NZ623864B2 - Optically active fluconazole analogues containing thiophenes as antifungal agents - Google Patents
Optically active fluconazole analogues containing thiophenes as antifungal agents Download PDFInfo
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- NZ623864B2 NZ623864B2 NZ623864A NZ62386412A NZ623864B2 NZ 623864 B2 NZ623864 B2 NZ 623864B2 NZ 623864 A NZ623864 A NZ 623864A NZ 62386412 A NZ62386412 A NZ 62386412A NZ 623864 B2 NZ623864 B2 NZ 623864B2
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N Fluconazole Chemical class C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 title description 18
- 239000003429 antifungal agent Substances 0.000 title description 9
- 150000003577 thiophenes Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 230000000843 anti-fungal Effects 0.000 claims abstract description 25
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 6
- 239000000460 chlorine Substances 0.000 claims abstract description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011630 iodine Substances 0.000 claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 206010017533 Fungal infection Diseases 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000004296 chiral HPLC Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M Tetra-n-butylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- 150000002430 hydrocarbons Chemical class 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960001866 silicon dioxide Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000002118 epoxides Chemical class 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- IWTBVKIGCDZRPL-LURJTMIESA-N 3-Methylbutanol Natural products CC[C@H](C)CCO IWTBVKIGCDZRPL-LURJTMIESA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000001184 potassium carbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-Ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- 229940093475 2-ethoxyethanol Drugs 0.000 claims description 2
- 229920000856 Amylose Polymers 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- CRRYCJOJLZQAFR-UHFFFAOYSA-N cyclohexane;pentane Chemical compound CCCCC.C1CCCCC1 CRRYCJOJLZQAFR-UHFFFAOYSA-N 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- 239000008079 hexane Substances 0.000 claims description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-M p-toluate Chemical compound CC1=CC=C(C([O-])=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-M 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 238000010829 isocratic elution Methods 0.000 claims 1
- POECFFCNUXZPJT-UHFFFAOYSA-M sodium;carbonic acid;hydrogen carbonate Chemical compound [Na+].OC(O)=O.OC([O-])=O POECFFCNUXZPJT-UHFFFAOYSA-M 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- -1 2-F 4-F butyl Chemical group 0.000 description 16
- 241000233866 Fungi Species 0.000 description 6
- 150000003851 azoles Chemical class 0.000 description 6
- 229960004884 fluconazole Drugs 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000222122 Candida albicans Species 0.000 description 4
- 238000002815 broth microdilution Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 241000228245 Aspergillus niger Species 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N BRL-49594 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 241000235645 Pichia kudriavzevii Species 0.000 description 2
- 229960003942 amphotericin B Drugs 0.000 description 2
- 238000002827 antifungal susceptibility testing Methods 0.000 description 2
- 229940121375 antifungals Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 230000001747 exhibiting Effects 0.000 description 2
- 230000002538 fungal Effects 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007430 reference method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 229940100197 ANTIMETABOLITES Drugs 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 229940091771 Aspergillus fumigatus Drugs 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 240000008923 Camelina sativa Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 229940095731 Candida albicans Drugs 0.000 description 1
- 241000222178 Candida tropicalis Species 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- 206010014698 Endocrine disease Diseases 0.000 description 1
- 241000690372 Fusarium proliferatum Species 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 210000004392 Genitalia Anatomy 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 206010021425 Immune system disease Diseases 0.000 description 1
- 206010022000 Influenza Diseases 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 239000007759 RPMI Media 1640 Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 201000007336 cryptococcosis Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000000855 fungicidal Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000001861 immunosuppresant Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000004291 polyenes Polymers 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The disclosure provides enantiomeric antifungal compounds of Formula (1a) and Formula (1b), wherein each R1 and R2, which may be the same or different, is independently selected from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3 and R4, which may be the same or different, is independently selected from hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR' (wherein R'= methyl or ethyl). ifferent, is independently selected from hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR' (wherein R'= methyl or ethyl).
