EP1278755A2 - Azolverbindungen als therapeutika für pilzinfektionen - Google Patents

Azolverbindungen als therapeutika für pilzinfektionen

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Publication number
EP1278755A2
EP1278755A2 EP01906061A EP01906061A EP1278755A2 EP 1278755 A2 EP1278755 A2 EP 1278755A2 EP 01906061 A EP01906061 A EP 01906061A EP 01906061 A EP01906061 A EP 01906061A EP 1278755 A2 EP1278755 A2 EP 1278755A2
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EP
European Patent Office
Prior art keywords
hydroxy
group
amino
compound
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01906061A
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English (en)
French (fr)
Inventor
Ashwani Kumar Verma
Sudershan K. Arora
Jasbir Singh Arora
Ashok Rattan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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Filing date
Publication date
Priority claimed from IN198DE2000 external-priority patent/IN191188B/en
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP1278755A2 publication Critical patent/EP1278755A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to the derivatives of specially substituted azole compounds which have improved antifungal activity as compared to known compounds such as fluconazole and itraconazole and the processes for the preparation thereof.
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention and their use in treating and/or preventing fungal infections in mammals, preferably humans.
  • AIDS AIDS or other physiologically or immunologically compromising syndromes
  • opportunistic fungal infections Most of these infections are caused by opportunistic pathogens, like species of Candida and Aspergillus and Cryptococcus neoformans.
  • pathogens like species of Candida and Aspergillus and Cryptococcus neoformans.
  • Candida species During the last 20 years, the incidence of sepsis fungal infection caused by Candida species has increased significantly in debilitated and immuno-compromised patients.
  • antineoplastic and immunosuppressive chemotherapies have also augmented fungal infections.
  • Cryptococcosis is a leading cause of morbidity among AIDS patients. The incidence of life threatening cryptococcal infection among these patients have been estimated to vary from 10 to 30%.
  • Aspergillus species is difficult to determine due to lack of accurate, reliable diagnostic methodologies and poor diagnosis.
  • the majority of Aspergillus infections in AIDS patients occur in late stage disease when immune cell functions are minimal. Impaired neutrophil and macrophage function is related to increased infection rates with Aspergillus species.
  • the most common species of Aspergillus causing disease in AIDS patients are A. fumigatus (83%), A. flavus (9%), A. niger (5%) and A. terreus (3%).
  • azole class Within the available drugs to treat fungal infections, the azole class appears to be most promising. This class of compounds inhibits the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Of the various representative antifungals, early azoles used were miconazole, clotrimazole and tioconazole, which were potent against a wide range of fungi pathogenic to human. However, their in-vitro activity was not well exhibited in in- vivo models due to poor oral bioavailability and metabolic vulnerability.
  • Ketoconazole was the first drug that could be used against systemic fungal infection and successfully delivered through oral route. However, it was still quite susceptible to metabolic inactivation and also caused impotence and gynacomastia probably due to its activity against human cytochrome P450 enzymes.
  • Fluconazole is the current drug of choice for treatment of severe infections caused by Candida species and C. neoformans. However, fluconazole has only weak activity against isolates of Aspergillus species [minimum inhibitory concen ⁇
  • Itraconazole another triazole antifungal compound, generally is more active than fluconazole in the treatment of aspergillosis, but its activity in the clinic remains mixed as it showed variable oral availability, low solubility and caused ovarian cancer in animals. This may be due to its high protein binding properties.
  • the antifungals available in the market suffer with drawbacks such as, toxicity, narrow spectrum of activity and fungistatic profile rather fungicidal. Some of them also exhibit drug-drug interactions and, as a result, therapy becomes very complex.
  • demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties has increased.
  • Voriconazole also shows non-linear pharmacokinetics besides some concern regarding its ocular toxicity, while ER 30346's anti-aspergillus activity, both in vitro and in vivo, is at best, only equal to itraconazole's activity.
  • SCH 56592 is a hydroxylated analogue of itraconazole with potent in-vitro and in-vivo activity, but is undetectable even when the serum drug concentration after several days of treatment are 25 to 100 times above the MIC for the most resistant C. neoformans.
  • the potent activity of SCH 56592 for C.neoformans is partially negated by its low concentration at the site of infection to the central nervous system.
  • the present invention relates to new substituted azole compounds which can be utilized to treat and/or prevent the fungal infections in mammals, preferably in humans.
