibitory Concentration (MIC) Against Yeast
Example 3 In vivo toxicity: intraperitoneal (IP) dosage in mice resulting in 50% lethality (LDso).
Male CD-I mice (Charles River Labs) at age 4-6 weeks with a body weight of about 25 g were divided into groups of 5 mice each. Animals were fed with commecial diet and water ad lib. Each group of 5 mice received, intraperitoneally (IP), a single dosage of 0, 31.25, 62.5, 125, 250, 500, and 1,000 mg/kg compound. Test compounds were provided as 400 mg/mL stock solutions in 100% dimethyl sulfoxide (DMSO). An equivalent volume was injected into each animal. Animals were observed for 14 days following injection, and body weight was measured every other day. The LD50 was determined from a plot of death rate (%) versus log dose (mg/kg).
Table 3. In Vivo Toxicity for Selected Antifungal Compounds In Mice.
Example 4 - IN VITRO STUDY OF INHIBITION OF GROWTH AND LETHALITY AGAINST YEAST
STRUCTURES OF NAD SYNTHETASE INHIBITORS USED IN THE YEAST ASSAY
Compound Structure IC50 (μg/mL) for Inhibit, of NAD Synthetase
10
35
TABLE 4A - RESULTS FOR IN VITRO STUDY OF INHIBITION OF GROWTH AND LETHALITY AGAINST YEAST
TABLE 4B - Summary Of Minimum Lethal Concentration (MLC; μg/mL)
late Compound A B C D E F G H
1 1108 4 2 4 8 4 4 2 2
2 1174 8 4 8 16 32 32 16 16
3 1072 >32 16 >32 >32 >32 >32 >32 >32
4 1127 >32 >32 >32 >32 >32 >32 >32 >32
5 0270 2 2 8 8 1 2 2 2
6 1198 2 1 2 4 2 2 2 2
7 1264 1 1 2 2 1 2 4 4
8 1274 >32 16 >32 >32 >32 >32 >32 >32
9 1308 >32 8 >32 >32 >32 >32 >32 >32
10 0951 1 1 1 2 2 2 4 4
11 0409 1 0.5 1 1 2 2 2 2
12 1197 1 1 2 2 2 2 4 4
ISOLATE ORGANISM [
A ATCC 750 Candida tropicalis
B ATCC 28707 Candida tropicalis
C KJP-000531594 Candida albicans
D LH-000664533 Candida albicans
E JHC-BC9951635 Torulopsis glabrata
F ERH-BC9938274 Torulopsis glabrata
G DLB-1027594CNC Cryptococcus neoformans
H SLP-BC0012854 Cryptococcus neoformans
The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected without departing from the scope and spirit of the invention.
Throughout this application, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. References
1. E. G. Weinberg, "Antifungal Agents," in W. O. Foye, T. L. Lemke, and D.
A. Williams, Principles of Medicinal Chemistry, 4th edition, Williams and Jenkins, Media, PA, 1995, pp. 803-811.
2. N. H. Georgopapadakou, Curr. Opin. Microbiol, 1, 547-557 (1998).
3. (a) A. H. Groll and T. J. Walsh, Curr. Opin. Infect. Dis., 10, 449 (1997). (b) C. A. Kauffman and PI L. Carver, Drugs, 53, 539 (1997).
4. K. Richardson, "Fluconazole, an Orally Active Antifungal Agent," in C. R. Ganellin and S. M. Roberts, Medicinal Chemistry, 2" ed., Academic Press, San Diego, 1993.
5. (a) B. C. Monk and D. S. Perlin, Crit. Rev. Microbiol, 20, 209 (1994). (b)
B. C. Monk, A. B. Mason, T. B. Kardos, and D. S. Perlin, Acta Biochim. Pol, 42, 481 (1995). 6. (a) J. Fostel and D. Montgomery, Antimicro. Agents Chemother., 39, 586
(1995). (b) J. Fostel, D. Montgomery, and P. Lartey, FEMS Microbiol. Lett., 138, 105 (1996).