Description
GNA 1412 WO 1
“OPTICALLY ACTIVE FLUCONAZOLE ANALOGUES CONTAINING
THIOPHENES AS ANTIFUNGAL AGENTS”
FIELD OF INVENTION:
The present invention relates to enantiomers of fluconazole analogues containing
thiophenes as antifungal agents, which are depicted by Formula (1a) and Formula (1b),
and pharmaceutically acceptable salts thereof.
N R3
Formula 1b
Formula 1a
Wherein each R1 and R2, which may be the same or different, is independently selected
from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3
and R4, which may be the same or different, is independently selected from hydrogen,
alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together
form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR’ (wherein R’=
methyl or ethyl).
The invention further relates to a process for preparation of the enantiomers of
fluconazole analogues containing thiophenes of Formula (1a) and Formula (1b), and
pharmaceutical preparations containing these compounds for prevention and treatment of
fungal infections in a subject.
GNA 1412 WO 2
BACKGROUND OF THE INVENTION:
Fungus is a type of microorganism that causes fungal infection. A fungal infection is an
inflammatory condition in which fungi multiply and invade the skin, the digestive tract,
the genitals and other body tissues, particularly the lungs and liver. Fungal infections
mainly include superficial and systemic fungal infections. Fungal infections are more
common in people taking antibiotics, corticosteroids, immunosuppressant drugs and
contraceptives. The fungal infections are prominent in people with endocrine disorders,
immune diseases and other conditions such as obesity, AIDS, tuberculosis, major burns,
leukemia and diabetes.
The current antifungal agents belong to various groups like polyenes, heterocyclic
benzofuran, allylamines, antimetabolites, azoles, glucan synthesis inhibitors, etc. out of
which azoles are presently the most extensively used antifungal agents. Azoles are further
classified into imidazoles and triazoles. Fluconazole belongs to the family of triazole
antifungals. Fluconazole is an important antifungal agent which is orally active and has
low toxicity but its extensive use has resulted in emergence of fluconazole-resistant
fungal strains. Therefore, it is necessary to meet the long-felt need to develop novel
fluconazole analogues which exert high anti-fungal activity against various fungi. The
presence of one triazole ring, halogenated phenyl ring and tertiary alcoholic oxygen
functionality in azole class of compounds, is necessary for antifungal activity.
Various fluconazole analogues having antifungal activity have been reported in the
literature. Some of the recent references describing synthesis and antifungal activity are
given below:
Bioorganic & Medicinal Chemistry Letters 17 (2007) 3686-9; Bioorganic & Medicinal
Chemistry Letters 18 (2008) 6538–6541; Bioorganic & Medicinal Chemistry Letters 19
(2009) 301–304; Bioorganic & Medicinal Chemistry Letters 19 (2009) 759–763;
Bioorganic & Medicinal Chemistry Letters 19 (2009) 2013–2017; Bioorganic &
Medicinal Chemistry Letters 19 (2009) 3559–3563; Bioorganic & Medicinal Chemistry
Letters 20 (2010) 2942–2945.
GNA 1412 WO 3
The racemic fluconazole analogues containing thiophene moiety of Formula (2) and their
excellent fungicidal activities have already been described by the inventors in WO
2010/046912, with the method of preparing such racemic compounds, which have high
antifungal activity against various fungi.
Formula 2
Wherein, R1, R2, R3, R4 and R5 are defined as above.
It has been found by the present invention that one of the enantiomers of chiral
fluconazole analogues containing thiophene moiety has enhanced antifungal activity than
corresponding racemic compound. Hence, there is a need to develop such enantiomers
which exert high antifungal activity against various fungal strains.
The present invention seeks to provide enantiomers of chiral fluconazole analogues of
Formula (1a) and Formula (1b) containing thiophene moiety and process thereof as an
effort to come up with antifungal agents having broad spectrum of antifungal activity.
SUMMARY OF THE INVENTION:
Accordingly, to meet the above stated objectives, the present invention discloses
enantiomers of fluconazole analogues containing thiophene moiety as antifungal agents,
which are depicted by Formula (1a) and Formula (1b).