  • the first aspect of the present invention provides compounds of Formula IA and its pharmaceutically acceptable salts, enantiomers, diastereomers, N- oxides, prodrugs or metabolites,
  • R is selected from the group consisting of (1 ) C- ⁇ -C alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C-i-C alkoxy and amino (2) C C 4 alkoxy, (3) halogen (4) formyl, (5) carboxyl (6) C-t-C acyloxy, (7) phenyl or substituted phenyl, (8) hydroxy, (9) nitro (10) amino
  • R-i and R 2 are each independently (1 ) hydrogen, (2) C 1 -C 4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C
  • Y is a phenyl group which is unsubstituted or substituted by substituents each independently selected from the group consisting of (1 ) halogen (2) nitro, (3) amino, (4) cyano (5) carboxyl or protected carboxyl (6) hydroxy
  • R 3 is selected from the group consisting of C C alkyl group, halogen, hydroxy, C ⁇ -C alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and
  • X-i, X 2 , Y ⁇ , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl, C ⁇ -C alkyl, C- ⁇ -C alkoxy, carboxyl or protected carboxyl.
  • Formula I A When R-i is other than hydrogen, Formula I A has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and S.S.
  • This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
  • R is selected from the group consisting of hydrogen, C C 4 alkyl group which is unsubstituted or substituted, B is selected from oxygen and sulphur atoms;
  • R 5 is selected from the group, (1 ) hydrogen, (2) C C 4 alkyl group which is unsubstituted or substituted by 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C- ⁇ -C alkoxy and amino (3) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of (a) C 1 -C 4 alkyl which is unsubstituted or substituted with 1-3 substituted each independently selected from the group consisting of halogen, hydroxy, C-i- C 4 alkoxy and amino (b) C C 4 alkoxy, (c) halogen, (d) formyl (e) carboxyl (f) C ⁇ -C 4 alkoxy (g) C C 4 alkoxycarboxyl amino (h) phenyl or naphthyl oxycarbonyl amino (i) semicarbazido (j) formamido (k) thioformamide (I) hydroxy (m)
  • Formula IA When Ri is other than hydrogen, Formula IA has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
  • Formula II When Ri is other than hydrogen, Formula II has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS.
  • This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR.
  • the fourth aspect of the present invention provides compounds of Formula III and its pharmaceutically acceptable salts, enantiomers, diastereomers, N- oxides, prodrugs or metabolites,
  • Formula III When Ri is other than hydrogen, Formula III has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS. This invention relates to the mixture of enantiomers as well as individual isomers and the most preferred in this situation is RR.
  • Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention of Formulae IA, 1 B, II and 111 may be formed with inorganic or organic acids, by methods well known in the art.
  • compositions containing the novel compounds of the present invention in the treatment of fungal infections.
  • the present invention also includes within its scope prodrugs of the compounds of Formulae IA, IB, II and III.
  • prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds.
  • Conventional procedures for the selection and preparation of suitable prodrugs are known.
  • the invention also includes pharmaceutically acceptable salts, enantiomers, diastereomers, N-oxides, prodrugs, metabolites of the above formulae in combination with pharmaceutically acceptable carriers and optional excipients.
  • R is selected from the group consisting of (1 ) C ⁇ -C 4 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C-i-C 4 alkoxy and amino (2) C 1 -C 4 alkoxy, (3) halogen (4) formyl (5) carboxyl (6) C 1 -C 4 acyloxy (7) phenyl or substituted phenyl (8) hydroxy (9) nitro (10) amino (11 ) furyl (12) triazolyl (13) thienyl (14) piperazinyl (15) morpholinyl (16) thiomorpholinyl (17) imidazolyl (18) oxazolyl and (19) triazolone-yl, R-i and R 2 are each independently selected from the group consisting of (1 ) hydrogen, (2) C 1 -C 4 alkyl group
  • R 3 is selected from the group consisting of C- 1 -C 4 alkyl group, halogen, hydroxy, C 1 -C 4 alkoxy, nitro, amino, cyano, carboxyl and SO 2 R' wherein R' is hydrogen, alkyl or aryl; and
  • X ⁇ , X 2 , Y 1 , Y 2 and Z are independently selected from the group consisting of halogen, nitro, cyano, amino, sulphonyl, aryl or substituted aryl C 1 -C 4 alkyl, C 1 -C 4 alkoxy, carboxyl or protected carboxyl.