7. M. Rizzi, C. Nessi, A. Mattevi, A. Coda, M. Bolognesi, and A. Galizzi, The EMBO Journal, 15, 5125-5134 (1996). 8. C. K. Yu and L. S. Dietrich, J. Biol. Chem., 247, 4794-4802 (1972).
9. W. J. Brouillette et al., "Methods of Synthesizing and Screening Inhibitors of Bacterial NAD Synthetase Enzyme, Compounds Thereof, and Methods of Treating Bacterial and Microbial Infections with Inhibitors of Bacterial NAD Synthetase Enzyme," International Patent Application No. PCT/US99/00810, International Filing Date January 14, 1999.

Claims

WHAT IS CLAIMED IS:
1. A method of treating or preventing an antifungal infection in a host comprising administering to a host a treatment effective or treatment preventive amount of a yeast NAD synthetase enzyme inhibitor compound.
2. The method of Claim 1 wherein the compound administered is selected from the group consisting of: he method of Claim 1 wherein the compound admimstered is selected from the
13
174
group consisting of:
769
832
886
887 889
894
906
909
921
917
924 936
939
941
942
970 972
975 976
977
981 982
983 984
985 986
988
990
1090
. The method of Claim 1 wherein the compound administered has Structure 2:
Structure 2
wherein n is an integer of from 1 to 12, Ri - R7 each, independently, is an H, an unsubstituted or a substituted cyclic or aliphatic group, or a branched or an unbranched group, and 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.
5. The method of Claim 4 wherein n is an integer of from 3 to 10.
6. The method of Claim 4 wherein n is an integer of from 5 to 9.
7. The method of Claim 4 wherein n is an integer of from 6 to 9.
8. The method of Claim 4 wherein Ri - R7 each, independently, is an H, alkyl, alkenyl, alknyl, or an aryl group.
9. The method of Claim 4 wherein R1-R7, each, independently, is a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups.
10. The method of Claim 1 wherein the compound administered has Structure 4:
Structure 4
wherein 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, R R7 each, independently, is an H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, and 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.
11. The method of Claim 10 wherein n is an integer of from 3 to 10.
12. The method of Claim 10 wherein n is an integer of from 5 to 9.
13. The method of Claim 10 wherein n is an integer of from 6 to 9.
14. The method of Claim 10 wherein R]-R7 each, independently, is an H, alkyl, alkenyl, alkynyl, or an aryl group.
15. The method of Claim 10 wherein R1.-R-7 each, independently, is a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups.
16. The method of Claim 1 wherein the compound administered has Structure 6:
Structure 6
wherein X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and Ri-R7 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
17. The method of Claim 16 wherein n is an integer of from 3 to 10.
18. The method of Claim 16 wherein n is an integer of from 5 to 9.
19. The method of Claim 16 wherein n is an integer of from 6 to 9.
20. The method of Claim 16 wherein R R7 each, independently, is an H, alkyl, alkenyl, or alkynyl, or an aryl group.
21. The method of Claim 16 wherein R!-R7 each, independently, is an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen and the common derivatives of these groups.
2. The method of Claim 1 wherein the compound administered has Structure 7:
Structure 7
wherein X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and Rι-R6 each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.
23. The method of Claim 22 wherein n is an integer of from 3 to 10.
24. The method of Claim 22 wherein n is an integer of from 5 to 9.
25. The method of Claim 22 wherein n is an integer of from 6 to 9.
26. The method of Claim 22 wherein Ri-Rβ each, independently, is an H, alkyl, alkenyl, or alkynyl, or an aryl group.
27. The method of Claim 22 wherein Rι-R6 each, independently, is an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen and the common derivatives of these groups.
