US20010016662A1 - Water-soluble prodrugs of azole compounds - Google Patents
Water-soluble prodrugs of azole compounds Download PDFInfo
- Publication number
- US20010016662A1 US20010016662A1 US09/729,404 US72940400A US2001016662A1 US 20010016662 A1 US20010016662 A1 US 20010016662A1 US 72940400 A US72940400 A US 72940400A US 2001016662 A1 US2001016662 A1 US 2001016662A1
- Authority
- US
- United States
- Prior art keywords
- compound
- pharmaceutically acceptable
- formula
- compounds
- azole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 *.*I.*n1*cc(C(*)(C)OP(=O)(O)O)c1.*n1*cc(C(*)(C)OP(=O)(O)O)c1.*n1*cc(C(*)(C)OP(=O)(O)O[Y])c1 Chemical compound *.*I.*n1*cc(C(*)(C)OP(=O)(O)O)c1.*n1*cc(C(*)(C)OP(=O)(O)O)c1.*n1*cc(C(*)(C)OP(=O)(O)O[Y])c1 0.000 description 18
- KDQNMHFQTCAGIB-UHFFFAOYSA-N CC(=O)N1CCN(C2=CC=C(OCC3COC(CC(C)(C)C)(C4=CC=C(Cl)C=C4Cl)O3)C=C2)CC1.CC(C)(C)CC(OCC1=C(Cl)C=C(Cl)C=C1)C1=CC=C(Cl)C=C1Cl Chemical compound CC(=O)N1CCN(C2=CC=C(OCC3COC(CC(C)(C)C)(C4=CC=C(Cl)C=C4Cl)O3)C=C2)CC1.CC(C)(C)CC(OCC1=C(Cl)C=C(Cl)C=C1)C1=CC=C(Cl)C=C1Cl KDQNMHFQTCAGIB-UHFFFAOYSA-N 0.000 description 2
- OPAHEYNNJWPQPX-XLEXHMCLSA-N C[C@@H](C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=CC=C(F)C=C1F Chemical compound C[C@@H](C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=CC=C(F)C=C1F OPAHEYNNJWPQPX-XLEXHMCLSA-N 0.000 description 2
- RUEACSBUDJTKKO-UHFFFAOYSA-N C=NC1=CC=C(C2=CSC(C(C)C(O)(CN3C=N(COP(=O)(O)O)C=N3)C3=C(F)C=C(F)C=C3)=N2)C=C1.CC(C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=C(F)C=C(F)C=C1.CP(C)(=O)OCCl Chemical compound C=NC1=CC=C(C2=CSC(C(C)C(O)(CN3C=N(COP(=O)(O)O)C=N3)C3=C(F)C=C(F)C=C3)=N2)C=C1.CC(C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=C(F)C=C(F)C=C1.CP(C)(=O)OCCl RUEACSBUDJTKKO-UHFFFAOYSA-N 0.000 description 1
- CPUSYRXDACFCOP-UHFFFAOYSA-N CC(C)(C)CC(c(c(Cl)c1)ccc1Cl)OCc(ccc(Cl)c1)c1Cl Chemical compound CC(C)(C)CC(c(c(Cl)c1)ccc1Cl)OCc(ccc(Cl)c1)c1Cl CPUSYRXDACFCOP-UHFFFAOYSA-N 0.000 description 1
- OPAHEYNNJWPQPX-UHFFFAOYSA-N CC(C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=CC=C(F)C=C1F Chemical compound CC(C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(O)(CN1C=NC=N1)C1=CC=C(F)C=C1F OPAHEYNNJWPQPX-UHFFFAOYSA-N 0.000 description 1
- XEIXWNWXBNDUOI-SVBNVKNSSA-N CC1=CC(CC2=CN(CC(O)(C3=CC=C(F)C=C3F)[C@@H](C)C3=NC(C4=CC=C(C#N)C=C4)=CS3)N=C2)=CC(C)=C1OC(=O)C1CCCN1 Chemical compound CC1=CC(CC2=CN(CC(O)(C3=CC=C(F)C=C3F)[C@@H](C)C3=NC(C4=CC=C(C#N)C=C4)=CS3)N=C2)=CC(C)=C1OC(=O)C1CCCN1 XEIXWNWXBNDUOI-SVBNVKNSSA-N 0.000 description 1
- NCRUEJLJTUSWKT-YOJHGRMCSA-N CCC(C)N1N=CN(C2=CC=C(N3CCN(C4=CC=C(OC[C@@H]5CO[C@@](CN6C=N(COP(=O)(O)O)C=N6)(C6=CC=C(Cl)C=C6Cl)O5)C=C4)CC3)C=C2)C1=O Chemical compound CCC(C)N1N=CN(C2=CC=C(N3CCN(C4=CC=C(OC[C@@H]5CO[C@@](CN6C=N(COP(=O)(O)O)C=N6)(C6=CC=C(Cl)C=C6Cl)O5)C=C4)CC3)C=C2)C1=O NCRUEJLJTUSWKT-YOJHGRMCSA-N 0.000 description 1
- QBXVFMDTGHYTJM-UHFFFAOYSA-N CCC1(c(c(Cl)c2)ccc2Cl)OC(COc(cc2)ccc2N(CC2)CCN2C(C)=O)CO1 Chemical compound CCC1(c(c(Cl)c2)ccc2Cl)OC(COc(cc2)ccc2N(CC2)CCN2C(C)=O)CO1 QBXVFMDTGHYTJM-UHFFFAOYSA-N 0.000 description 1
- WXINNFXEPNDEPJ-UTTGIEMOSA-L C[C@@H](C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(CN1C=NC=N1)(OP(=O)(O[Na])O[Na])C1=CC=C(F)C=C1F Chemical compound C[C@@H](C1=NC(C2=CC=C(C#N)C=C2)=CS1)C(CN1C=NC=N1)(OP(=O)(O[Na])O[Na])C1=CC=C(F)C=C1F WXINNFXEPNDEPJ-UTTGIEMOSA-L 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N ClC1=CC=C(C(CN2C=CN=C2)OCC2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1 Chemical compound ClC1=CC=C(C(CN2C=CN=C2)OCC2=C(Cl)C=C(Cl)C=C2)C(Cl)=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
Definitions