  • Formula I when Ri is other than hydrogen, Formula I has two asymmetric centres and there are four possible enantiomers i.e. RR, RS, SR and SS, this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting 1-[2- (2,4-disubstituted phenyl)-2,3-epoxy derivative of 1 ,2,4-triazole of Formula IV, wherein X, R and R 1 f are the same as defined above, with triazol-3-one derivatives of Formula V, wherein R 2 ,, R 3 , Xi, X 2 , Y, Y ⁇ , Y2 and Z have the same meanings, as defined above, in the presence of sodium hydride to afford the desired compound of Formula I A, wherein X, X1 2, Y-i, Y2. Z, R, R-i, R 2 and R 3 have the same meanings as defined above.
  • substituents selected from (a) Ci - C 5 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and amino, (b) halogen (c) (C ⁇ -C 4 alkyl) halo, (d) C ⁇ -C 4 alkoxy (e)hydroxy (f) amino (g) carboxyl (h) trifluoromethoxyl (i) trifluoromethyl (j) tetrafluoroethyl (k) tetrafluoroethoxyl (I) tetrafluoropropyl and
  • this invention relates to the mixture of enantiomers as well as individual isomers and the most preferred isomer in this situation is RR, which comprises reacting epoxide derivative of Formula VI, wherein X, R, R 1 ( R 2 , R 3 , X-i, X 2 , Y, Y-i, Y2 and Z are the same as defined above with 1 ,2,4-triazole to afford a compound of Formula IA.
  • FORMULA H There is provided a process for preparing a compound of Formula II, wherein X, R, R-i, R 4 , R 5 , Y and B have the same meanings as defined earlier, also when Ri is other than hydrogen, Formula II has two asymmetric centres and there are four possible enantiomers i.e.
  • This compound of Formula XII is further reacted with 1 ,2,4-triazole to obtain 2- (1 H-1 ,2,4-triazol-1-yl)-2'-4'-difluoroacetophenone of Formula XIII.
  • TMSI trimethyl sulphoxonium iodide
  • X ⁇ > X2, Y1 , Y2 and Z are the same as defined earlier, are prepared by reacting substituted phenyl piperazine of Formula XIV, wherein X 1 f X 2 , Y ⁇ , Y 2 and Z are the same as defined earlier, is reacted with 4-chloronitrobenzene to give the corresponding nitroaryl compound of Formula XV, which on catalytic reduction affords the anilino derivative of Formula XVI.
  • the compound of Formula XVI is acylated with phenyl chloroformate to afford phenyl carbamate derivatives of Formula XVII.
  • TMSI trimethylsulphoxonium iodide
  • reaction temperature and duration of the reaction may be used.
  • Schemes IA, IB to IX include:
  • Step 1 Preparation of 2-chloro-2', 4'-difluoro acetophenone.
  • Step -1 The product obtained in Step -1 was reacted with 1 ,2,4-triazole (1.2 molar equivalent) in the presence of sodium bicarbonate as base and toluene as solvent under refluxing condition. After the reaction was over, the reaction mixture was poured into crushed ice and extracted with toluene. The combined organic layer was then washed with water and concentrated under reduced pressure to give brown semisolid compound which was recrystallized from ethyl acetate - hexane mixture to give light yellow solid compound which was then used as such in the next step.
  • 1 ,2,4-triazole 1.2 molar equivalent
  • Step 3 Preparation of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1 H-1 ,2,4- triazole
  • Step 2 product was dissolved in toluene, followed by the addition of trimethylsulfoxonium iodide (TMSI), cetramide and 20% aq. sodium hydroxide solution. This mixture was then heated at 60° C for 4 hrs. After the reaction was over, it was diluted with toluene and poured into chilled water. The organic layer was washed with water and concentrated under reduced pressure to give light brown oil which was used after column chromatographic purification (silica gel) in the next step.
  • TMSI trimethylsulfoxonium iodide
  • cetramide 20% aq. sodium hydroxide solution
  • Step 4 Preparation of 1 -(substituted phenyl)-4-(4-nitrophenyl) piperazine.