28. The method of Claim 1 wherein the compound administered has Structure 8:
R2
Structure 8
wherein n is an integer of from 1 to 12, Ri is an H, methoxy, benzyloxy, or nitro and R2 is 3-pyridyl, N-methyl-3-pyridyl, 3-quinolinyl, N-methyl-3-quinolinyl, 3- (dimethylamino)phenyl, 3-(trimethylammonio)phenyl, 4-(dimemylamino)phenyl, 4-(trimethylammonio)phenyl, 4-(dimemylamino)phenylmethyl, or 4- (trimethy lammonio)pheny lmethy 1.
29. The method of Claim 28 wherein n is an integer of from 3 to 10.
30. The method of Claim 28 wherein n is an integer of from 5 to 9.
31. The method of Claim 28 wherein n is an integer'of from 6 to 9.
32. The method of Claim 1 wherein the compound administered has Structure 10:
Structure 10
wherein n is an integer of from 1 to 12, Ri is an H, CO2H, -OCH3, or -OCH2PI1, R2 is H, CO2H, or CH=CHCO2H, R3 is H or CO2H, and Y is N-linked pyridine-3- carboxylic acid, N-linked pyridine, N-linked quinoline, or N-linked isoquinoline.
33. The method of Claim 32 wherein n is an integer of from 3 to 10.
34. The method of Claim 32 wherein n is an integer of from 5 to 9.
35. The method of Claim 32 wherein n is an integer of from 6 to 9.
36. The method of Claim 1 wherein the compound administered has Structure 12:
Structure 12
wherein n is an integer of from 1 to 12, Ri is H, F, or NO2, R2 is H, CH3, CF3, NO2, phenyl, n-butyl, isopropyl, F, phenyloxy, triphenylmethyl, methoxycarbonyl, methoxy, carboxy, acetyl, or benzoyl, R3 is H or CF3 and Y is N-linked pyridine-3 -carboxylic acid, N-hnked pyridine, N-linked quinoline, or N- linked isoquinoline.
37. The method of Claim 36 wherein n is an integer of from 3 to 10.
38. The method of Claim 36 wherein n is an integer of from 5 to 9.
39. The method of Claim 36 wherein n is an integer of from 6 to 9.
40. The method of Claim 1 wherein the compound administered has Structure 14:
Structure 14
wherein n is an integer of from 1 to 12, Rj is H, phenyloxy, isopropyl, acetyl, or benzoyl, R2 is H or CF3, and Y is 3-(dimethylamino)phenyl, 3- (trimelthylammomo)phenyl, 4-(dimethylamino)phenyl, 4- (trimethylammonio)phenyl, 2-(phenyl)phenyl, diphenyhnethyl, 3-pyridyl, 4- pyridyl, or pyridine-3 -methyl.
41. The method of Claim 40 wherein n is an integer of from 3 to 10.
42. The method of Claim 40 wherein n is an integer of from 5 to 9.
43. The method of Claim 40 wherein n is an integer of from 6 to 9.
44. The method of Claim 1 wherein the compound administered has Structure 100:
Structure 100
wherein R' is:
IX
and n is an integer of from 1 to 12.
45. The method of Claim 44 wherein n is an integer of from 3 to 10.
46. The method of Claim 44 wherein n is an integer of from 5 to 9.
47. The method of Claim 44 wherein n is an integer of from 6 to 9.
48. The method of Claim 1 wherein the compound administered has Structure 101 :
Structure 101 wherein R' is:
IX wherein RI is:
wherein the R group in Fragments A-G is a benzyl group, a methyl group or a hydrogen and wherein n is an integer of from 1 to 12.
49. The method of Claim 48 wherein n is an integer of from 3 to 10.
50. The method of Claim 48 wherein n is an integer of from 5 to 9.
51. The method of Claim 48 wherein n is an integer of from 6 to 9.
52. The method of Claim 1 wherein the compound administered has Structure 130:
Structure 130 wherein n is an integer of from 1 to 12.
53. The method of Claim 52 wherein n is an integer of from 3 to 10.
54. The method of Claim 52 wherein n is an integer of from 5 to 9.
55. The method of Claim 52 wherein n is an integer of from 6 to 9.
56. The method of Claim 1 wherein the compound administered has Structure 132:
Structure 132 wherein n is an integer of from 1 to 12 and R is 5-H, 6-CF3j 5-CH3, 5,7-diF, 5,7- diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5- CF3, 5-COCH3, 5-OCH3, 5-COOCH3 or 5-COOH.
