Classifications

• • 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

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