GNA 1412 WO 4
N R3
N R3
Formula 1b
Formula 1a
Wherein each R1 and R2, which may be the same or different, is independently selected
from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3
and R4, which may be the same or different, is independently selected from hydrogen,
alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together
form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR’ (wherein R’=
methyl or ethyl).
The invention further discloses a process for preparation of compounds of Formula (1a)
and Formula (1b), and pharmaceutical preparations containing these compounds, for
prevention and treatment of fungal infections. Such chiral, optically-active compounds
acting as antifungals proved to have MIC values much smaller than that of racemic
compounds of Formula (2) as well as fluconazole.
DETAILED DESCRIPTION
According to the present invention, there are provided enantiomers of fluconazole
analogues containing thiophene moiety, as depicted in Formula (1a) and Formula (1b).
These compounds belong to azole class of antifungal compounds and are analogues of
fluconazole, which are active against fungi and used in pharmaceutical preparations as
active agents.
GNA 1412 WO 5
N R3
N R3
Formula 1b
Formula 1a
Wherein each R1 and R2, which may be the same or different, is independently selected
from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3
and R4, which may be the same or different, is independently selected from hydrogen,
alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together
form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR’ (wherein R’=
methyl or ethyl).
According to another embodiment, the invention provides process for preparation of the
compounds of Formula (1a) and Formula (1b). The compounds of Formula (1a) and
Formula (1b) of the present invention are prepared either by a synthetic process as
illustrated in Scheme 1, or by chiral separation using HPLC (High Performance Liquid
Chromatography) as illustrated in Scheme 2.
Scheme 1:
GNA 1412 WO 6
Base, catalyst
Formula 3
Formula 4
N R3
N R3
Formula 1b
Formula 1a
Wherein, R1, R2, R3, R4 and R5 are defined as above, and ‘*’ is used to designate R or S
configuration at carbon atom.
Accordingly, the process for the preparation of compound of Formula (1a) and Formula
(1b) comprises reacting a compound of Formula (3) with a chiral epoxide of Formula (4),
in presence of a suitable base and a catalyst. The suitable base used in the present
invention is selected from various organic or inorganic bases preferably inorganic base
such as potassium carbonate, sodium carbonate or cesium carbonate. The suitable catalyst
used in the present invention is selected from various phase transfer catalysts such as
tetrabutylammonium bromide, tertrabutylammonium chloride, triethylbenzylammonium
chloride or cetyltrimethylammonium bromide.
Compounds of Formula (1a) and Formula (1b) can also be prepared by chiral separation
of racemic compounds of Formula (2) using chiral HPLC in order to obtain desired
enantiomers, as shown in Scheme 2. The chiral HPLC is performed using a chiral
GNA 1412 WO 7
preparative HPLC column and a mobile phase. Compounds of Formula (2) can be
prepared as per the method disclosed in .
Scheme 2:
N R3
Chiral HPLC
Formula 2
N R3
Formula 1b
Formula 1a
Wherein, R1, R2, R3, R4 and R5 are defined as above.
According to the present invention, the chiral preparative HPLC column is selected from
but not limited to cellulose tris (3,5-dimethylphenylcarbamate) coated on silica-gel,
cellulose tris (4-methylbenzoate) coated on silica-gel or tris-(3,5-dimethylphenyl)-
carbamoyl amylose coated on silica-gel; and the eluent system is an isocratic system
comprising a mixture of hydrocarbon(s), alcohol(s) and/or acid(s).
The hydrocarbons used in the present invention are selected from a group consisting of
pentane, hexane, heptane, petroleum ether (60-80 fraction), iso-octane, cyclohexane and
cyclopentane.
GNA 1412 WO 8
The alcohol used in the present invention is selected from the group consisting of
methanol, ethanol, propanol, propanol, butanol, butanol, tert-butanol, 3-
methylbutanol, 2-methylpropanol, 2-methoxyethanol and 2-ethoxyethanol.
The acid used in the present invention is trifluoroacetic acid.