57. The method of Claim 56 wherein n is an integer of from 3 to 10.
58. The method of Claim 56 wherein n is an integer of from 5 to 9.
59. The method of Claim 56 wherein n is an integer of from 6 to 9.
60. The method of Claim 1 wherein the compound administered has Structure 134:
TfO
Structure 134 wherein n is an integer of from 1 to 12 and R is 5-H, 6-CF3, 5-CH3, 5,7-diF, 5,7- diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5- CF3, 5-COCH3, 5-OCH3, 5-COOCH3, or 5-COOH.
61. The method of Claim 60 wherein n is an integer of from 3 to 10.
62. The method of Claim 60 wherein n is an integer of from 5 to 9.
63. The method of Claim 60 wherein n is an integer of from 6 to 9.
64. The method of Claim 1 wherein the compound administered has Structure 136:
Structure 136 wherein n is an integer of from 1 to 12 and R is 5-H, 6-CF , 5-CH3, 5,7-diF, 5,7- diNO2, 5-Butyl, 5-iPropyl, 5-Phenyl, 5-NO2, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5- CF3, 5-COCH3, 5-OCH3, 5-COOCH3, or 5-COOH.
65. The method of Claim 64 wherein n is an integer of from 3 to 10.
66. The method of Claim 64 wherein n is an integer of from 5 to 9.
67. The method of Claim 64 wherein n is an integer of from 6 to 9.
68. The method of Claim 1 wherein the compound administered has Structure 138:
Structure 138 wherein n is an integer of from 1 to 12 and R is 5-CF3, 5-OPh, 5-iPropyl, 5- COCH3, or 5-COPh and Y is 3-N,N-dimethylamino(phenyl), 4-N,N- dimethylamino(phenyl), or 2-Ph.
69. The method of Claim 68 wherein n is an integer of from 3 to 10.
70. The method of Claim 68 wherein n is an integer of from 5 to 9.
71. The method of Claim 68 wherein n is an integer of from 6 to 9.
72. The method of Claim 1 wherein the compound admimstered has Structure 140:
Structure 140 wherein n is an integer of from 1 to 12, R is 5-CF3, 5-OPh, 5-iPropyl, 5-COCH3 or 5-COPh, and Z is CH(Ph)2 or 3-Pyridyl.
73. The method of Claim 72 wherein n is an integer of from 3 to 10.
74. The method of Claim 72 wherein n is an integer of from 5 to 9.
75. The method of Claim 72 wherein n is an integer of from 6 to 9.
76. The method of Claim 1 wherein the compound administered has Structure 142:
Structure 142
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-iPropyl, 5- COCH3, or 5-COPh.
77. The method of Claim 76 wherein n is an integer of from 3 to 10.
78. The method of Claim 76 wherein n is an integer of from 5 to 9.
79. The method of Claim 76 wherein n is an integer of from 6 to 9.
80. The method of Claim 1 wherein the compound administered has Structure 144:
Structure 144
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-iPropyl, 5- COCH3, or 5-COPh.
81. The method of Claim 80 wherein n is an integer of from 3 to 10.
82. The method of Claim 80 wherein n is an integer of from 5 to 9.
83. The method of Claim 80 wherein n is an integer of from 6 to 9.
84. The method of Claim 1 wherein the compound administered has Structure 146:
Structure 146 wherein n is an integer of from 1 to 12.
85. The method of Claim 84 wherein n is an integer of from 3 to 10.
86. The method of Claim 84 wherein n is an integer of from 5 to 9.
87. The method of Claim 84 wherein n is an integer of from 6 to 9.
88. The method of Claim 1 wherein the compound admimstered has Structure 148:
Structure 148.
89. The method of Claim 1 wherein the compound admimstered has Structure 150:
Structure 150
wherein R is an integer of from 1 to 12.