  • Step 5 Preparation of 1 -(substituted phenyl)-4-(4-aminophenyl)piperazine
  • Method 1 The compound of Step 4 was dissolved in methanol and Palladium on charcoal (wet, 10% w/w) was added under nitrogen followed by the addition of ammonium formate (5 molar equivalent). The reaction mixture was
  • Step 4 The compound of Step 4 was refluxed in ethyl acetate in the presence of 5.0 molar equivalent stannous chloride dihydrate for 6-8 hrs. After completion of the reaction, the reaction mixture was poured into 10% aq. sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was then washed with water dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product.
  • Step 6 Preparation of [4-(4-(substituted/unsubstituted phenyl) -1 -piperazinyl] phenyl carbamate
  • the amine obtained from Step 5 was dissolved in a mixture of dichloroethane (DCE) and pyridine and cooled to 5°C. A solution of phenylchloroformate (1.4 molar equivalent) in DCE was added into the solution of
  • reaction mixture was stirred at 25-30°C for 3-5 hours. Solvent was evaporated off under reduced pressure to give brownish residue which on triturating with n-hexane gave brown solid. It was then obtained was washed with 5% aq. solution of sodium bicarbonate and water. It was then dried under
  • Step 7 Preparation of N-[4-[(4-substituted phenyl) 1-piperazinyl]phenyl]hydrazine carboxamide.
  • Step 8 4-(4-Substituted phenyl)-1-piperazin]phenyl-3H-1 ,2,4-triazol-3-ones.
  • Step 9 Preparation of 2-[(2,4-Difluorophenyl)-2-hydroxy-3-(1 H-1 ,2,4-triazoM -yl)- propyl]-4-[4-[4-substitutedphenyl-1-piperazinyl]phenyl]-3-(2H,4H)-1 ,2,3- substituted triazol-4-one.
  • reaction mixture was cooled to 35-40°C, poured it into chilled water (50 ml) and extracted with ethyl acetate (3x 100ml). The combined organic layer was washed with water (4x50ml), dried over anhydrous sodium sulphate and concentrated under vacuum to give an oily residue (0.3 gm). The oil was purified by column chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate (1 :1 ) followed by ethyl acetate or by crystallisation from suitable solvent to give the required compound.
  • Step 1 Preparation of 2-chloro-2-methyl-2',4'-difluoro acetophenone
  • reaction mixture was stirred at room temperature for 5-7 hours.
  • reaction mixture was diluted with DCE and poured into chilled aq. hydrochloric acid solution (5%). The mixture was extracted with DCE and the combined organic layer was washed with 5% aq. sodium bicarbonate solution and water. The solvent was evaporated off under reduced pressure to afford an oil.
  • Step 2 Preparation of 2- ⁇ [4-[4-[4-(substituted/unsubstituted phenyl)piperazin- yl]phenyl-(2H,4H)-1 ,2,4-triazol-3-one-2-yl] ⁇ -2(R/S)-methyl-2',4'- difluoroacetophenone
  • reaction mixture was cooled to 25-30°C, poured into chilled water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give an oily residue under vacuum.
  • the crude product was purified by column chromatography (silica gel 100-200 mesh) using hexane-ethyl acetate (1 :1) followed by using ethyl acetate to give the required compound.
  • Step 3 Preparation of 2- ⁇ [1 (R/S)-methyl-2-(2',4'-difluorophenyl)-2,3-epoxy- propyl]-4-[4-(substituted phenyl)piperazinyl]phenyl] ⁇ -3-(2H,4H)-1 ,2,4-substituted thiazolone.
  • TMSI trimethylsulfoxonium iodide
  • Step 4 Preparation of 2- ⁇ [1 R,2R/1S,2S/1 R,2S/1S,2R]2-[(2,4-Difluoro phenyl)-2- hydroxy-3-methyl-3-(1 -H-1 ,2,4-triazoM -yl)propyl] ⁇ -4- ⁇ 4-[4- (substituted/unsubstituted phenyl)-1-piperazinyl]phenyl] ⁇ -3-(2H,4H)-1 ,2,3- substituted triazol-4-one].
  • the nitro compound (18.0g) was refluxed in ethyl acetate (150ml) in the presence of stannous chloride dihydrate (55.5g) for 8 hours. After completion of the reaction, the reaction mixture was poured into 10% aqueous sodium bicarbonate (500ml) and extracted with ethyl acetate (3 x 150ml). The combined organic layer was washed with water (3 x 100ml) and then dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum to give the desired amine (15.3g, brown oil; yield:93%).