The ratio of alcohol in the mobile phase of the eluent system ranges from 10% to 60%.
The ratio of hydrocarbon in the mobile phase of the eluent system ranges from 40% to
90%. The ratio of trifluoroacetic acid in the mobile phase of the eluent system ranges
from 0% to 2%.
In yet another embodiment, the present invention provides a pharmaceutical preparation
for treating or preventing fungal infections, comprising compounds of Formula (1a) or
Formula (1b), in association with at least one pharmaceutically acceptable excipient
known in the art.
The pharmaceutical preparations can be selected from various dosage forms such as solid
dosage form including tablets, capsules, pellets, powders, soft gelatin capsules and oral
liquids. The pharmaceutical compositions can be prepared using conventional techniques
well known in the art.
In further embodiment, the invention provides a method for treating or preventing fungal
infections in a subject, wherein the said method comprises administering to the subject,
therapeutically effective amounts of the compounds of Formula (1a) or Formula (1b) of
the present invention. The compounds of the present invention can also be administered
optionally with other actives depending on the disease conditions.
The term “therapeutically effective amount” as used herein, means an amount used in the
pharmaceutical preparations to achieve the desired therapeutic effect.
The amount/quantity of the compound used in pharmaceutical compositions of the
present invention will vary depending upon the body weight of the patient and the mode
GNA 1412 WO 9
of administration, and can be of any effective amount to achieve the desired therapeutic
effect.
In yet another embodiment, the invention provides use of therapeutically effective
amounts of compounds of formula 1a or 1b for the treatment or prevention of fungal
infections in a subject. The invention also provides use of formula 1a and 1b of the
present invention in the preparation of medicament useful for treating fungal infections in
a subject. The subject for trhe purpose of the invention is an animal or a mammal.
The invention is further illustrated with the following examples and should not be
construed to limit the scope of the present invention. The features of the present invention
will become more apparent from the following description of the inventive concept and
the description of the preferred embodiments.
The compounds of Formula 1a are depicted in Table 1.
Compounds of Formula (1a):
Formula 1a
GNA 1412 WO 10
Table 1:
Compd
1 2 3 4 5
R R R R R Structure
2-F 4-F methyl H CN
1a-01
N Pr
1a-02 2-F 4-F propyl H CN
N Bu
1a-03 2-F 4-F butyl H CN
Pent
1a-04 2-F 4-F pentyl H CN
The compounds of Formula 1b are depicted in Table 2.
GNA 1412 WO 11
Compounds of Formula (1b):
N R3
Formula 1b
Table 2:
Compd
1 2 3 4 5
R R R R R Structure
N Me
1b-01 2-F 4-F methyl H CN
N Pr
1b-02 2-F 4-F propyl H CN
2-F 4-F butyl H CN
1b-03
GNA 1412 WO 12
N Pent
1b-04 2-F 4-F pentyl H CN
The compounds of Formula 2 are depicted in Table 3.
Compounds of Formula (2):
N R3
Formula 2
Table 3:
Compd
1 2 3 4 5
R R R R R Structure
N Me
2-01 2-F 4-F methyl H CN
GNA 1412 WO 13
N Pr
2-02 2-F 4-F propyl H CN
N Bu
2-03 2-F 4-F butyl H CN
Pent
2-04 2-F 4-F pentyl H CN
The compounds of Formula 3 are depicted in Table 4.
Compounds of Formula (3):
Formula 3
GNA 1412 WO 14
Table 4:
Compd
3 4 5
R R R Structure
methyl H CN
3-01
3-02 propyl H CN
3-03 butyl H CN
3-04 pentyl H CN
Pent
The compounds of Formula 4 are depicted in Table 5.
Compounds of Formula (4):
Formula 4
GNA 1412 WO 15
Table 5:
Compd No. R R Structure
4a 2-F 4-F
4b 2-F 4-F
Examples:
General method of preparation of compounds of Formula (1a) and Formula (1b) via
Scheme 1:
Base, catalyst
Formula 3
Formula 4
N R3
Formula 1b
Formula 1a
GNA 1412 WO 16
Wherein, R1, R2, R3, R4 and R5 are defined as above, and ‘*’ is used to designate R or S
configuration at carbon atom.
