CA2797001A1 - Diyne compositions - Google Patents
Diyne compositions Download PDFInfo
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- CA2797001A1 CA2797001A1 CA2797001A CA2797001A CA2797001A1 CA 2797001 A1 CA2797001 A1 CA 2797001A1 CA 2797001 A CA2797001 A CA 2797001A CA 2797001 A CA2797001 A CA 2797001A CA 2797001 A1 CA2797001 A1 CA 2797001A1
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- infection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/08—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings with oxygen as the ring hetero atom
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- 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
Abstract
A novel class of diyne compounds and diyne salts provided herein are effective and potent Ole1 protein inhibitors, useful for treating fungal pathogens. Compounds, fungicides and methods are provided as novel, potent and broad spectrum antifungal agents for treatment against a wide variety of fungal pathogens in humans and animals, and in the agricultural setting.
Claims (44)
1. A crystalline diyne compound of the formula I:
K+ Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COO- or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
K+ Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COO- or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
2. The compound according to claim 1, wherein the compound has a solubility in water of at least 50 mg/ml, preferably at least 60 mg/ml, more preferably at least 70 mg/ml, yet more preferably at least 80 mg/ml, even more preferably at least 90 mg/ml.
3 The compound according to any one of the preceding claims, wherein the weight change of the compound is less than 5%, preferably less than 2% at a humidity of 60%
RH compared to a humidity of 10% RH.
RH compared to a humidity of 10% RH.
4. The compound according to any one of the preceding claims, wherein the melting point of said compound is at least 100°C, preferably at least 110°C, more preferably at least 120°C, yet more preferably at least 130°C, even more preferably at least 140°C.
5. The compound according to any one of the preceding claims, wherein when the compound is stored as a solid, said solid retains at least 95%, preferably at least 98% of said compound after storage at in the range of 2 to 25°C, such as in the range of 2 to 8°C, for example at 25°C for 6 months.
6. A compound of structure IX", R1 - C(O) - (C(R2)2)x - C2 H4 - C4 - R4 IX"
wherein R1 is a hydroxyl group or a moiety that can be replaced by a hydroxyl group in a hydrolysis reaction; each R2 is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms, inclusive; R4 is a heterocyclic ring, optionally substituted at one or more positions, preferably with one or more substituents selected from the group consisting of a C1-5 alkyl, a C1-5 alkenyl, a C1-5 alkoxy, a C1-5 alcohol, a hydroxyl, an amine, a nitrate and a halogen; and x is an integer between 4 and 10, inclusive.
wherein R1 is a hydroxyl group or a moiety that can be replaced by a hydroxyl group in a hydrolysis reaction; each R2 is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms, inclusive; R4 is a heterocyclic ring, optionally substituted at one or more positions, preferably with one or more substituents selected from the group consisting of a C1-5 alkyl, a C1-5 alkenyl, a C1-5 alkoxy, a C1-5 alcohol, a hydroxyl, an amine, a nitrate and a halogen; and x is an integer between 4 and 10, inclusive.
7. The compound of claim 6, wherein the compound is one of: X" , XI" and XII".
8. The crystalline compound according to any one of claims 1-7, wherein the diyne is a diyne of formula III
wherein Y is a carbon chain of 6 to 20 carbon atoms and up to three double bonds, wherein each carbon of said alkyl or alkenyl is linked to none, one or two R2 groups, wherein each R2 independently is -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
wherein Y is a carbon chain of 6 to 20 carbon atoms and up to three double bonds, wherein each carbon of said alkyl or alkenyl is linked to none, one or two R2 groups, wherein each R2 independently is -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
9. The compound according to any one of claims 1-8, wherein Y is a linear C9 alkyl or C9 alkenyl.
10. The compound according to any one of claims 1-5, wherein Y is a linear C6-12alkenyl, preferably a linear C9 alkenyl, comprising in the range of 1 to 3 double bonds, preferably one double bond.