- This invention relates to novel water-soluble azole compounds useful for the treatment of serious systemic fungal infections and suitable for both oral and, particularly, parenteral administration. More particularly, the invention relates to novel water-soluble prodrugs having the general formula
- R and R 1 are each independently hydrogen or (C 1 -C 6 )alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula
- X ⁇ is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
- WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula
- Q is the remainder of an azole compound of the formula
- Z is nitrogen or methine
- R 1 and R 2 are each independently hydrogen or —OY in which Y is an easily hydrolyzable ester
- R 3 and R 4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower-alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X ⁇ is a pharmaceutically acceptable anion.
- R 1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
- R 2 is a hydrogen atom or a lower alkyl group
- X is a nitrogen atom or a methine group
- n is 0 or 1.
- the present invention provides water-soluble azole antifungal agents of the formula
- R and R 1 are each independently hydrogen or (C 1 -C 6 )alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula
- X ⁇ is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
- the compounds of general formula IA, IB and IC function as “prodrugs” when administered in vivo, being converted to the biologically active parent azole in the presence of alkaline phosphatase.
- Preferred among the compounds of formula I are those wherein R and R 1 are both hydrogen.
- (C 1 -C 6 )alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, etc.
- An anion represented by X ⁇ is derived from a pharmaceutically acceptable organic or inorganic acid, e.g. inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrofluoric, hydrobromic, hydroiodic, etc. or aliphatic, aromatic or araliphatic organic acids such as acetic, propionic, methanesulfonic, benzenesulfonic, maleic, citric, succinic, fumaric, mandelic, ascorbic, lactic, gluconic, toluenesulfonic, trifluoromethanesulfonic, trifluoroacetic, etc.
- organic or inorganic acid e.g. inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrofluoric, hydrobromic, hydroiodic, etc. or aliphatic, aromatic or araliphatic organic acids such as acetic, propionic, methanesulfonic, benzenesulfonic
- the “Y” substituent shown in structure IC above is a pharmaceutically acceptable cation such as ammonium, an alkali metal (e.g. Na, K, Li, etc.), an alkaline earth metal (e.g. Ca, Mg) or salts with suitable organic bases such as (lower) alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted (lower) alkylamines, e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with bases such as piperidine or morphiline.
- suitable organic bases such as (lower) alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted (lower) alkylamines, e.g. hydroxyl-substituted alkylamines such as diethanolamine, tri
- the compounds of the present invention can be solvated or non-solvated.
- a preferred solvate is a hydrate.
- Substituent “Z” in the azole ring may be nitrogen, e.g.
- the azole of formula II can be a wide variety of azole antifungal agents, including known azole antifungal agents such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, Sch-56592, Sch-51048, VR-9746, MFB-1041, VR-9751, T-8581, VR-9825, SSY-726, D-0870, KP-103, ER-30346, etc.
- known azole antifungal agents such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole,
- azole compounds are not limited to known antifungal agents and any azole compound of formula II possessing clinically useful antifungal activity is suitable for use in the present invention.
- the azoles having optical centers may be employed in the form of racemic mixtures or individual separated enantiomers.