90. The method of Claim 89 wherein n is an integer of from 3 to 10.
91. The method of Claim 89 wherein n is an integer of from 5 to 9.
92. The method of Claim 89 wherein n is an integer of from 6 to 9.
93. The method of Claim 1 wherein the compound administered has Structure 152:
Structure 152
wherein n is an integer of from 1 to 12.
94. The method of Claim 93 wherein n is an integer of from 3 to 10.
95. The method of Claim 93 wherein n is an integer of from 5 to 9.
96. The method of Claim 93 wherein n is an integer of from 6 to 9.
97. The method of Claim 1 wherein the compound administered has Structure 154:
Structure 154
wherein Z is CH(diPh), 4-(N,N-dimethylamino)phenyl, CH2CH2-(3-pyridyl), or (2-phenyl)-phenyl.
98. The method of Claim 1 wherein the compound administered has Structure 156:
Structure 156
wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
99. The method of Claim 98 wherein n is an integer of from 3 to 10.
100. The method of Claim 98 wherein n is an integer of from 5 to 9.
101. The method of Claim 98 wherein n is an integer of from 6 to 9.
102. The method of Claim 1 wherein the compound administered has Structure 158:
Structure 158
wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
103. The method of Claim 102 wherein n is an integer of from 3 to 10.
104. The method of Claim 102 wherein n is an integer of from 5 to 9.
105. The method of Claim 102 wherein n is an integer of from 6 to 9.
106. The method of Claim 1 wherein the compound administered has Structure 160:
Structure 160 wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
107. The method of Claim 106 wherein n is an integer of from 3 to 10.
108. The method of Claim 106 wherein n is an integer of from 5 to 9.
109. The method of Claim 106 wherein n is an integer of from 6 to 9.
110. The method of Claim 1 wherein the compound admimstered has Structure 162
Structure 162 wherein n is an integer of from 1 to 12 and R is -OCH or -OCH2Ph.
111. The method of Claim 110 wherein n is an integer of from 3 to 10.
112. The method of Claim 110 wherein n is an integer of from 5 to 9.
113. The method of Claim 110 wherein n is an integer of from 6 to 9.
114. The method of Claim 1 wherein the compound aciministered has Structure 164:
Structure 164
wherein n is an integer of from 1 to 12 and R is -OCH or -OCH2Ph.
115. The method of Claim 114 wherein n is an integer of from 3 to 10.
116. The method of Claim 114 wherein n is an integer of from 5 to 9.
117. The method of Claim 114 wherein n is an integer of from 6 to 9.
118. The method of Claim 1 wherein the compound has Structure 166:
Structure 166
wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
119. The method of Claim 118 wherein n is an integer of from 3 to 10.
120. The method of Claim 118 wherein n is an integer of from 5 to 9.
121. The method of Claim 118 wherein n is an integer of from 6 to 9.
122. The method of Claim 1 wherein the compound administered has Structure 168:
Structure 168
wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
123. The method of Claim 122 wherein n is an integer of from 3 to 10.
124. The method of Claim 122 wherein n is an integer of from 5 to 9.
125. The method of Claim 122 wherein n is an integer of from 6 to 9.
126. The method of Claim 1 wherein the compound administered has Structure 170:
Structure 170 wherein n is an integer of from 1 to 12 and R is -OCH or -OCH2PI1.
127. The method of Claim 126 wherein n is an integer of from 3 to 10.
128. The method of Claim 126 wherein n is an integer of from 5 to 9.
129. The method of Claim 126 wherein n is an integer of from 6 to 9.
130. The method of Claim 1 wherein the compound administered has Structure 172:
Structure 172
wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
131. The method of Claim 130 wherein n is an integer of from 3 to 10.
132. The method of Claim 130 wherein n is an integer of from 5 to 9.
133. The method of Claim 130 wherein n is an integer of from 6 to 9.
134. The method of Claim 1 wherein the compound admimstered has Structure 174:
Structure 174 wherein n is an integer of from 1 to 12 and R is -OCH3 or -OCH2Ph.
