Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • 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

Definitions

• amphotericin B (AmB) has served as the gold standard for treating systemic fungal infections.
• AmB has a broad spectrum of activity, is fungicidal, and is effective even against fungal strains that are resistant to multiple other agents.
• clinically significant microbial resistance has remained exceptionally rare while resistance to next generation antifungals has appeared within just a few years of their clinical introduction.
• AmB is also highly toxic. Deray, G, J
• R 1 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl; or the two instances of R 3 , together with the carbon to which they are attached, may form a substituted or unsubstituted 3- to 10-membered aliphatic or heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic; and
• R 3 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl,
• R 4 is secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, or guanidinyl;
• R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.
• An aspect of the invention is a compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:
• R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl; or R 1 and R 2 , together with the nitrogen to which they are attached, may form a substituted or unsubstituted 3- to 10-membered heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic;
• Amphotericin B is a polyene macrolide with a mycosamine appendage, the complete compoun having the following structure:
• a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof, thereby treating the fungal infection.
• Representative examples of alkoxycarbonyl include, but are not limited to, methoxy carbonyl, ethoxy carbonyl, and fert-butoxy carbonyl.
• alkyl means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
• Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
• alkylcarbonyloxy means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• aminoalkyl as used herein, means an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, also as defined herein.
• arylene is art-recognized, and, as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms of an aryl ring, as defined above.
• hydroxyalkyl means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
• Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hydroxyheptyl.
• nitro means a -N0 2 group.
• each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
• Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
• compositions of the invention may exist in particular geometric or stereoisomeric forms.
• polymers of the invention may also be optically active.
• the invention contemplates all such compounds, including cis- and trans-isomers, R- and ⁇ -enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
• Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
• substituents include, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, (heterocyclyl)alkyl, (cycloalkyl)alkyl, alkoxy, aryloxy, alkoxycarbonyl, alkoxysulfonyl, aryloxycarbonyl, aryloxysulfonyl, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylsulfonyl, arylsulfonyl,
• the invention provides a number of derivatives of AmB, including derivatives characterized by (i) certain modifications at CI 6; (ii) the combination of certain
• R 1 is hydrogen, halogen, hydroxyl, sulfhydryl, nitro, cyano, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, azido, aminoalkyl, and alkoxyl; or the two instances of R 3 , together with the carbon to which they are attached, may form a substituted or unsubstituted 3- to 10-membered aliphatic or heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic; and when X is -0-, R 1 is a substituted or unsubstituted 3- to 10-membered aliphatic or heterocyclic ring
• R d is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl; or, when -
• R 4 is secondary amino, tertiary amino, amido, azido, isonitrile, nitro, urea, isocyanate, carbamate, or guanidinyl;
• R 5 is selected from the group consisting of hydrogen, alkyl, and haloalkyl.
• X is -N(R 2 )-.
• -XR 1 is selected from the group consisting of - HCH 3 ,
• an aspect of the invention is a compound represented by Formula (III) or a pharmaceutically acceptable salt thereof:
• R 9 is hydrogen, halogen, hydroxyl, sulfhydryl, or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, carboxyl, acyl, acyloxy, amino, amido, aminoalkyl, and alkoxyl;
• R 4 is nitro. In certain embodiments, R 4 is urea
• R a is hydrogen or a substituted or unsubstituted group selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, aminoalkyl, and alkoxyl.
• R 5 is alkyl
• R 1 is a substituted or unsubstituted group selected from the group consisting of alkyl, alkenyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, amino, amido, and aminoalkyl.
• X is -N(R 2 )-.
• X is -N(R 2 )-, wherein R 2 is hydrogen.
• XR 1 is , R a and R d , together with the nitrogen to which they are attached, may form a substituted or unsubstituted 3- to 10-membered heterocyclic ring, wherein said ring is monocyclic, bicyclic, tricyclic, or spirocyclic.
• the -N(H)-C(0)-XR 1 moiety is replaced with -N(alkyl)-C(0)-XR 1 .