- a preferred group of compounds I are those wherein Z is nitrogen and Q is
- Another preferred group of azole antifungal agents II for use in preparing compounds I are those wherein Z is CH and Q represents
- a preferred azole antifungal agent II is itraconazole.
- An especially preferred azole antifungal agent II is (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H,1,2,4-triazol-1-yl)-butan-2-ol described in U.S. Pat. No. 5,648,372 and having the structural formula
- R and R 1 are as defined above and Pr represents a hydroxyl protecting group such as t-butyl, benzyl or allyl in the presence or absence of an organic solvent such as tetrahydrofuran, acetonitrile or acetone at a temperature above about 75° C. to form
- the quaternization may be achieved in the absence or in the presence of other aprotic solvents such as dimethylformaldehyde, dimethylacetaldehyde and N-methylpyrrolidinone at an elevated temperature of above about 75° C.
- aprotic solvent such as dimethylformaldehyde, dimethylacetaldehyde and N-methylpyrrolidinone
- the solvent may be slowly evaporated with a stream of anhydrous nitrogen to form IV.
- the most preferred hydroxy protecting group is the t-butyl group, in which case, the t-butyl group is removed during the quaternization process.
- the preferred organic solvent is tetrahydrofuran and the preferred bath temperature range is from about 75° C. to 85° C.
- the so-obtained compound may be thereafter converted to a compound having a different anion X ⁇ , e.g. by anion exchange, or converted to a desirable pharmaceutically acceptable solvate, e.g. hydrate.
- Zwitterionic form IB may be prepared from salt form IA by use of column chromatography e.g. using reverse phase C 18 silica gel, eluting with acetonitrile-water, followed by crystallization from water.
- the compound in form IC may be prepared from the salt form IA by basification followed by column chromatography, e.g. using reverse phase C 18 silica gel, eluting with acetonitrile-water.
- the compounds of the present invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent.
- the compounds may be administered by a variety of means, for example, parenterally (intravenous or intramuscular injection), orally or topically.
- the pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions.
- Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents.
- the compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
- the compounds of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
- the compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans.
- the compounds of the present invention are useful for the treatment of systemic fungal infections caused, for example, by species of Candida such as Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus , Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces, for the treatment of mucosal infections caused by Candida albicans , and for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Trichophyton, Microsporum, or Epidermophyton.
- a method of treating a fungal infection which comprises administering a therapeutically effective amount of a compound of the present invention to a host, particularly a mammalian host and most particularly a human patient.
- a host particularly a mammalian host and most particularly a human patient.
- the use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of fungal infections are also provided.
- the dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited, and such dosages are within the scope of this invention. Furthermore, administration of the compounds of the present inventions can be conducted in either single or divided doses.
- the in vitro evaluation of the antifungal activities of the compounds of the invention can be performed by determining the minimum inhibitory concentration (MIC).
- MIC is the concentration of test compound which inhibits the growth of the test microorganism.
- a series of agar plates, each having the test compound incorporated at a specific concentration is inoculated with a fungal strain and each plate is then incubated for 48 h at 37° C. The plates are examined for the presence or absence of fungal growth, and the relevant concentration is noted.
- Microorganisms which can be used in the test include Candida albicans, Asperigillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis , and Torulopsos galbrata . It should be recognized that, as prodrugs, some compounds of the invention may not be active in the in vitro test.
- the in vivo evaluation of compounds of the present invention can be carried out at a series of dose levels by intraperitoneal, subcutaneous or intravenous injection or by oral administration to mice which have been inoculated with a strain of fungus (e.g. Candida albicans ). Activity is determined by comparing the survival of the treated group of mice at different dosage levels after the death of an untreated group of mice. The dose level at which the test compound provides 50% protection against the lethal effect of the infection is noted.
- a strain of fungus e.g. Candida albicans
- the compounds of the present invention substantially increase the solubility of the parent triazole antifungal compound and also release the bioactive parent compound (i.e. function as a prodrug) in both rat and human liver homogenates (S 9 preparations).
- the sodium salt of the title compound was prepared as amorphous powder from the trifluoroacetate salt by basification with sodium hydroxide followed by column chromatography on reverse phase C 18 silica gel, eluting with acetonitrile-water.
- Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was prepared by mixing di-t-butyl phosphate (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and by lyophilizing to dryness, was placed together with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure.
Abstract
Water soluble prodrugs of azole antifungal agents are provided by quaternizing a nitrogen atom of the azole ring with a phosphonooxymethyl group.
Description
- 1. Field of the Invention
-
-
- possessing antifungal activity, X⊖ is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
- 2. Description of the Prior Art
-
- The utility of this class of compounds is limited by their low water-solubility. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.