  • reaction mixture was cooled to about 15°C.
  • a solution of phenylchloroformate (11.67g) in DCE (10ml) was added into the solution of amine at such a rate that reaction temperature remained below 20°C.
  • reaction mixture was stirred at 25-30°C for about 3 hours.
  • Solvent was evaporated off under reduced pressure to give brownish residue which on triturating with n-hexane (150ml) gave brown solid. Solid was washed with n-hexane (2x100ml), 5% aq.
  • Step 1 Preparation of 2- ⁇ 4-[4-[4-(2-methyl-5-chlorophenyl)piperazinyl]phenyl ⁇ - (2H,4H)-1 ,2,4-triazol-3-one-2-yl ⁇ -2(R/S)-methyl-2,4-difluoroacetophenone.
  • Step 2 Preparation of 2-[1-(R/S)-methyl-2-(2'-4'-difluorophenyl)-2,3-epoxy- propyl]-4- ⁇ 4-[4-(5-chloro-2-methylphenyl)piperazinyl]phenyl] ⁇ -3-(2H,4H)-1 ,2,4- triazolone.
  • Step 3 2- ⁇ [1 R2R/1 S2S]-2-(2,4-Difluoropheny!)-2-hydroxy-1 -methyl-3-(1 H-1 ,2,4- triazoM -yl) propyl ⁇ -4- ⁇ 4-[4-(5-chloro-2-methylphenyl)-1 -piperazinyl]phenyl ⁇ -3- (2H,4H)-1 ,2,4-triazolone (Compound No. 21 )
  • reaction mixture was cooled to 25-30°C, poured into chilled brine (70.0ml) and extracted with ethyl acetate (3 x 75ml). The combined organic layer was washed with water (2x250ml), dried over sodium sulfate and concentrated under vacuum to give an oil.
  • Compound obtained actually was a mixture of two pairs of diastereomers showing two spots on TLC (Ethyl acetate).
  • Step 1 Preparation of 3-[N-methyl-N-(4-nitrophenyl)]-2-(2,4-difluorophenyl)-1- (1 H-1 ,2,4-triazolyl)- propan-3-amino-2-ol.
  • Step 2 Preparation of 3-[N-methyl-N-(4-aminophenyl)]-2-(2,4-difluorophenyl)-1- (1 H-1 ,2,4-triazolyl)- propane-3-amino-2-ol.
  • Step 3 Preparation of 3-[4-(4-Chlorophenylthioureido)N-methyl-N-phenyl]-2-(2,4- difluorophenyl)-1-(1 H-1 ,2,4-triazolyl)-propan-3-amino-2-ol (Compound No. 89)
  • Step 1 Preparation of 2- ⁇ 4-[4-acetyl-1 -piperazinyl]-phenyl]-2(R/S)-methyl-2,4- difluoroacetophenone
  • Step 2 Preparation of 1-(R/S)-methyl-2,3-epoxypropyl-2- ⁇ 4-[(4- acetylpiperazinyl)] phenoxy ⁇ -2-(2',4'- difluorobenzene)
  • Step 3 Preparation of 1- ⁇ 4-[4-Acetylpiperazinyl)-phenyl]-2-(2,4-difluorophenyl)- 1 (R/S)- methyl-3-(1 H-1 ,2,4- triazolyl)-propane-2-ol)]
  • Step 2 product (7.0 g) in
  • Step 4 Preparation of 1-[4-(4-(piperazinyl)phenoxy]-2-(2,4-difluorophenyl)-
  • Step 3 product (6.0 g) was dissolved in 1 ,4-dioxane (50 ml) followed by the addition of a solution of sodium hydroxide (1.0 g) in water (50 ml). Heated the reaction mixture to reflux, stirred it at reflux for about 5 hrs and concentrated under reduced pressure to give a brown semi-solid residue. This brown semi solid was redissolved in ethyl acetate (200 ml), washed with DM water (2x100 ml), dried over sodium sulphate and concentrated to get a pure brown semi-solid (4.5 g; 81 %).
  • Step 5 Preparation of [1 R2R/1S2S) 1- ⁇ 4-[4-(4-chlorophenylureido)-piperaziny]- phenoxy ⁇ -2-(2,4- difluorophenyl)-1 -methyl-3-(1 H-1 ,2,4-triazolyl)-propan-2-ol. (Compound No. 77) and
  • Step 4 product (Formula VII) (800 mg) in anhydrous acetonitrile (5 ml) followed by the addition of p-chlorophenyl isocyanate (3.44 mg).