A mixture of compound of Formula 3 (1 equivalent), base (0.5-5 equivalents) and
catalyst (0.1-2 equivalents) in a suitable organic solvent was taken in two- necked round
bottom flask equipped with a reflux condenser and a guard tube. The mixture was stirred
at room temperature for 0.5-4 h and a compound of Formula 4 (1 equivalent) in organic
solvent such as ethyl acetate was added. The mixture was stirred under reflux for 5-18 h,
cooled, diluted with water, extracted with ethyl acetate, dried over Na SO and
concentrated. Purification by column chromatography afforded the pure product.
Example 1:
(S)((2-(2,4-Difluorophenyl)hydroxy(1H-1,2,4-triazolyl)propyl)amino)
methylthiophenecarbonitrile (1a-01)
N Me
A mixture of compound of Formula 3-01 (166 mg, 1 mmol), flame dried potassium
carbonate (414 mg, 3 mmol) and tetra-butyl ammonium bromide (322 mg, 1 mmol) in
ethyl acetate (10 ml) was taken in two- necked round bottom flask equipped with reflux
condenser and guard tube. The mixture was stirred at room temperature for 0.5 h and
compound of Formula 4a (244 mg, 1.03 mmol) in ethyl acetate (4 ml) was added. The
mixture was stirred under reflux for 13 h, cooled, diluted with water, extracted with ethyl
acetate (3 x 10 ml), dried over Na SO and concentrated. Purification by column
chromatography afforded the pure product; 255 mg (68%); H NMR (200 MHz, CDCl ):
δ 2.28 (s, 3H), 3.64 (d, J = 8 Hz, 1H), 3.68 (d, J = 8 Hz, 1H), 4.65 (d, J = 14 Hz, 1H),
4.87 (d, J = 14 Hz, 1H), 5.24 (t, J = 8 Hz, 1H), 5.30 (bs, 1H), 6.36 (s, 1H), 6.37-6.87 (m,
GNA 1412 WO 17
0
2H), 7.45-7.57 (m, 1H), 7.86 (s, 1H), 7.92 (s, 1H); [ ] = -10 (C=1, methanol ); ee
98.99% by chiral HPLC.
Example 2:
(S)((2-(2,4-Difluorophenyl)hydroxy(1H-1,2,4-triazolyl)propyl)amino)
propylthiophenecarbonitrile (1a-02)
The compound of Formula 3-02 (200 mg, 1.03 mmol) in dry ethyl acetate (5 ml) was
added to a mixture of flame-dried K CO (284 mg, 2.06 mmol), tetra-butyl ammonium
bromide (TBAB, 332 mg, 1.03 mmol) and dry ethyl acetate (10 ml). Reaction mixture
was stirred at 70 ºC for 30 min and then epoxide 4a (244 mg, 1.03 mmol) dissolved in dry
ethyl acetate (3 ml) was added drop wise over a period of 10 min and stirring was
continued for further 15 h at the same temperature. It was then cooled to room
temperature, diluted with water (20 ml), extracted with ethyl acetate (3 x 10 mL), dried
over Na SO , concentrated and purified by column chromatography to give pure
compound of the Formula 1a-02 (335 mg); Yield: 81%; H NMR (200 MHz, CDCl ): δ
0.89 (t, J=7 Hz, 3H), 1.43-1.60 (m, 2H), 2.50 (t J=7 Hz, 2H), 3.63 (bs, 2H), 4.67 (d, J=14
Hz, 1H), 4.80 (d, J=14 Hz, 1H), 5.05 (bs, 1H), 6.31 ( s, 1H), 6.66-6.82 (m, 2H), 7.41-7.58
(m, 1H), 7.77 (s, 1H), 8.07, (s, 1H); [ ] = -12 (C=1, THF ); ee 99.16% by chiral
HPLC.