-
-
-
- wherein
-
- possessing antifungal activity;
- Z is nitrogen or methine;
- R1 and R2 are each independently hydrogen or —OY in which Y is an easily hydrolyzable ester;
- R3 and R4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower-alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X⊖ is a pharmaceutically acceptable anion.
- Published PCT Application WO 98/43970 discloses quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compounds where one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an azole antifungal compound. Specifically disclosed are prodrugs wherein the nitrogen atom of the azole ring is quaternized by a group of the formula
- wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R2 is a hydrogen atom or a lower alkyl group; X is a nitrogen atom or a methine group; and n is 0 or 1.
-
-
- possessing antifungal activity, X⊖ is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
- The compounds of general formula IA, IB and IC function as “prodrugs” when administered in vivo, being converted to the biologically active parent azole in the presence of alkaline phosphatase.
- Preferred among the compounds of formula I are those wherein R and R1 are both hydrogen.
- As used herein “(C1-C6)alkyl” refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, etc.
- An anion represented by X⊖ is derived from a pharmaceutically acceptable organic or inorganic acid, e.g. inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrofluoric, hydrobromic, hydroiodic, etc. or aliphatic, aromatic or araliphatic organic acids such as acetic, propionic, methanesulfonic, benzenesulfonic, maleic, citric, succinic, fumaric, mandelic, ascorbic, lactic, gluconic, toluenesulfonic, trifluoromethanesulfonic, trifluoroacetic, etc. Such compounds are also referred to as “pharmaceutically acceptable salts.”
- The “Y” substituent shown in structure IC above is a pharmaceutically acceptable cation such as ammonium, an alkali metal (e.g. Na, K, Li, etc.), an alkaline earth metal (e.g. Ca, Mg) or salts with suitable organic bases such as (lower) alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted (lower) alkylamines, e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with bases such as piperidine or morphiline.
- The compounds of the present invention can be solvated or non-solvated. A preferred solvate is a hydrate.
-
-
- The azole of formula II can be a wide variety of azole antifungal agents, including known azole antifungal agents such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, Sch-56592, Sch-51048, VR-9746, MFB-1041, VR-9751, T-8581, VR-9825, SSY-726, D-0870, KP-103, ER-30346, etc. The azole compounds, however, are not limited to known antifungal agents and any azole compound of formula II possessing clinically useful antifungal activity is suitable for use in the present invention. The azoles having optical centers may be employed in the form of racemic mixtures or individual separated enantiomers.
-
-
- Compounds where R and R1 are both hydrogen are most preferred in the above-mentioned two groups.
- A preferred azole antifungal agent II is itraconazole.
-
- Compounds I prepared from this azole, especially the compounds where R and R1 are both hydrogen, exhibit much improved aqueous solubility (>1 mg/ml) over the parent triazole which enables them to be useful for parenteral administration as well as oral administration. Also, these compounds are stable in solution, can be isolated in crystalline form and are readily converted to parent drug in vivo.
-
-
-
- in which Q, Z, X⊖, R, R1 and Pr are as defined above, followed by removal of the hydroxyl protecting groups to give compound IA.
- The quaternization may be achieved in the absence or in the presence of other aprotic solvents such as dimethylformaldehyde, dimethylacetaldehyde and N-methylpyrrolidinone at an elevated temperature of above about 75° C. When a separate solvent is employed the solvent may be slowly evaporated with a stream of anhydrous nitrogen to form IV.
- The most preferred hydroxy protecting group is the t-butyl group, in which case, the t-butyl group is removed during the quaternization process.
- The preferred organic solvent is tetrahydrofuran and the preferred bath temperature range is from about 75° C. to 85° C.
- The so-obtained compound may be thereafter converted to a compound having a different anion X⊖, e.g. by anion exchange, or converted to a desirable pharmaceutically acceptable solvate, e.g. hydrate.
- Zwitterionic form IB may be prepared from salt form IA by use of column chromatography e.g. using reverse phase C18 silica gel, eluting with acetonitrile-water, followed by crystallization from water.
- The compound in form IC may be prepared from the salt form IA by basification followed by column chromatography, e.g. using reverse phase C18 silica gel, eluting with acetonitrile-water.
- The compounds of the present invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent. The compounds may be administered by a variety of means, for example, parenterally (intravenous or intramuscular injection), orally or topically. The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
- Alternatively, the compounds of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
- The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. Specifically, the compounds of the present invention are useful for the treatment of systemic fungal infections caused, for example, by species of Candida such asCandida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces, for the treatment of mucosal infections caused by Candida albicans, and for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Trichophyton, Microsporum, or Epidermophyton.
- Thus, according to another aspect of the invention, there is provided a method of treating a fungal infection which comprises administering a therapeutically effective amount of a compound of the present invention to a host, particularly a mammalian host and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of fungal infections are also provided.