• the pharmaceutical composition is a lipid complex of the compound in aqueous suspension.
• the terms “treat” and “treating” refer to performing an intervention that results in (a) preventing a condition or disease from occurring in a subject that may be at risk of developing or predisposed to having the condition or disease but has not yet been diagnosed as having it; (b) inhibiting a condition or disease, e.g., slowing or arresting its development; or (c) relieving or ameliorating a condition or disease, e.g., causing regression of the condition or disease.
• the compound is administered orally.
• the compound is administered topically.
• the phrase "effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
• daily oral doses of active compounds will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or several administrations per day, will yield the desired results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
• polymers that could be used are poly-l,3-dioxolane and poly-l,3,6-tioxocane.
• the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
• the stomach the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
• One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine.
• the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
• compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added.
• Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• 5,284,656 granulocyte colony stimulating factor
• a method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569, issued Sep. 19, 1995 to Wong et al.
• Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
• Formulations suitable for use with a nebulizer will typically comprise compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution.
• the formulation may also include a buffer and a simple sugar (e.g., for compound of the invention stabilization and regulation of osmotic pressure).
• the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.
• a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
• the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
• the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
• the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
• the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527- 33 (1990), which is incorporated herein by reference.
• Step 1 A 1 L round-bottom flask was charged with 1-2 (Example 1 ; 1 1.36 g, ca. 9.8 mmol). Anhydrous THF (100 mL) was added and the suspension / solution was stirred at RT for 10 min. Methyl amine (40 mL, 2 M in THF, 80 mmol ) was then added and the mixture was stirred at RT for 12 h. More methyl amine (10 mL, 2 M in THF, 20 mmol) was added and the mixture was further stirred for 15 h until most of the starting material was consumed as determined by LCMS analysis (Method 1).
• Compound 2-AF was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with 2-morpholinoethanamine.
• 1H NMR 400 MHz, Methanol-d4+Pyr-d5): ⁇ 8.62 (s, 1 H) 6.18 - 6.52 (m, 14 H) 5.39 - 5.51 (m, 2 H) 4.86 (s, 1 H) 4.68 (br.
• Compound 2-BV was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with 3,3-difluorocyclobutanamine.
• Compound 2-CG was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with spiro[3.3]heptan-2-amine.
• Step 2 To a solution of compound 2 (500.00 mg, 1.94 mmol, 1.00 equiv.) in MeOH (2.00 mL) was added HCI/MeOH (1 M, 1.94 mL, 1.00 equiv.). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to give 380 mg of compound 3. The residue was alkalized by Ion-exchange resin and submitted to the next step without further purification.
• Step 1 H 4 C1 (3.28 g, 61.41 mmol, 3.00 equiv.) and NaN 3 (3.99 g, 61.41 mmol, 3.00 equiv.) were added to a solution of compound 1 (5.00 g, 20.47 mmol, 1.00 equiv.) in DMF (50.00 mL) and the resulting mixture was stirred at 100 °C for 15hrs. The reaction mixture was poured into H 2 0 (300 mL), and extracted with EtOAc (200 mL*3). Combined the organic phases were washed with brine (100 mL * 5), dried over Na 2 S0 4 , filtered.
• Compound 2-AT was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with (1 S,4S)-2-oxa-5-azabicyclo[2.2. ljheptane.
• Compound 2-CL was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with allyl piperidine-4-carboxylate.
• Compound 2-CT was synthesized in the manner similar to Compound 2-1 (Example 3) and 2-CL (Example 55), except piperazine was substituted with allyl-4- (aminomethyl)benzoate. Two peaks were isolated upon deprotection and prep-HPLC purification.
• Compound 2-AR was synthesized in the manner similar to Compound 2-1 (Example 3), except piperazine was substituted with 8-oxa-3-azabicyclo[3.2. ljoctane.
• diethyl ether provides a yellow precipitate, which is filtered off, washed with diethyl ether and purified to produce 5-C.