GNA 1412 WO 18
Example 3:
(S)Butyl((2-(2,4-difluorophenyl)hydroxy(1H-1,2,4-triazol
yl)propyl)amino)thiophenecarbonitrile (1a-03)
The compound of Formula 3-03 (104 mg, 0.5 mmol) in dry ethyl acetate (5 ml) was
added to a mixture of flame-dried K CO (284 mg, 2.06 mmol), tetra-butyl ammonium
bromide (TBAB, 32 mg, 0.1 mmol) and dry ethyl acetate (10 ml). Reaction mixture was
stirred at 70 ºC for 30 min and then epoxide 4a (118 mg, 0.5 mmol) dissolved in dry ethyl
acetate (3 ml) was added drop wise over a period of 10 min and stirring was continued for
further 20 h at the same temperature. It was then cooled to room temperature, diluted with
water (20 ml), extracted with ethyl acetate (3 x 10 mL), dried over Na SO , concentrated
and purified by column chromatography to give pure compound of the Formula 1a-03
(131 mg); Yield: 63%; H NMR (200 MHz, CDCl ): δ 0.88 (t, J = 8 Hz, 3H), 1.20-1.40
(m, 2H), 1.46-1.59 (m, 2H), 2.56 (t, J = 8 Hz, 2H), 3.61 (d, J = 8 Hz, 1H), 3.67 (d, J = 8
Hz, 1H), 4.66 (d, J = 16 Hz, 1H), 4.81 (d, J = 16 Hz, 1H), 5.41-5.49 (m, 2H), 6.32 (s,
1H), 6.69-6.85 (m, 2H), 7.44-7.57 (m, 1H), 7.78 (s, 1H), 7.99 (s, 1H); [ ] = -10
(C=1, methanol ); ee 97.45% by chiral HPLC.
GNA 1412 WO 19
Example 4:
(S)((2-(2,4-Difluorophenyl)hydroxy(1H-1,2,4-triazolyl)propyl)amino)
pentylthiophenecarbonitrile (1a-04)
Pent
To a mixture of compound of Formula 3-04 (178 mg, 0.8 mmol), flame-dried K CO (552
mg, 4.0 mmol) and tetra-butyl ammonium bromide (TBAB, 32 mg, 0.1 mmol), dry ethyl
acetate (10 ml) was added and the reaction mixture was stirred at 65 ºC for 20 min and
then epoxide 4a (190 mg, 0.8 mmol) dissolved in dry ethyl acetate (5 ml) was added drop
wise over a period of 10 min and stirring was continued for further 12 h at the same
temperature. It was then cooled to room temperature and extracted with ethyl acetate (3 x
mL) after dilution with water (20 ml). The organic layer was dried over Na SO ,
concentrated and purified by column chromatography to give pure compound of the
Formula 1a-04 (270 mg); Yield: 78%; H NMR (500 MHz, CDCl ): δ 0.90 (t, J = 10 Hz,
3H), 1.26-1.35 (m, 4H), 1.52-1.58 (m, 2H), 2.57 (t, J = 10 Hz, 2H), 3.62 (d, J = 10 Hz,
1H), 3.68 (d, J = 10 Hz, 1H), 4.67 (d, J = 10 Hz, 1H), 4.86 (d, J = 10 Hz, 1H), 5.27-5.31
(m, 2H), 6.36 (s, 1H), 6.75-6.83 (m, 2H), 7.49-7.54 (m, 1H), 7.85 (s, 1H), 7.93 (s, 1H);
[ ] = -12 (C=1, methanol ); ee 99.89% by chiral HPLC.
General method of preparation of compounds of Formula (1a) and Formula (1b) via
Scheme 2:
Compounds of Formula 2 in Scheme 2 were prepared as described in .