- The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited, and such dosages are within the scope of this invention. Furthermore, administration of the compounds of the present inventions can be conducted in either single or divided doses.
- The in vitro evaluation of the antifungal activities of the compounds of the invention can be performed by determining the minimum inhibitory concentration (MIC). The MIC is the concentration of test compound which inhibits the growth of the test microorganism. In practice, a series of agar plates, each having the test compound incorporated at a specific concentration, is inoculated with a fungal strain and each plate is then incubated for 48 h at 37° C. The plates are examined for the presence or absence of fungal growth, and the relevant concentration is noted. Microorganisms which can be used in the test includeCandida albicans, Asperigillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis, and Torulopsos galbrata. It should be recognized that, as prodrugs, some compounds of the invention may not be active in the in vitro test.
- The in vivo evaluation of compounds of the present invention can be carried out at a series of dose levels by intraperitoneal, subcutaneous or intravenous injection or by oral administration to mice which have been inoculated with a strain of fungus (e.g.Candida albicans). Activity is determined by comparing the survival of the treated group of mice at different dosage levels after the death of an untreated group of mice. The dose level at which the test compound provides 50% protection against the lethal effect of the infection is noted.
- The compounds of the present invention substantially increase the solubility of the parent triazole antifungal compound and also release the bioactive parent compound (i.e. function as a prodrug) in both rat and human liver homogenates (S 9 preparations).
- The following examples illustrate the invention, but are not intended as a limitation thereof.
- In the examples, all temperatures are given in degrees Centigrade. Melting points were determined on an electrothermal apparatus and are not corrected. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker DPX-300, AM-300, DRX-500, AM-500 or a Varian Gemini 300 spectrometer. Fluorine nuclear magnetic resonance (19F NMR) spectra were recorded on a Bruker DPX-300 spectrometer using trifluoroacetic acid as an external reference (δ-76.0 ppm). All spectra were determined in CDCl3, DMSO-d6, CD3OD, or D2O unless otherwise indicated. Chemical shifts are reported in 8 units relative to tetramethylsilane (TMS) or a reference solvent peak and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt, doublet of triplets; and app d, apparent doublet, etc. Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron spray ionization (ESI).
-
- To a suspension of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 1 (2.17 g, 5 mmol) in THF (5 mL) was added di-tert-butyl chloromethyl phosphate 2 (2.58 g, 10 mmol). The mixture was heated at 75° C. in an oil bath with stirring under stream of anhydrous nitrogen. The THF was slowly evaporated during 5-6 hrs period. After 18 hrs, the viscous reaction mixture was heated at 85° C. for another 20 hrs. After cooling, this crude thick oil was dissolved in a minimum amount of 25% acetonitrile-water containing 10 mmol of trifluoroacetic acid (TFA) and chromatographed on reverse phase C18 silica using 25% acetonitrile-water containing 0.1% TFA as an eluent. The concentration of acetonitrile was raised up to 35% as the chromatography progressed. Pure fractions were concentrated, frozen and lyophilized to give the title compound 3 (1.4 g, 2.12 mmol, 42% yield) as a white fluffy powder: 1H NMR (DMSO-d6): δ 10.12 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 8.20 (d, 2H, J=9), 7.93 (d, 2H, J=9), 7.36-7.25 (m, 2H), 7.01-6.94 (m, 1H), 5.93-5.72 (m, 2H), 5.04 (d, 1H, J=14), 4.77 (d, 1H, J=14), 4.01 (q, 1H, J=7), 1.16 (d, 3H, J=7); MS (MH+=548); 19F NMR (DMSO-d6): d -74.55 (s, 4F), -107.5 (s, 1F), -111.1 (s, 1F); Anal. Calcd for C23H20F2N5O5SP/1.5CF3CO2H/0.5H2O: C 42.92, H 3.12, N 9.63, F 16.97, H2O 1.30. Found: C 43.38, H3.13, N 9.60, F 17.21, H2O 1.12 (Karl Fischer Method).
- The zwitterionic form of the title compound was prepared as white crystals from the trifluoroacetate salt by column chromatography on reverse phase C18 silica gel, eluting with 30% acetonitrile-water as an eluent, followed by crystallization from water: mp 145-155° C.; 1H NMR (DMSO-d6): δ 10.21 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 8.17 (d, 2H, J=9), 7.90 (d, 2H, J=9), 7.38-7.25 (m, 2H), 6.97-6.91 (m, 1H), 5.76-5.60 (m, 2H), 5.00 (d, 1H, J=14), 4.75 (d, 1H, J=14), 4.04 (q, 1H, J=7), 1.16 (d, 3H, J=7); MS (MH+=548); 19F NMR (DMSO-d6): δ-73.87 (s, 0.1F), -107.5 (s, 1F), -111.3 (s, 1F); Anal. Calcd for C23H20F2N5O5SP/0.05CF3CO2H/0.4H2O: C 49.51, H 3.75, N 12.50, F 7.29, H2O 1.29. Found: C 49.39, H3.71, N 12.42, F 7.98, H2O 1.21 (Karl Fischer Method).