135. The method of Claim 135 wherein n is an integer of from 3 to 10.
136. The method of Claim 135 wherein n is an integer of from 5 to 9.
137. The method of Claim 135 wherein n is an integer of from 6 to 9.
138. The method of Claim 1 wherein the compound admimstered has Structure 176:
Structure 176 wherein n is an integer of from 1 to 12 and Z is 3-quinoline, 3-(N,N- dime ylamino)phenyl, or 4-(N,N-dimemylamino)phenyl.
139. The method of Claim 138 wherein n is an integer of from 3 to 10.
140. The method of Claim 138 wherein n is an integer of from 5 to 9.
141. The method of Claim 138 wherein n is an integer of from 6 to 9.
142. The method of Claim 1 wherein the compound administered has Structure 178:
Structure 178
wherein n is an integer of from 1 to 12.
143. The method of Claim 142 wherein n is an integer of from 3 to 10.
144. The method of Claim 142 wherein n is an integer of from 5 to 9.
145. The method of Claim 142 wherein n is an integer of from 6 to 9.
146. The method of Claim 1 wherein the compound admimstered has Structure 180:
Structure 180 wherein n is an integer of from 1 to 12.
147. The method of Claim 146 wherein n is an integer of from 3 to 10.
148. The method of Claim 146 wherein n is an integer of from 5 to 9.
149. The method of Claim 146 wherein n is an integer of from 6 to 9.
150. The method of Claim 1 wherein the compound administered has Structure 182:
Structure 182 wherein n is an integer of from 1 to 12.
151. The method of Claim 150 wherein n is an integer of from 3 to 10.
152. The method of Claim 150 wherein n is an integer of from 5 to 9.
153. The method of Claim 150 wherein n is an integer of from 6 to 9.
154. The method of Claim 1 wherein the compound admimstered has Structure 184:
Structure 184
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5- COCH3 or 5-COPh.
155. The method of Claim 154 wherein n is an integer of from 3 to 10.
156. The method of Claim 154 wherein n is an integer of from 5 to 9.
157. The method of Claim 154 wherein n is an integer of from 6 to 9.
158. The method of Claim 1 wherein the compound administered has Structure 186:
Structure 186
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5- COCH3 or 5-COPh.
159. The method of Claim 158 wherein n is an integer of from 3 to 10.
160. The method of Claim 158 wherein n is an integer of from 5 to 9.
161. The method of Claim 158 wherein n is an integer of from 6 to 9.
162. The method of Claim 1 wherein the compound admimstered has Structure 188:
Structure 188
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5- COCH3 or 5-COPh.
163. The method of Claim 162 wherein n is an integer of from 3 to 10.
164. The method of Claim 162 wherein n is an integer of from 5 to 9.
165. The method of Claim 162 wherein n is an integer of from 6 to 9.
166. The method of Claim 1 wherein the compound admimstered has Structure 190:
Structure 190
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5- COCH3 or 5-COPh.
167. The method of Claim 167 wherein n is an integer of from 3 to 10.
168. The method of Claim 167 wherein n is an integer of from 5 to 9.
169. The method of Claim 167 wherein n is an integer of from 6 to 9.
170. The method of Claim 1 wherein the compound admimstered has Structure 192:
Structure 192
wherein n is an integer of from 1 to 12 and R is 6-CF3, 5-OPh, 5-CH(CH3)2, 5- COCH3 or 5-COPh.
171. The method of Claim 170 wherein n is an integer of from 3 to 10.
172. The method of Claim 170 wherein n is an integer of from 5 to 9.
173. The method of Claim 170 wherein n is an integer of from 6 to 9.
174. The method of Claim 1 wherein the compound administered has Structure 194:
Structure 194
1 1 wherein n is an integer of from 1 to 12 and R is an H or -OCH2Ph and R is H or COOCH3.