The racemic compounds of Formula 2 were analyzed by analytical HPLC on chiral
column to get separation and to develop the conditions for preparative chiral HPLC in
order to isolate the enantiomers in pure form. The racemic compounds of Formula 2
were separated into their S and R enantiomers of Formula (1a) and Formula (1b)
GNA 1412 WO 20
respectively, using chiral preparative HPLC. The analytical as well as chiral preparative
HPLC was carried out under following general conditions:
HPLC column Chiracel-OD-H (DAICEL)
or its equivalent, or Chiracel OJ or its equivalent, or Chiralpak AD or its equivalent
Mobile Phase Alcohol: Hydrocarbon or
Alcohol: Hydrocarbon: acid
Wavelength 254 nm
Example 5:
(R)((2-(2,4-Difluorophenyl)hydroxy(1H-1,2,4-triazolyl)propyl)amino)
propylthiophenecarbonitrile (1b-02)
N Pr
The racemic compound of Formula 2-02 was separated into its S and R enantiomers of
Formula (1a-02) and Formula (1b-02) respectively using preparative HPLC under
following conditions:
HPLC column KromasilCelluCoat (250 X 4.6 mm)
Mobile Phase iso-Propanol-Pet ether-Trifluoroacetic acid
(20:80:0.1)
Wavelength 254 nm
Retention time Formula (1a-02): 30.65 min
Formula (1b-02): 26.36 min
The retention time, rotation and spectral data of compound of Formula (1a-02) was
identical with the sample obtained in Example 2.
GNA 1412 WO 21
0
The rotation of compound of Formula (1b-02) was [ ] = +10 (C=1, THF); ee 81.3%
by chiral HPLC.
Antifungal Activity Testing:
The compounds of Formula (1a) and (1b) were tested for antifungal activity against
various strains of Candida (Candida albicans ATCC 24433, C. albicans ATCC 10231,
C. albicans ATCC 2091, C. albicans ATCC 90028, C. glabrata ATCC 90030, C. Krusei
ATCC 6258, C. tropicalis ATCC 750), Cryptococcus neoformans ATCC 34664,
Aspergillus niger ATCC 16404, Aspergillus fumigatus ATCC 46645 and Fusarium
proliferatum ATCC 10052. In vitro evaluation of antifungal activity was performed by
determining the minimum inhibitory concentration (MIC) following standard broth
dilution methods (CLSI: Reference method for broth dilution antifungal susceptibility
testing of yeasts; Approved standard, second edition M27-A2, 2002; CLSI: Reference
method for broth dilution antifungal susceptibility testing of filamentous fungi; Approved
standard M38-A, 2002) using RPMI 1640 medium buffered to pH 7.0 with MOPS buffer.
Known anti-fungal agents like Fluconazole and Amphotericin-B were used as standards.
End points were determined after 48 hours visually and by using spectrophotometer
wherever necessary. The activity parameters are enumerated in Table 1:
Table 1: MIC obtained by broth dilution method
MIC in μg/ml
Organism AM FLU 2-02 1b-02 1a- 2-01 1a- 2-04 1a- 2-03 1a-
B 02 01 04 03
C. 0.25 0.5 0.06 0.5 0.06 0.25 0.12 0.25 0.12 0.12 0.06
albicans
ATCC
24433
C. 0.5 0.5 0.12 1 0.12 0.5 0.25 1 0.5 0.12 0.06
albicans
ATCC
10231
C. 0.5 0.5 0.12 1 0.12 0.5 0.25 1 0.5 0.25 0.12
albicans
ATCC
2091
C. 0.5 0.5 0.12 0.5 0.06 0.5 0.25 0.5 0.25 0.12 0.06
GNA 1412 WO 22
albicans
ATCC
90028
C. 0.25 4 0.12 0.5 0.12 0.25 0.12 0.25 0.12 0.12 0.06
glabrata
ATCC
90030
C. krusei 0.5 64 8 >8 8 64 32 8 4 8 4
ATCC
6258
C. 0.5 2 2 >8 2 4 2 2 1 1 0.5
tropicalis
ATCC
C. 0.5 2 1 8 0.5 4 2 2 1 1 0.5
neoforman
s ATCC
34664
A. niger 0.25 >128 4 >8 8 >64 >64 >8 >8 >4 >4
ATCC
16404
A. 0.5 >128 >16 8 >16 >64 >64 >8 >8 >4 >4
fumigatus
ATCC
46645
F. 2 >128 >16 >128 >16 >64 >64 >8 >8 >4 >4
proliferatu
m ATCC
10052
*For azoles and NCEs: For Fluconazole and the NCEs, MIC is recorded as the
concentration exhibiting more than 50% inhibition as compared to the positive control.