  • the reaction mixture so obtained was stirred for 1 hour at room temperature and after the reaction was over, the solvent was evaporated off to give brown semi solid residue which was purified using column chromatography.
  • the two spots observed on TLC were separated by preparative HPLC (Upper spot, 50mg, 30%, compound No. 77; Lower spot, 25mg, 20%, Compound No. 78)
  • Compounds of the Formulae IA, IB, II and III as shown herein, and their salts are useful in the curative or prophylactic treatment of fungal infections in animals, including humans.
  • they are useful in treating topical fungal infection in man caused by, among other organisms, species of Candida, Trichophyton, Microsporum or Epidermophyton in mucosal infections caused by C. albicans (e.g., thrush and vaginal candidiasis).
  • C. albicans e.g., thrush and vaginal candidiasis
  • They can also be used in the treatment of systemic fungal infections caused by, for example, species of Candida (e.g., Candida albicans), Cryptococcus neoformans or Aspergillus fumigatus.
  • the compounds of the present invention have been found to have unexpectedly good activity against clinically important Aspergillus species fungi.
  • the in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (MIC) which is the concentration of the test compound in Rosewell Park Memorial Institute (RPMI) 1640 liquid medium buffered with (3-[Morpholino]propanesulphonic acid) MOPS to pH7. at which there is significant inhibition of the particular fungi
  • MIC minimum inhibitory concentration
  • RPMI Rosewell Park Memorial Institute
  • M27A document for Candida and Cryptococcus and M38P for Aspergillus was used to determine the MIC against yeast and filamentous fungi with suitable modifications for dermatophytes. Two quality control strains were included each time the MIC were determined and readings recorded only when the QC results fell into the
  • the in vivo evaluation of the compound can be carried out at a series of dose levels by oral or I.V. injection to mice which are inoculated I.V. with the minimum lethal dose of Candida albicans, Cryptococcus neoformans or Aspergillus fumigatus by the tail vein.
  • Activity is based on the survival of a treated group of mice after the death of an untreated group of mice.
  • Aspergillus and Cryptococcus infections target organs were cultured after treatment to document the number of mice cured of the infection for further assessment of activity.
  • the antifungal compounds of the formula and their salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.
  • They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • solubility of a compound of the Formulae IA, IB, II and III in an aqueous medium may be improved by complexation with a hydroxyalkyl derivative of a cyclodextrin in the preparation of an appropriate pharmaceutical composition.
  • the daily dosage level of the antifungal compounds of the Formulae IA, IB, II and III and their salts will be from 0.01 to 20 mg/kg (in single or divided doses) when administered by either the oral or parenteral routes.
  • tablets or capsules of the compound will contain from 5 mg to 0.5 gm of active compound for administration one, two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case, there can, of course, be individual instances, where higher or lower dosage ranges are required and such are within the scope of this invention.
  • the antifungal compound or Formulae IA, IB, II and III can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated, at a concentration between 1 and 10 % into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • Cryptococcosis is a leading cause of morbidity and mortality among AIDS patients. In many patients Cryptococcosis is the first indication of AIDS. The incidences of life-threatening cryptococcal infection among patients with AIDS has been estimated to vary from 10 - 30 %. During initial therapy, 10 - 20 % of these patients die and 30 - 60 % patients succumb within 12 months (Powderly WG: Cryptococcus meningitis and AIDS Clin. Infect. Dis. 1993; 17: 837 - 842).
  • Amphotericin B has changed disseminated cryptococcosis from uniformly fatal infection to curable infection, but since Amphotericin B penetrates the central nervous system poorly, intraventricular injection may have to be administered for successful management of severe cases of Cryptococcal meningitis. Fluconazole has excellent pharmacokinetics in CSF and performs equally well in patients with Cryptococcal meningitis.
  • Invasive aspergillosis has become a leading cause of death, mainly among patients suffering from acute leukaemia or after allogenic bone marrow transfusion and after cytotoxic treatment of these conditions. It also occurs in patients with conditions such as AIDS and chronic granulomatous disease. At present, only Amphotericin B and Itraconazole are available for treatment of aspergillosis. In spite of their activity in vitro, the effect of these drugs in vivo against Aspergillus fumigatus remains low and as a consequence mortality from invasive aspergillosis remains high.