175. The method of Claim 174 wherein n is an integer of from 3 to 10.
176. The method of Claim 174 wherein n is an integer of from 5 to 9.
177. The method of Claim 174 wherein n is an integer of from 6 to 9.
178. The method of Claim 1 wherein the compound administered has Structure 196:
Structure 196 wherein n is an integer of from 1 to 12 and R1 is H or -OCH2Ph and R2 is H or COOCH3.
179. The method of Claim 178 wherein n is an integer of from 2 to 12.
180. The method of Claim 178 wherein n is an integer of from 5 to 9.
181. The method of Claim 178 wherein n is an integer of from 6 to 9.
182. The method of Claim 1 wherein the compound admimstered has Structure 198:
Structure 198
wherein n is an integer of from 1 to 12, and R1 is H, -OCH2Ph, or OCPh3 and R2 is Hr COOCH3.
183. The method of Claim 182 wherein n is an integer of from 3 to 10.
184. The method of Claim 182 wherein n is an integer of from 5 to 9.
185. The method of Claim 182 wherein n is an integer of from 6 to 9.
186. The method of Claim 1 wherein the compound administered has Structure 200:
Structure 200
wherein n is an integer of from 1 to 12 and R1 is H or a -OCH2Ph and R2 is H or COOCH3.
187. The method of Claim 186 wherein n is an integer of from 3 to 10.
188. The method of Claim 186 wherein n is an integer of from 5 to 9.
189. The method of Claim 186 wherein n is an integer of from 6 to 9.
190. The method of Claim 1 wherein the compound administered has Structure 202 A:
structure 202A wherein n is an integer of from 1 to 12 and wherein R is H; 4-NO2; 2-CONHPh; 2-NO2; 4-[l,(4'-acetylpiperazine)]; 2-COCH3; 3-OCOCH3; 3-OCH3; 4-COCH3; 3- OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3'[2'- butylbenzo(b)furan]}; 3-NO2; 4-[5'-(5'-phenylhydantoin)]; 2-CH=CHCOPh; 2- OCH3; 4-COPh; 4-CONH2; 3-COCH3; 4-OPh; 4-(N-phthalimide); 3-(N- morphohne); 2-(N-pyrrolidine); 2-(N-morpholine); or 4-OCH2Ph.
191. The method of Claim 190 wherein n is an integer of from 3 to 10.
192. The method of Claim 190 wherein n is an integer of from 5 to 9.
193. The method of Claim 190 wherein n is an integer of from 6 to 9.
194. The method of Claim 1 wherein the compound administered has Structure 204A:
Structure 204A
wherein n is an integer of from 1 to 12 and wherein R is H; 4-NO2; 2-CONHPh; 2-NO2; 4-[l,(4'-acetylpiperazine)]; 2-COCH3; 3-OCOCH3; 3-OCH3; 4-COCH3; 3- OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3'[2'- butylbenzo(b)furan]}; 3-NO2; 4-[5'-(5'-phenylhydantoin)]; 2-CH=CHCOPh; 2- OCH3; 4-COPh; 4-CONH2; 3-COCH3; 4-OPh; 4-(N-phthalimide); 3-(N- morpholine); 2-(N-pyrrolidine); 2-(N-morpholine); or 4-OCH2Ph.
195. The method of Claim 194 wherein n is an integer of from 3 to 10.
196. The method of Claim 194 wherein n is an integer of from 5 to 9.
197. The method of Claim 194 wherein n is an integer of from 6 to 9.
198. The method of Claim 1 wherein the compound admimstered has Structure 206:
Structure 206
wherein n is an integer of from 1 to 12 and R is H; 4-NO2; 2-CONHPh; 2-NO2; 2- COCH3; 3-OCH3; 4-COCH3; 3-OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4- OCOPh; 4-CH=CHCOPh; 4-{CO-3'[2'-butylbenzo(b)furan]}; 3-NO2; 2- CH=CHCOPh; 2-OCH3; 4-COPh; 3-COCH3; 4-OPh; 4-(N-phthalimide); or 4- OCH2Ph.