For Amphotericin B: MIC is recorded as the concentration exhibiting complete inhibition.
It was observed that one of the enantiomers of each compound was more active than the
corresponding racemic compound.
It will be evident to those skilled in the art that the invention is not limited to the details
of the foregoing illustrative examples and that the present invention may be embodied in
other specific forms without departing from the essential attributes thereof, and it is
therefore desired that the present embodiments and examples be considered in all respects
as illustrative and not restrictive.
GNA 1412 WO 23
Claims (11)
1. An enantiomeric antifungal compounds of Formula (1a) and Formula (1b) N R3 N R3 Formula 1b Formula 1a wherein each R1 and R2, which may be the same or different, is independently selected from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3 and R4, which may be the same or different, is independently selected from hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR’ (wherein R’= methyl or ethyl).
2. A process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 1, comprising, a process selected from a synthetic process comprising reacting a compound of Formula (3) with a chiral epoxide of Formula (4), in presence of a base and a catalyst Formula 3 Formula 4 wherein each R1 and R2, which may be the same or different, is independently selected from hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; each R3 and R4, which may be the same or different, is GNA 1412 WO 24 independently selected from hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms or R3 and R4 together form a cycloalkyl ring of 3 to 10 carbon atoms, and R5 is CN or COOR’ (wherein R’= methyl or ethyl); or a chiral separation process using High Performance Liquid Chromatography (HPLC).
3. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 2, wherein the base is selected from organic and inorganic bases.
4. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 3, wherein said inorganic base is selected from potassium carbonate, sodium carbonate or cesium carbonate.
5. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 2, wherein the catalyst is selected from a phase transfer catalyst such as tetrabutylammonium bromide, tertrabutylammonium chloride, triethylbenzylammonium chloride or cetyltrimethylammonium bromide.
6. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 2, wherein said chiral separation process is carried using chiral HPLC columns selected from cellulose tris (3,5-dimethylphenylcarbamate) coated on silica-gel, cellulose tris (4-methylbenzoate) coated on silica-gel or tris-(3,5- dimethylphenyl)-carbamoyl amylose coated on silica-gel using an isocratic elution system comprising a mixture of hydrocarbon (s), alcohol(s) and/or acid(s).
7. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 6, wherein the hydrocarbon is selected from pentane, hexane, petroleum ether (60-80 fraction), heptane, iso-octane, cyclohexane or cyclopentane.
8. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 6, wherein the alcohol is selected from methanol, GNA 1412 WO 25 ethanol, propanol, propanol, butanol, butanol, tert-butanol, 3-methyl butanol, 2-methylpropanol, 2-methoxyethanol or 2-ethoxyethanol.
9. The process for preparation of antifungal compounds of Formula (1a) and Formula (1b) as claimed in claim 6, wherein the acid is trifluoroacetic acid.
10. A pharmaceutical composition for treating or preventing fungal infections comprising a compound of Formula (1a) or Formula (1b) according to claim 1 in association with at least one pharmaceutical excipient.
11. The use of enantiomeric antifungal compounds of formula 1a or 1b according to claim 1 and at least one pharmaceutical excipient for the preparation of a medicament for treating or preventing fungal infections.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3063MU2011 | 2011-10-31 | ||
IN3063/MUM/2011 | 2011-10-31 | ||
PCT/IN2012/000252 WO2013065065A1 (en) | 2011-10-31 | 2012-04-09 | Optically active fluconazole analogues containing thiophenes as antifungal agents |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623864A NZ623864A (en) | 2015-12-24 |
NZ623864B2 true NZ623864B2 (en) | 2016-03-30 |
Family
ID=
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