• the Fmoc protecting group is not cleaved from the substrate during the coupling reaction, it can be efficiently removed using l,5-diazabicyclo[4.3.0]non-5-ene (DBN) or piperidine in DMF, followed by reprecipitation by addition of the DMF mixture to a large volume of diethyl ether.
• DBN l,5-diazabicyclo[4.3.0]non-5-ene
• Step. 1 The mixture of compound (R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid (301.00 mg, 774.94 umol, 1.65 equiv.) and HOBt (126.92 mg, 939.32 umol, 2.00 equiv.) in DMF (0.6 mL) was prepared and cooled to 0 °C, DCC (145.36 mg, 704.49 umol, 142.5 luL, 1.50 equiv.) was added.
• DMF 0.6 mL
• Step 2 The mixture of intermediate 5-1 (247.00 mg, 181.27 ⁇ , 1.00 equiv.) in DMSO (3.00 mL) was added piperidine (154.35 mg, 1.81 ⁇ , 0.01 equiv.) at r.t. The mixture was stirred at r.t. for 0.2 hr. The mixture was filtered and purified by prep-HPLC (FA) to give 31.40 mg of Compound 5-DT as yellow solid.
• Example 66 except 2-AG (Example 25) was substituted with 2-BF (Example 4); and (R)- 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid with NN- dimethylglycine.
• Example 66 except 2-AG (Example 25) was substituted with 2-BF (Example 4) and (R)- 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid with fmoc- glycine.
• Example 66 except 2-AG (Example 25) was substituted with 2-BF (Example 4).
• Example 66 except 2-AG (Example 25) was substituted with 2-J (Example 8), and (R)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid with N- dimethylglycine.
• Example 66 except 2-AG (Example 25) was substituted with 2-J (Example 8), and (R)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-3-yl)propanoic acid with fmoc- glycine.
• C3 ' alkyl derivatives 6 are prepared according to the procedure defined by Paquet et al., Chem Eur J 14: 2465-81 (2008). Specifically, treatment of 2-BF (Example 4) with 1H- pyrazole-l-carboxamidine monohydrochloride (1 equiv.) and diisopropylethylamine (3 equiv.) in DMF at room temperature provides the guanidine compound 6-E. Analog 6-B is synthesized by treatment of 2-BF with N-(9-fluorenylmethoxycarbonyl)-3-aminopropanal (4 equiv.) and NaBH 3 CN (4 equiv.) in DMF with catalytic HCl.
• Step 1 To a solution of (9H-fluoren-9-yl)methyl (3-oxopropyl)carbamate (775.45 mg, 2.63 mmol, 5.00 equiv.) and 2-BF (Example 4) (500.00 mg, 525.14 umol, 1.00 equiv.) in DMF (15.00 mL) was added NaBH(OAc) 3 (1.11 g, 5.25 mmol, 10.00 equiv.) at r.t. for 1.5 hours. The mixture was poured into MTBE (200 mL) and filtered to give the solution of 3 g of crude (Fmoc)2-6-QB which was used to next step directly.
• Example 76 except 2-BF (Example 4) was substituted with 2-CR (Example 51).
• Example 76 except 2-BF (Example 4) was substituted with 2-AF (Example 15).
• a high therapeutic index is preferable for a drug to have a favorable safety profile.
• therapeutic index refers to the ratio of the dose of drug that causes adverse effects at an
• each compound is tested in a hemolysis assay against red blood cells which determines the concentration of compound required to cause 90% lysis of human red blood cells ( ⁇ 90 ). Additionally, each compound is exposed to human primary renal tubule cells to determine the toxicity of each compound against kidney cells. These assays, when compared against the known or measured values of AmB against the same cells, demonstrate the improvement in therapeutic index of each compound as compared to AmB.
• Example 87 In Vivo Assessment of Biological Activity
• mice neutropenic mice are infected with C. albicans via the tail vein, and then 2 hours post infection the mice are treated with a single intraperitoneal injection of AmB or test agent. Then 2, 6, 12, and 24 hours post infection the mice are sacrificed, and the fungal burden present in their kidneys is quantified.

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