  • Candida Histoplasma capsulatum, Cryptococcus neoformans, dermatophytes, Aspergillus fumigatus and A. flavus.
  • the action on many of these strains, especially against Cryptococcus and Aspergillus is fungicidal in vitro.
  • Compounds of this invention have enhanced antifungal activity against the important fungal pathogens of men and animals.
  • a single oral dose of 12.5 mg / kg bw. (0.25 mg per mouse) is adequate to offer significant protection to mice infected via the tail vein by lethal dose of C. albicans A-26.
  • the compounds of this invention cross the blood brain barrier to excert their potent anti cryptococcal activity in the brain.
  • lethal infection (1 million cells of C. neoformans) were injected into the cranium of the animal, oral dosing with 25 mg/kg bw. BID for 8 days reduced the count by 4 logs, causing 99.99 % reduction in the fungal load.

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EP01906061A 2000-03-07 2001-03-01 Azolverbindungen als therapeutika für pilzinfektionen Withdrawn EP1278755A2 (de)

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US575578 1990-08-31
IN198DE2000 IN191188B (de) 2000-03-07 2000-03-07
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US09/575,578 US6670363B1 (en) 2000-03-07 2000-05-22 Azole compounds as therapeutic agents for fungal infections
PCT/IB2001/000300 WO2001066551A2 (en) 2000-03-07 2001-03-01 Azole compounds as therapeutic agents for fungal infections

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AU2002218505A1 (en) * 2000-11-30 2002-06-11 Senju Pharmaceutical Co. Ltd. Pancreatitis remedies and medicines for prevention and therapy of reflux esophagitis
CA2433259A1 (en) 2000-12-26 2002-07-04 Ranbaxy Laboratories Limited Azole compounds as anti-fungals agents
US7867516B2 (en) 2001-01-29 2011-01-11 Shionogi & Co., Ltd. Medicinal preparation containing 5-methyl-1-phenyl-2-(1h)-pyridone as active ingredient
HUP0303249A3 (en) 2001-02-22 2007-03-28 Sankyo Co Water-soluble triazole fungicide compounds and pharmaceutical compositions containing them
IN192526B (de) * 2001-09-25 2004-04-24 Ranbaxy Lab
WO2004018485A1 (en) * 2002-08-26 2004-03-04 Ranbaxy Laboratories Limited Azole derivatives as antifungal agents
EP1413301A1 (de) * 2002-10-24 2004-04-28 Bayer CropScience SA Antimykotische Medikamente auf der Basis von Arylamidinderivaten
WO2007020888A1 (ja) 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited 脳・神経細胞保護剤および睡眠障害治療薬
JP6130827B2 (ja) 2011-05-17 2017-05-17 塩野義製薬株式会社 ヘテロ環化合物
US9907812B2 (en) 2011-06-22 2018-03-06 Vyome Biosciences Pvt. Ltd. Conjugate-based antifungal and antibacterial prodrugs
CN102617494B (zh) * 2012-03-15 2014-10-29 南京工业大学 一种含有烯醚结构的三唑类化合物及其制备方法和用途
MX2015016675A (es) 2013-06-04 2016-07-15 Vyome Biosciences Pvt Ltd Particulas recubiertas y composiciones que comprenden las mismas.
EP3099301B1 (de) 2014-01-29 2019-12-18 Vyome Therapeutics Limited Besifloxacin zur behandlung von resistenter akne
CA2937365C (en) 2016-03-29 2018-09-18 F. Hoffmann-La Roche Ag Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same
AR109545A1 (es) 2016-09-29 2018-12-19 Bayer Cropscience Ag Derivados de triazol

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US5639754A (en) * 1994-07-12 1997-06-17 Janssen Pharmaceutica N.V. Urea and thiourea derivatives of azolones
EP0957101A1 (de) * 1998-05-14 1999-11-17 Janssen Pharmaceutica N.V. Wasserlösliche Azole als Breitspektrum-antifungus

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WO2001066551A2 (en) 2001-09-13
JP2004501867A (ja) 2004-01-22
PL365072A1 (en) 2004-12-27
WO2001066551A3 (en) 2002-03-07
CA2402345A1 (en) 2001-09-13
RU2002126272A (ru) 2004-08-10

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