- The sodium salt of the title compound was prepared as amorphous powder from the trifluoroacetate salt by basification with sodium hydroxide followed by column chromatography on reverse phase C18 silica gel, eluting with acetonitrile-water.
- Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was prepared by mixing di-t-butyl phosphate (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and by lyophilizing to dryness, was placed together with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica and eluted with 2:1 hexanes-ethyl acetate. Appropriate fractions were concentrated to dryness to obtain the subtitle compound 2 (3.7 g, 71% yield):1H NMR (CDCl3) δ 5.63 (d, 2H, J=17), 1.51 (s, 18H); MS (MH+= 259).
-
- N-Phosphonooxymethyl itraconazole was prepared as trifluoroacetate salt in 32% yield by the method described for the preparation of 3 above from itraconazole (0.5 mmol) and di-tert-butyl chloromethyl phosphate 2 (2 mmol):1H NMR (DMSO-d6): δ 10.44 (s, 2/3H), 10.40 (s, ⅓H), 9.33 (s, ⅔H), 9.31 (s, ⅓H), 8.33 (s, 1H), 6.8-7.7 (m, 11H), 5.91 (d, 4/3H, J=14), 5.79 (d, ⅔H, J=14), 5.08-5.18 (m, 2H), 4.37 (m, 1H), 4.10 (m, 1H), 3.93 (m, 2H), 3.76 (m, 2H), 3.34 (br.s, 4H), 3.22 (m, 4H), 1.64-1.71 (m, 2H), 1.27 (d, 3H, J=7), 0.78 (t, 3H, J=7); MS (MH+=815); Anal. Calcd for C36H41Cl2N8O8P/1.6CF3CO2H/H2O: C 46.34, H 4.42, N 11.03, H2O 1.79. Found: C 46.03, H 4.46, N 11.08, H2O 1.64 (Karl Fischer Method).
Claims (11)
2. A compound of wherein R and R1 are both hydrogen.
claim 1
5. A compound of or wherein R and R1 are both hydrogen.
claim 3
claim 4
7. A compound of wherein R and R1 are both hydrogen.
claim 6
9. The compound, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H, 4-phosphonooxymethyl-1,2,4-triazol-1-yl)butan-2-ol, or a pharmaceutically acceptable salt thereof.
10. A method for the treatment of fungal infections, which comprises administering an effective antifungal amount of a compound of to a mammalian host in need thereof.
claim 1
11. A pharmaceutical composition comprising a compound of in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
claim 1
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/729,404 US20010016662A1 (en) | 1999-02-19 | 2000-12-04 | Water-soluble prodrugs of azole compounds |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12095499P | 1999-02-19 | 1999-02-19 | |
US12439799P | 1999-03-15 | 1999-03-15 | |
US09/503,616 US6235728B1 (en) | 1999-02-19 | 2000-02-11 | Water-soluble prodrugs of azole compounds |
US09/729,404 US20010016662A1 (en) | 1999-02-19 | 2000-12-04 | Water-soluble prodrugs of azole compounds |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/503,616 Division US6235728B1 (en) | 1999-02-19 | 2000-02-11 | Water-soluble prodrugs of azole compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US20010016662A1 true US20010016662A1 (en) | 2001-08-23 |
Family
ID=27382544
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/503,616 Expired - Lifetime US6235728B1 (en) | 1999-02-19 | 2000-02-11 | Water-soluble prodrugs of azole compounds |
US09/729,404 Abandoned US20010016662A1 (en) | 1999-02-19 | 2000-12-04 | Water-soluble prodrugs of azole compounds |
US09/729,409 Abandoned US20010014742A1 (en) | 1999-02-19 | 2000-12-04 | Water-soluble prodrugs of azole compounds |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/503,616 Expired - Lifetime US6235728B1 (en) | 1999-02-19 | 2000-02-11 | Water-soluble prodrugs of azole compounds |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/729,409 Abandoned US20010014742A1 (en) | 1999-02-19 | 2000-12-04 | Water-soluble prodrugs of azole compounds |
Country Status (1)
Country | Link |
---|---|
US (3) | US6235728B1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110016659A1 (en) * | 2009-07-24 | 2011-01-27 | Dyson Technology Limited | Surface treating appliance |
CN101282979B (en) * | 2005-09-13 | 2011-09-21 | 卫材R&D管理有限公司 | Composition containing chloromethyl phosphate derivative with improved stability and process for producing the same |