199. The method of Claim 198 wherein n is an integer of from 3 to 10.
200. The method of Claim 198 wherein n is an integer of from 5 to 9.
201. The method of Claim 198 wherein n is an integer of from 6 to 9.
202. The method of Claim 1 wherein the compound administered has Structure 208:
Structure 208
wherein R is 4-NO2; 2-CONHPh; 2-NO2; 2-COCH3; 3-OCH3; 4-COCH3; 3- OCOPh; 2-CONH2; 4-CH=CHCOCH3; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-3*[2'- butylbenzo(b)furan]}; 3-NO2; 2-CH=CHCOPh; 2-OCH3; 4-COPh; 3-COCH3; 4- OPh; 4-(N-phthalimide); 3-(N-moφholine); 2-(N-morpholine); or 4-OCH2Ph. 203. The method of Claim 1 wherein the compound administered has Structure 210:
Structure 210
wherein R is NH2; NMe2; NMe3.I; NH2.HC1; NMe2 or HC1
204. The method of Claim 1 wherein the compound administered has Structure 212:
Structure 212 wherein R' is PhCONH or Ph3C and R" is H or COOCH3. 205. The method of Claim 1 wherein the compound admimstered has Structure 214:
Structure 214 wherein R is 4-hydroxyphenyl or 3-hydroxy-4-methylphenyl. 206. The method of Claim 1 wherein the compound administered has Structure 216:
Structure 216 wherein R' is PhCONH and R" is H or COOCH3 and n is an integer of from 7 to 8.
207. The method of Claim 1 wherein the host is a mammal.
208. The method of Claim 1 wherein the host is a plant.
209. The method of Claim 1 wherein the compound administered has little or no inhibitory effect on the NAD synthetase enzyme of the host.
210. The method of Claim 1 comprising oral, rectal, intramuscularly, intravenous, intravesicular or topical administration.
211. The method of Claim 1 wherein the compound is administered in a dosage of between about 0.1 to about 15g per day and wherein the dosage is admimstered from about 1 to about 4 times per day.
212. A method of killing yeast with an amount of yeast NAD synthetase enzyme inhibitor to reduce or eliminate the production of NAD whereby the yeast is killed.
213. A method of decreasing yeast growth, comprising contacting the yeast with an amount of a yeast NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby yeast growth is decreased.
214. The method of Claim 213 wherein the NAD synthetase enzyme inhibitor is a compound that selectively binds with one or more catalytic sites on a yeast NAD synthetase enzyme to reduce or eliminate the production of NAD by the yeast.
215. The method of Claim 1 wherein the compound administered has Structure 300:
R
Structure 300 146 wherein 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, and RΪ-RS each, independently, is an 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 while R R may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group, and the (CH2)„ linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents, and further wherein the linker may also contain heteroatoms while the aryl group is an aromatic grouping which may contain one or more rings.
216. The method of Claim 215 wherein n is an integer of from 3 to 10.
217. The method of Claim 215 wherein n is an integer of from 5 to 9.
218. The method of Claim 215 wherein n is an integer of from 6 to 9.
219. The method of Claim 1 wherein the compound administered has Structure 1300
1300
220. The method of Claim 1 wherein the compound administered has Structure 400:
Structure 400
wherein 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 α-, β-, γ-, or δ-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; and Ri-Rs each, independently, is an 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 wherein Rt-R2 may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group and the (CH2)„ linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkynyl substituents, and further wherein the linker may also contain heteroatoms.
221. The method of Claim 220 wherein n is an integer of from 3 to 10. 222. The method of Claim 220 wherein n is an integer of from 5 to 9. 223. The method of Claim 220 wherein n is an integer of from 6 to 9.
224. The method of Claim 1 wherein the compound administered has Structure 1230:
225. The method of Claim 1 wherein the compound admimstered has Structure 1260:
EP00943322A 1999-06-29 2000-06-29 Methods of treating fungal infections with inhibitors of nad synthetase enzyme Withdrawn EP1194135A2 (en)

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