11. The compound according to any one of claims 1-5, wherein Y is a linear C6-12alkenyl, preferably a linear C9 alkenyl, wherein any double bonds are cis double bonds.
12. The compound according to any one of claims 1-8, wherein the diyne is a diyne of formula IV:
K+ R4-(C(R2)2)n-X-(C(R2)2)m-[C.ident.C- C.ident.C]-R3 wherein R4 is -COO- or a bioistere thereof, preferably -COO-, and n is an integer, preferably an integer in the range of 4 to 10, inclusive, preferably in the range of to 9, even more preferably in the range of 6 to 8, yet more preferably n is 7;
and m is an integer, preferably an integer in the range of 0 to 10, such as in the range of 0 to 8, for example in the range of 0 to 6, such as in the range of 0 to 4, for example in the range of 0 to 2, such as 0; and each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; and X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
K+ R4-(C(R2)2)n-X-(C(R2)2)m-[C.ident.C- C.ident.C]-R3 wherein R4 is -COO- or a bioistere thereof, preferably -COO-, and n is an integer, preferably an integer in the range of 4 to 10, inclusive, preferably in the range of to 9, even more preferably in the range of 6 to 8, yet more preferably n is 7;
and m is an integer, preferably an integer in the range of 0 to 10, such as in the range of 0 to 8, for example in the range of 0 to 6, such as in the range of 0 to 4, for example in the range of 0 to 2, such as 0; and each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; and X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
13. The compound according to any one of claims 1-8, wherein the diyne is a diyne of formula V:
wherein each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; n is an integer between 4 and 10, inclusive; X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
wherein each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; n is an integer between 4 and 10, inclusive; X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
14. The compound according to any one of claims 1-13, wherein R3 is furan.
15. The compound according to any one of claims 12 to 14, wherein X is -CH=CH-in the cis conformation.
16. The compound according to any one of claims 12 to 14, wherein X is -CH2-CH2-.
17. The compound according to any one of claims 1 to 5, wherein the diyne is potassium (Z)-14-(furan-2-yl)tetradeca-9-en-11,13 -diynoate.
18. The compound according to any one of claims 1 to 5, wherein the diyne is potassium 14-(furan-2-yl)tetradeca-11,13-diynoate.
19. A pharmaceutical composition comprising the diyne compound according to any one of claims 1 to 18 and one or more pharmaceutically acceptable excipients.
20. The pharmaceutical composition according to claim 19, wherein the composition further comprises at least one antifungal polyene, such as amphotericin B
21. A pharmaceutical composition comprising the diyne compound according to any one of claims 1 to 18 for treatment of an infection by a fungus in an individual in need thereof.
22. The pharmaceutical composition according to any one of claims 20 to 21, wherein the composition is prepared for administration of in the range of 0.001mg/kg to 100mg/kg.
23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the fungal infection is infection by one or more fungi selected from the group consisting of Candida spp.
(for example C. albicans, C. krusei, C. glabrata, C. tropicalis, C.
parapsilosis, C.
guilliermondii, C. haemulonii, C. lusitaniae, C. lipolytica, C. norvegensis, C. viswanathii, C.
kefyr or C. dubliniensis), Aspergillus spp. (for example A. fumigatus, A. f avus, A. niger or A.
terreus), Histoplasma capsulatum, Coccidioides immitis,Coccidioides posadasii, Cryptococcus spp. (for example C. neoformans (for example var. neoformans or var. gattii), C. bidus, C.
laurentii, or C. fusarium), Zygomycetes (such as Rhizopus oryzae, R.
micropsorus, R. pusillus, Cunninghamelle bertholletiae, Saksenaea vasiformis, Mucor circinelloides, M.
ramosissimus, Absidia corynbifera, Apophysomyces elegans, Cokeromyces recurvatus or Syncephalastrum racemosum), Malassezia spp. (for example M.furfur or M. globosa), Hyalohyphomycetes (for example Fusarium solani or Scedosporium spp., such as S. prolificans or S.
apiospermum), Dermatophytes (for example Trichophyton spp. (for example T. mentagrophytes, T. rubrum or T. tonsurans), Epidermophytonfloccosum, Microsporum spp (for example M.
cookei, M. canis, M. vanbreuseghemii, M. gallinae or M. gypseum) or Trichosporon terrestre), Blastomyces dermatitidis, Sporothrix schenkii, Chromomycotic fungi (for example Fonsecaeapedrosoi, F. compacta, Cladophylophora carrionii or Phialophora verrucosa)and Madurella spp. (for example M. mycetomatis or M. griseum), Pneumocystis jirovecii, Pneumocystis carinii, Botrytis cinerea; Magnaporthe grisea; Anamorph: Pyricularia oryzae Colletotrichum gleoesporioides-Chilli strain; Colletotrichum gleoesporioides- mango strain; Fusarium verticillioides; Fusarium oxysporum; Alternaria solani; Uncinula necator Syn Erysiphe necator;
Macrophomina phaseolina; Syn. Sclerotium bataticola and Rizoctonia bataticola;
Botryodiplodia theobromae;
Basidiomycota Sclerotium rolfsii; Rhizoctonia solani; Puccinia arachidis;
Oomycota Pythium aphanidermatum; and Plasmopara viticola Syn. Personopora viticola.
(for example C. albicans, C. krusei, C. glabrata, C. tropicalis, C.
parapsilosis, C.
guilliermondii, C. haemulonii, C. lusitaniae, C. lipolytica, C. norvegensis, C. viswanathii, C.
kefyr or C. dubliniensis), Aspergillus spp. (for example A. fumigatus, A. f avus, A. niger or A.
terreus), Histoplasma capsulatum, Coccidioides immitis,Coccidioides posadasii, Cryptococcus spp. (for example C. neoformans (for example var. neoformans or var. gattii), C. bidus, C.
laurentii, or C. fusarium), Zygomycetes (such as Rhizopus oryzae, R.
micropsorus, R. pusillus, Cunninghamelle bertholletiae, Saksenaea vasiformis, Mucor circinelloides, M.
ramosissimus, Absidia corynbifera, Apophysomyces elegans, Cokeromyces recurvatus or Syncephalastrum racemosum), Malassezia spp. (for example M.furfur or M. globosa), Hyalohyphomycetes (for example Fusarium solani or Scedosporium spp., such as S. prolificans or S.
apiospermum), Dermatophytes (for example Trichophyton spp. (for example T. mentagrophytes, T. rubrum or T. tonsurans), Epidermophytonfloccosum, Microsporum spp (for example M.
cookei, M. canis, M. vanbreuseghemii, M. gallinae or M. gypseum) or Trichosporon terrestre), Blastomyces dermatitidis, Sporothrix schenkii, Chromomycotic fungi (for example Fonsecaeapedrosoi, F. compacta, Cladophylophora carrionii or Phialophora verrucosa)and Madurella spp. (for example M. mycetomatis or M. griseum), Pneumocystis jirovecii, Pneumocystis carinii, Botrytis cinerea; Magnaporthe grisea; Anamorph: Pyricularia oryzae Colletotrichum gleoesporioides-Chilli strain; Colletotrichum gleoesporioides- mango strain; Fusarium verticillioides; Fusarium oxysporum; Alternaria solani; Uncinula necator Syn Erysiphe necator;
Macrophomina phaseolina; Syn. Sclerotium bataticola and Rizoctonia bataticola;
Botryodiplodia theobromae;
Basidiomycota Sclerotium rolfsii; Rhizoctonia solani; Puccinia arachidis;
Oomycota Pythium aphanidermatum; and Plasmopara viticola Syn. Personopora viticola.
24. The pharmaceutical composition according to any one of claims 20 to 23, wherein said individual is an immunocompromised individual.
25. A method of treating a fungal infection in an individual in need thereof, said method comprising administering a therapeutically effective amount of the diyne compound according to any one of claims 1 to 18 to said individual.
26. Use of a diyne compound according to any one of claims 1 to 18 for the preparation of a medicament for treatment of a fungal infection in an individual in need thereof.
27. Use of the diyne compound according to any one of claims 1 to 18 for preventing or treating fungal infections of a plant.
28. A method for reducing the risk of infection by a fungus or treating infection by a fungus in a plant, said method comprising contacting said plant with the diyne compound according to anyone of claims 1 to 18.
29. The method according to claim 28, wherein the method comprises contacting said plant with the aqueous solution comprising the compound according to any one of claims 1 to 18.
30 A pharmaceutical composition comprising a diyne of formula I':
Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, and wherein said pharmaceutical composition is for treatment of an infection by a fungus dependent on activity of stearoyl-CoA desaturase in an individual in need thereof, and wherein i) the infection causes formation of a biofilm of said fungus; or ii) the infection causes formation of macronodules of said fungus, preferably macronodules surrounded by a perimeter of ground-glass opacity; or iii) the pharmaceutical composition is prepared for killing at least 50%, preferably at least 80%, more preferably at least 95% of the infecting fungus; or iv) said fungal infection is a recurrent fungal infection; or v) said fungus is resistant to one or more antifungal agents, which are not of formula I' .
vi) said fungus is resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2.
vii) said infection is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions.
viii) said infection at least involves infection of one or more inner organs, tissues or cells of a human being.
Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, and wherein said pharmaceutical composition is for treatment of an infection by a fungus dependent on activity of stearoyl-CoA desaturase in an individual in need thereof, and wherein i) the infection causes formation of a biofilm of said fungus; or ii) the infection causes formation of macronodules of said fungus, preferably macronodules surrounded by a perimeter of ground-glass opacity; or iii) the pharmaceutical composition is prepared for killing at least 50%, preferably at least 80%, more preferably at least 95% of the infecting fungus; or iv) said fungal infection is a recurrent fungal infection; or v) said fungus is resistant to one or more antifungal agents, which are not of formula I' .
vi) said fungus is resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2.
vii) said infection is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions.
viii) said infection at least involves infection of one or more inner organs, tissues or cells of a human being.
31. The pharmaceutical composition according to claim 30, wherein said infection is an infection involving at least partly infection of a body surface, for example infection of skin, nails or mucosal membranes of body surfaces.
32. The pharmaceutical composition according to any one of claims 30 to 31, wherein the fungus is a dermatophyte.
33. The pharmaceutical composition according to any one of claims 30 to 32, wherein one or more fungus is selected from the group consisting of Candida spp. (for example C. albicans, C.
krusei, C. glabrata, C. tropicalis, C. parapsilosis, C. guilliermondii, C.
haemulonii, C.
lusitaniae, C. lipolytica, C. norvegensis, C. viswanathii, C. kefyr or C.
dubliniensis), Aspergillus spp. (for example A. fumigatus, A. flavus, A. niger or A. terreus), Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Cryptococcus spp. (for example C. neoformans (for example var. neoformans or var. gattii), C. bidus, C. laurentii, or C.fusarium), Zygomycetes (such as Rhizopus oryzae, R. micropsorus, R. pusillus, Cunninghamelle bertholletiae, Saksenaea vasiformis, Mucor circinelloides, M. ramosissimus, Absidia corymbifera, Apophysomyces elegans, Cokeromyces recurvatus or Syncephalastrum racemosum), Malassezia spp.
(for example M. furfur or M. globosa), Hyalohyphomycetes (for example Fusarium solani or Scedosporium spp., such as S. prolificans or S. apiospermum), Dermatophytes (for example Trichophyton spp. (for example T. mentagrophytes, T. rubrum or T. tonsurans), Epidermophyton floccosum, Microsporum spp (for example M. cookei, M. canis, M.
vanbreuseghemii, M. gallinae or M. gypseum) or Trichosporon terrestre), Blastomyces dermatitidis, Sporothrix schenkii, Chromomycotic fungi (for example Fonsecaea pedrosoi, F. compacta, Cladophylophora carrionii or Phialophora verrucosa) and Madurella spp. (for example M.
mycetomatis or M. griseum), Pneumocystis jirovecii, Pneumocystis carinii, Botrytis cinerea;
Magnaporthe grisea; Anamorph: Pyricularia oryzae Colletotrichum gleoesporioides- Chilli strain;
Colletotrichum gleoesporioides- mango strain; Fusarium verticillioides;
Fusarium oxysporum;
Alternaria solani; Uncinula necator Syn Erysiphe necator; Macrophomina phaseolina; Syn.
Sclerotium bataticola and Rizoctonia bataticola; Botryodiplodia theobromae;
Basidiomycota Sclerotium rolfsii; Rhizoctonia solani; Puccinia arachidis; Oomycota Pythium aphanidermatum;
and Plasmopara viticola Syn. Personopora viticola.
krusei, C. glabrata, C. tropicalis, C. parapsilosis, C. guilliermondii, C.
haemulonii, C.
lusitaniae, C. lipolytica, C. norvegensis, C. viswanathii, C. kefyr or C.
dubliniensis), Aspergillus spp. (for example A. fumigatus, A. flavus, A. niger or A. terreus), Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Cryptococcus spp. (for example C. neoformans (for example var. neoformans or var. gattii), C. bidus, C. laurentii, or C.fusarium), Zygomycetes (such as Rhizopus oryzae, R. micropsorus, R. pusillus, Cunninghamelle bertholletiae, Saksenaea vasiformis, Mucor circinelloides, M. ramosissimus, Absidia corymbifera, Apophysomyces elegans, Cokeromyces recurvatus or Syncephalastrum racemosum), Malassezia spp.
(for example M. furfur or M. globosa), Hyalohyphomycetes (for example Fusarium solani or Scedosporium spp., such as S. prolificans or S. apiospermum), Dermatophytes (for example Trichophyton spp. (for example T. mentagrophytes, T. rubrum or T. tonsurans), Epidermophyton floccosum, Microsporum spp (for example M. cookei, M. canis, M.
vanbreuseghemii, M. gallinae or M. gypseum) or Trichosporon terrestre), Blastomyces dermatitidis, Sporothrix schenkii, Chromomycotic fungi (for example Fonsecaea pedrosoi, F. compacta, Cladophylophora carrionii or Phialophora verrucosa) and Madurella spp. (for example M.
mycetomatis or M. griseum), Pneumocystis jirovecii, Pneumocystis carinii, Botrytis cinerea;
Magnaporthe grisea; Anamorph: Pyricularia oryzae Colletotrichum gleoesporioides- Chilli strain;
Colletotrichum gleoesporioides- mango strain; Fusarium verticillioides;
Fusarium oxysporum;
Alternaria solani; Uncinula necator Syn Erysiphe necator; Macrophomina phaseolina; Syn.
Sclerotium bataticola and Rizoctonia bataticola; Botryodiplodia theobromae;
Basidiomycota Sclerotium rolfsii; Rhizoctonia solani; Puccinia arachidis; Oomycota Pythium aphanidermatum;
and Plasmopara viticola Syn. Personopora viticola.
34. The pharmaceutical composition according to any one of claims 30 to 33, wherein the diyne is a diyne of formula III' wherein R1 is a hydroxyl group or a moiety that can be replaced by a hydroxyl group in a hydrolysis reaction; Y is a carbon chain of 6 to 20 carbon atoms and up to three double bonds, wherein each carbon of said alkyl or alkenyl is linked to none, one or two R2 groups, wherein each R2 independently is -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; R3 is a heterocyclic ring, which optionally may be substituted at one or more positions; or a pharmaceutically acceptable salt of said diyne.
35. The pharmaceutical composition according to any one of claims 30 to 34, wherein the diyne is a diyne of formula IV' :
R4-(C(R2)2)n-X-(C(R2)2)m-[C.ident.C- C.ident.C]-R3 wherein R4 is -COOH or a bioistere thereof, and n is an integer, preferably an integer in the range of 4 to 10, inclusive, preferably in the range of to 9, even more preferably in the range of 6 to 8, yet more preferably n is 7;
and m is an integer, preferably an integer in the range of 0 to 10, such as in the range of 0 to 8, for example in the range of 0 to 6, such as in the range of 0 to 4, for example in the range of 0 to 2, such as 0; and each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; and X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
R4-(C(R2)2)n-X-(C(R2)2)m-[C.ident.C- C.ident.C]-R3 wherein R4 is -COOH or a bioistere thereof, and n is an integer, preferably an integer in the range of 4 to 10, inclusive, preferably in the range of to 9, even more preferably in the range of 6 to 8, yet more preferably n is 7;
and m is an integer, preferably an integer in the range of 0 to 10, such as in the range of 0 to 8, for example in the range of 0 to 6, such as in the range of 0 to 4, for example in the range of 0 to 2, such as 0; and each R2 is, independently, -H, -OH or a hydrocarbon moiety containing between 1 and 6 carbon atoms, inclusive; and X is -CH2-CH2- or -CH=CH- or phenyl; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions.
36. The pharmaceutical composition according to any one of claims 30 to 35, wherein said diyne comprises a bioisoster of -COOH, and said bioisoster of -COOH is selected from the group consisting of -COR1, tetrazoles, tetrazolates and salts thereof, wherein R1 is a hydroxyl group or a moiety that can be replaced by a hydroxyl group in a hydrolysis reaction.
37. The pharmaceutical composition according to any one of claims 30 to 36, wherein R3 is selected from the group consisting of pyrrole, furan and thiophene which optionally may be substituted with one or more selected from the group consisting of lower alkyl, lower alkenyl, lower alkoxy, lower alcohol, hydroxyl, amine, -NO2 and halogen.
38. The pharmaceutical composition according to any one of claims 35 to 37, wherein X is -CH=CH- in the cis conformation.
39. The pharmaceutical composition according to any one of claims 35 to 37, wherein X is -CH2-CH2-.
40. The pharmaceutical composition according to any one of claims 30 to 39, wherein the diyne is (Z)-14-(furan-2-yl)tetradeca-9-en-11,13-diynoic acid or a pharmaceutically acceptable salt thereof.
41. The pharmaceutical composition according to any one of claims 30, wherein the diyne is (Z)-14-(furan-2-yl)tetradeca-9-en-11,13-diynoic acid or a pharmaceutically acceptable salt thereof.
42. The pharmaceutical compositions according to any one of claims 30 to 39, wherein the diyne is the compound according to any one of claims 1 to 18.
43. A method of treating an infection by a fungus dependent on activity of stearoyl-CoA
desaturase in an individual in need thereof, said method comprising administering to said individual a pharmaceutical composition comprising a therapeutically effective amount of a diyne of the formula I' Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions; and wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, and wherein the infection is one or more of the following i) the infection causes formation of a biofilm of said fungus;
ii) the infection causes formation of macronodules of said fungus;
iii) causes formation of macronodules of said fungus surrounded by a perimeter of ground-glass opacity;
iv) is a recurrent fungal infection;
v) is an infection by a fungus resistant to one or more antifungal agents, which are not of formula I';
vi) is an infection by a fungus resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2;
vii) is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions;
xiii) involves infection of one or more inner organs, tissues or cells of a human being.
desaturase in an individual in need thereof, said method comprising administering to said individual a pharmaceutical composition comprising a therapeutically effective amount of a diyne of the formula I' Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions; and wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, and wherein the infection is one or more of the following i) the infection causes formation of a biofilm of said fungus;
ii) the infection causes formation of macronodules of said fungus;
iii) causes formation of macronodules of said fungus surrounded by a perimeter of ground-glass opacity;
iv) is a recurrent fungal infection;
v) is an infection by a fungus resistant to one or more antifungal agents, which are not of formula I';
vi) is an infection by a fungus resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2;
vii) is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions;
xiii) involves infection of one or more inner organs, tissues or cells of a human being.
44. Use of a diyne of the formula I' :
Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions;
wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, for the preparation of a pharmaceutical composition for treatment of an infection by a fungus dependent on activity of stearoyl-CoA
desaturase in a individual in need thereof, and wherein the infection is one or more of the following:
i) causes formation of a biofilm of said fungus;
ii) causes formation of macronodules of said fungus;
iii) causes formation of macronodules of said fungus surrounded by a perimeter of ground-glass opacity;
iv) is a recurrent fungal infection;
v) is an infection by a fungus resistant to one or more antifungal agents, which are not of formula I';
vi) is an infection by a fungus resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2;
vii) is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions;
viii) involves infection of one or more inner organs, tissues or cells of a human being.
Z-[C.ident.C- C.ident.C]-R3 wherein Z is a carbon chain substituted with -COOH or a bioisostere thereof and optionally also substituted with one or more additional substituents; and R3 is a heterocyclic ring, which optionally may be substituted at one or more positions;
wherein said diyne is capable of inhibiting conversion of a saturated fatty acid to a .DELTA.9-monounsaturated fatty acid in a fungus, for the preparation of a pharmaceutical composition for treatment of an infection by a fungus dependent on activity of stearoyl-CoA
desaturase in a individual in need thereof, and wherein the infection is one or more of the following:
i) causes formation of a biofilm of said fungus;
ii) causes formation of macronodules of said fungus;
iii) causes formation of macronodules of said fungus surrounded by a perimeter of ground-glass opacity;
iv) is a recurrent fungal infection;
v) is an infection by a fungus resistant to one or more antifungal agents, which are not of formula I';
vi) is an infection by a fungus resistant to one or more antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis;
b) binding to ergosterol;
c) inhibiting 1,3-.beta.-glucan synthase;
d) inhibiting epoxidase;
e) inhibiting Leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2;
vii) is an infection involving at least partly infection of tissue, organs or cells with hypoxic conditions;
viii) involves infection of one or more inner organs, tissues or cells of a human being.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33016910P | 2010-04-30 | 2010-04-30 | |
| US61/330,169 | 2010-04-30 | ||
| US34638110P | 2010-05-19 | 2010-05-19 | |
| US61/346,381 | 2010-05-19 | ||
| PCT/EP2010/063161 WO2011134538A1 (en) | 2010-04-30 | 2010-09-08 | Diyne compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2797001A1 true CA2797001A1 (en) | 2011-11-03 |
Family
ID=43446965
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2797001A Abandoned CA2797001A1 (en) | 2010-04-30 | 2010-09-08 | Diyne compositions |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2563769A1 (en) |
| AU (1) | AU2010352387B2 (en) |
| CA (1) | CA2797001A1 (en) |
| WO (1) | WO2011134538A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023001905A1 (en) | 2021-07-20 | 2023-01-26 | Selmod Gmbh | Novel antifungal compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1224168T3 (en) | 1999-10-07 | 2006-12-11 | Phytera Inc | Antifungal ends |
| KR20120079054A (en) * | 2009-07-10 | 2012-07-11 | 에볼바 아게 | Diyne compositions |
-
2010
- 2010-09-08 CA CA2797001A patent/CA2797001A1/en not_active Abandoned
- 2010-09-08 WO PCT/EP2010/063161 patent/WO2011134538A1/en active Application Filing
- 2010-09-08 AU AU2010352387A patent/AU2010352387B2/en not_active Ceased
- 2010-09-08 EP EP10754715A patent/EP2563769A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010352387B2 (en) | 2014-05-29 |
| EP2563769A1 (en) | 2013-03-06 |
| WO2011134538A1 (en) | 2011-11-03 |
| AU2010352387A1 (en) | 2012-02-02 |
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