US8895545B2 (en) | 2006-07-20 | 2014-11-25 | Debiopharm International Sa | Acrylamide derivatives as Fab I inhibitors |
US8901105B2 (en) | 2012-06-19 | 2014-12-02 | Debiopharm International Sa | Prodrug derivatives of (E)-N-methyl-N-((3-M ethylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1669348A4 (en) * | 2003-09-30 | 2009-03-11 | Eisai R&D Man Co Ltd | Novel antifungal agent comprising heterocyclic compound |
WO2005115990A1 (en) * | 2004-05-26 | 2005-12-08 | Eisai R & D Management Co., Ltd. | Cinnamide compound |
US20090227799A1 (en) * | 2004-08-09 | 2009-09-10 | Kazutaka Nakamoto | Novel Antimalarial Agent Containing Heterocyclic Compound |
EP1808432B1 (en) * | 2004-10-26 | 2010-02-24 | Eisai R&D Management Co., Ltd. | Amorphous form of cinnamide compound |
EP1864980A4 (en) * | 2005-03-30 | 2010-08-18 | Eisai R&D Man Co Ltd | Antifungal agent containing pyridine derivative |
JO2691B1 (en) * | 2005-05-03 | 2013-03-03 | ايساي آر آند دي مانجمنت كو.، ليمتد | Mono-lysine salts of azole compounds |
TWI385169B (en) * | 2005-10-31 | 2013-02-11 | Eisai R&D Man Co Ltd | Heterocyclic substituted pyridine derivatives and antifungal agent containing same |
WO2007052479A1 (en) * | 2005-11-04 | 2007-05-10 | Ngk Insulators, Ltd. | Honeycomb structure and honeycomb catalyst |
JPWO2007058304A1 (en) * | 2005-11-18 | 2009-05-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Salts of cinamide compounds or solvates thereof |
AU2006316005A1 (en) * | 2005-11-18 | 2007-05-24 | Eisai R & D Management Co., Ltd. | Process for production of cinnamamide derivative |
TWI386207B (en) * | 2005-11-24 | 2013-02-21 | Eisai R&D Man Co Ltd | Morpholine type cinnamide compound |
TWI370130B (en) * | 2005-11-24 | 2012-08-11 | Eisai R&D Man Co Ltd | Two cyclic cinnamide compound |
US20070148240A1 (en) * | 2005-12-23 | 2007-06-28 | Fang-Yu Lee | Oral formulation containing itraconazole and methods for manufacturing and using the same |
TWI378091B (en) * | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
AR062095A1 (en) * | 2006-07-28 | 2008-10-15 | Eisai R&D Man Co Ltd | CINAMIDE COMPOUND PROFARMACO |
EP2065377B1 (en) * | 2006-09-21 | 2011-11-23 | Eisai R&D Management Co., Ltd. | Pyridine derivative substituted by heteroaryl ring, and antifungal agent comprising the same |
PE20081791A1 (en) * | 2007-02-28 | 2009-02-07 | Eisai Randd Man Co Ltd | TWO CYCLIC DERIVATIVES OF OXOMORPHOLIN |
US20100094001A1 (en) * | 2007-03-06 | 2010-04-15 | Eisai R&D Management Co., Ltd. | Composition containing stability-improved chloromethyl phosphate derivative and process for producing same |
TW200841879A (en) * | 2007-04-27 | 2008-11-01 | Eisai R&D Man Co Ltd | Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same |
CN101622251B (en) * | 2007-04-27 | 2012-07-04 | 卫材R&D管理有限公司 | Salt of heterocycle-substituted pyridine derivative or crystal thereof |
EP2147917A4 (en) * | 2007-05-16 | 2010-05-26 | Eisai R&D Man Co Ltd | One-pot production process for cinnamide derivative |
JP5433418B2 (en) | 2007-08-31 | 2014-03-05 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Polycyclic compound |
US7935815B2 (en) * | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
US8513287B2 (en) * | 2007-12-27 | 2013-08-20 | Eisai R&D Management Co., Ltd. | Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same |
JPWO2009096349A1 (en) * | 2008-01-28 | 2011-05-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Crystalline cinnamide compound or salt thereof |
US8188119B2 (en) * | 2008-10-24 | 2012-05-29 | Eisai R&D Management Co., Ltd | Pyridine derivatives substituted with heterocyclic ring and γ-glutamylamino group, and antifungal agents containing same |
JP2012176900A (en) * | 2009-06-24 | 2012-09-13 | Eisai R & D Management Co Ltd | Pyridin derivative containing ((phosphonooxy)methyl) pyridinium ring and anti-fungal agent containing these derivative |
WO2011009075A2 (en) * | 2009-07-17 | 2011-01-20 | Rigel Pharmaceuticals, Inc. | Deuterated 2, 4-pyrimidinediamine compounds and prodrugs thereof and their uses |
EP2558093A4 (en) * | 2010-04-08 | 2013-10-02 | Merck Sharp & Dohme | Prodrugs of an hiv reverse transcriptase inhibitor |
US9907812B2 (en) | 2011-06-22 | 2018-03-06 | Vyome Biosciences Pvt. Ltd. | Conjugate-based antifungal and antibacterial prodrugs |
MX2015016675A (en) | 2013-06-04 | 2016-07-15 | Vyome Biosciences Pvt Ltd | Coated particles and compositions comprising same. |
KR20170013854A (en) | 2014-01-29 | 2017-02-07 | 바이옴 바이오사이언스 피브이티. 엘티디. | Treatments for resistant acne |
CN105669573B (en) * | 2016-01-05 | 2018-02-23 | 中国人民解放军第二军医大学 | A kind of isopropylamine is for azole antifungal compound and its preparation method and application |
CN105503753B (en) * | 2016-01-05 | 2018-02-27 | 中国人民解放军第二军医大学 | A kind of allyl amine is for azole antifungal compound and its preparation method and application |
WO2018149359A1 (en) * | 2017-02-17 | 2018-08-23 | 武汉朗来科技发展有限公司 | Triazole antibacterial derivative and pharmaceutical composition and use thereof |
US20210346506A1 (en) * | 2020-05-07 | 2021-11-11 | Guibai Liang | Prodrug of itraconazole and uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2832233A1 (en) * | 1978-07-21 | 1980-01-31 | Bayer Ag | ALPHA -AZOLYL- BETA -HYDROXY-KETONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
DE3313719A1 (en) * | 1983-04-15 | 1984-10-18 | Bayer Ag, 5090 Leverkusen | PHOSPHORYLATED AZOLYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS FUNGICIDES |
NZ270418A (en) | 1994-02-07 | 1997-09-22 | Eisai Co Ltd | Polycyclic triazole & imidazole derivatives, antifungal compositions |
GB9602080D0 (en) | 1996-02-02 | 1996-04-03 | Pfizer Ltd | Pharmaceutical compounds |
EP0829478A3 (en) | 1996-09-09 | 1998-03-25 | F. Hoffmann-La Roche Ag | N-Benzylimidazolium and N-benzyltriazolium derivatives, their preparation and their use as antifungal and antimycotic agents |
KR20010005792A (en) | 1997-03-31 | 2001-01-15 | 다케다 야쿠힌 고교 가부시키가이샤 | Azole compounds, their production and their use |
EP1051181B1 (en) | 1997-12-31 | 2004-03-17 | The University Of Kansas | Water soluble prodrugs of tertiary amine containing drugs and methods of making thereof |
-
2000
- 2000-02-11 US US09/503,616 patent/US6235728B1/en not_active Expired - Lifetime
- 2000-12-04 US US09/729,404 patent/US20010016662A1/en not_active Abandoned
- 2000-12-04 US US09/729,409 patent/US20010014742A1/en not_active Abandoned
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101282979B (en) * | 2005-09-13 | 2011-09-21 | 卫材R&D管理有限公司 | Composition containing chloromethyl phosphate derivative with improved stability and process for producing the same |
US8895545B2 (en) | 2006-07-20 | 2014-11-25 | Debiopharm International Sa | Acrylamide derivatives as Fab I inhibitors |
US20110016659A1 (en) * | 2009-07-24 | 2011-01-27 | Dyson Technology Limited | Surface treating appliance |
US8901105B2 (en) | 2012-06-19 | 2014-12-02 | Debiopharm International Sa | Prodrug derivatives of (E)-N-methyl-N-((3-M ethylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
US10035813B2 (en) | 2012-06-19 | 2018-07-31 | Debiopharm International Sa | Prodrug derivatives of (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide |
US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
Also Published As
Publication number | Publication date |
---|---|
US20010014742A1 (en) | 2001-08-16 |
US6235728B1 (en) | 2001-05-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6235728B1 (en) | Water-soluble prodrugs of azole compounds | |
KR100748299B1 (en) | Water Soluble Prodrugs of Azole Compounds | |
PT2078682E (en) | Plastic net bag | |
JP4579496B2 (en) | Improved method for water-soluble azole compounds | |
AU2006241694B2 (en) | Mono-lysine salts of azole compounds | |
AU2002213317A1 (en) | Improved process for water soluble azole compounds | |
WO1999061017A1 (en) | Water-soluble prodrugs of azole compounds | |
US20020049216A1 (en) | Water soluble prodrugs of azole compounds | |
ZA200204332B (en) | Water soluble prodrugs of azole compounds. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |