IE922264A1 - Novel compounds - Google Patents
Novel compoundsInfo
- Publication number
- IE922264A1 IE922264A1 IE922264A IE922264A IE922264A1 IE 922264 A1 IE922264 A1 IE 922264A1 IE 922264 A IE922264 A IE 922264A IE 922264 A IE922264 A IE 922264A IE 922264 A1 IE922264 A1 IE 922264A1
- Authority
- IE
- Ireland
- Prior art keywords
- decarboxy
- hydroxymethylamphotericin
- ascorbate salt
- salt
- ascorbate
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 17
- 150000000994 L-ascorbates Chemical class 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical class OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 15
- 206010017533 Fungal infection Diseases 0.000 claims description 14
- 208000031888 Mycoses Diseases 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 12
- 239000012458 free base Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=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-KKGHZKTASA-N 0.000 claims description 5
- 150000001412 amines Chemical group 0.000 claims description 5
- 229960003942 amphotericin b Drugs 0.000 claims description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 230000000843 anti-fungal effect Effects 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B 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 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 abstract description 2
- 229940121375 antifungal agent Drugs 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 206010008803 Chromoblastomycosis Diseases 0.000 description 1
- 208000015116 Chromomycosis Diseases 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 201000007336 Cryptococcosis Diseases 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 241001480035 Epidermophyton Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- 206010065764 Mucosal infection Diseases 0.000 description 1
- 241001537205 Paracoccidioides Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241001238303 Turdus fuscater Species 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- 206010061418 Zygomycosis Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000005889 eumycotic mycetoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- -1 triethylsilyl Chemical group 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to the L-ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B, a process for preparing it and to its use as an antifungal agent.
Description
Novel Compounds This invention relates to the L-ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B, its preparation and its use as a therapeutic agent.
EP-A-0375222 (Beecham Group p.l.c.) discloses a class of compounds which are described as possessing anti-fungal activity. One compound which is specifically mentioned in this patent specification is Example 4 i.e. 16-decarboxy-16-hydroxymethylamphotericin B. This compound is only described as the free base which has been found to possess poor solubility in aqueous media.
It has now been discovered that the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B is particularly stable and has improved solubility in aqueous media.
Accordingly, the present invention provides the L- ascorbate salt of 16decarboxy-16-hydroxymethylamphotericin B. , , I The present invention further provides the L- ascorbate salt of 16decarboxy-16-hydroxymethylamphotericin B in substantially pure form.
In a further aspect, the present invention provides the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B in greater than 5% purity, preferably greater than 60% purity, yet more preferably greater than 80% purity, yet more preferably greater than 90% purity and most preferably greater than 95% purity.
The present invention also provides a process for the preparation of the Lascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B which comprises reacting the free base or a salt other than the L- ascorbate of 16-decarboxy-16-hydroxymethylamphotericin B in solution with Lascorbic acid and isolating the resulting product.
The reaction is preferably carried out in aqueous media at ambient temperature. The addition of ascorbic acid is preferably controlled so that P30120 =-5 22 2 6 4 -2the pH of the solution of 16-decarboxy-16-hydroxymethylamphotericin B does not fall below pH5.
The ascorbate salt is suitably isolated by freeze drying. 16-Decarboxy-16-hydroxymethylamphotericin B, free base may be prepared according to the procedures outlined in EP-0375222 (Beecham Group p.l.c.) Alternatively, 16-decarboxy-16-hydroxymethylamphotericin B free base is prepared by the process which comprises the selective reduction of a wherein Rj_‘ is an activated carboxylic acid derivative; R2' is C^.g alkyl; R3' is an amine protection group; and each R4' is a silyl protecting group; and thereafter, optionally or as necessary and in any appropriate order converting R2' to hydrogen removing any amine protection group and removing any R4 silyl protecting group and/or forming a pharmaceutically acceptable salt thereof, this forms a further aspect of the invention, and the free base may be converted to the L-ascorbate salt as hereinbefore described.
Preferred values for Ri', R2' and R3' and interconversions of R2' to hydrogen and the removal of amine protection groups are disclosed in EP-A-0375222 (Beecham Group p.l.c.).
Preferred silyl protecting groups are described in EP-A-0375223 (Beecham Group p.l.c.) R2' is preferably methyl, R3' is preferably 9Fluoroenylmethyoxy-carbonyl and R4' is most preferably triethylsilyl.
P30120 ® 2 2 2 -3Compounds of formula (II) may be prepared using the procedures outlined in EP-A-037522 (Beecham Group p.l.c.).
The L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B is an anti-fungal agent, potentially useful in combating fungal infections in animals, including humans. For example it is potentially useful in treating topical fungal infections in man caused by, among other organisms, species of Candida. Trichophyton. Microsporum or Epidermophyton. or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). It may also be used in the treatment of systemic fungal infections caused by, for example Candida albicans. Cryptococcus neoformans. Aspergillus fumigatus. Coccidioides. Paracoccidioides. Histoplasma or Blastomyces spp. It may also be of use in treating eumycotic mycetoma, chromoblastomycosis, and phycomycosis.
The invention further provides a pharmaceutical composition comprising the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B together with a pharmaceutically acceptable diluent or carrier. The I composition is preferably for human use in tablet, capsule, injectable or cream form.
For human use, the L- ascorbate salt or 16-decarboxy-16hydroxymethylamphotericin B 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. For example it may be administered orally in the form of a tablet containing such excipients as starch or lactose, or in a capsule or ovule either alone or in admixture with excipients, or in the form of an elixir or suspension containing a flavouring or colouring agent. It may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, it is 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.
For oral and parenteral administration to human patients, it is expected P30120 -1' 2 2 2 <§ -4that the daily dosage level of the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B will be from 0.1 to 20 mg/kg preferably 0.5 to 2 mg/kg (in divided doses) when administered by either the oral or parenteral route. Thus tablets or capsules of the compounds can be expected to contain from 5 mg to 0.5 g of active compound for administration singly or 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 will vary with the 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 merited, and such are within the scope of this invention.
Alternatively, the L- ascorbate salt or 16-decarboxy-16hydroxymethylamphotericin B 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. For example, it can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or it 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.
Within the indicated dose range, no adverse toxicological effects have been observed with the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B which would preclude it administration to suitable patients for the treatment of fungal infections.
The present invention further provides the L- ascorbate salt of 16decarboxy-16-hydroxymethylamphotericin B for use as an active therapeutic substance.
A compound for use as an active therapeutic substance is intended for use in the treatment of disorders in animals including humans. As stated above, the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B has anti-fungal activity and is potentially useful in combating fungal infections in animals including humans.
P30120 -5Accordingly the present invention further provides the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B for use in the treatment of fungal infections.
The present invention additionally provides a method of treatment of fungal infections in animals, including humans, which comprises administering an effective anti-fungal amount of the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B thereof to the animal.
The present invention also provides the use of the L- ascorbate salt of 16decarboxy-16-hydroxymethylamphotericin B for the manufacture of a medicament for use as an active therapeutic substance in the treatment of fungal infections in animals, including humans.
The present invention also provides pharmaceutical composition for use in the treatment of fungal infection which comprises an anti-fungally effective amount of the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphaterin B and a pharmaceutically acceptable carrier.
The present invention further provides the use of the L- ascorbate salt of 16-decarboxy-16-hydroxymethyl- amphotericin B in the treatment of fungal infections in animals.
The following Example illustrates the preparation of the compound of the invention and the following Descriptions illustrate the preparation of intermediates thereto.
P30120 -6Description 1 N-(9-FluorenyImethoxycarbonyI)-16-decarboxy-16-hvdroxymethyl amphotericin B (Dl) A solution ofN-(9-fluorenylmethoxycarbonyI)-16-decarboxy-16hydroxymethyl-13-0-methyl-3,5,8,9,ll,15,35,2',4'-nona-0triethylsilylamphotericin B (prepared as described in EP375223) (25.90g, 11.90mmoles) in tetrahydrofuran (60ml) was added via a canula to HF-pyridine solution (prepared from 26.3g of HF-pyridine and 186ml of pyridine made up to 460ml with tetrahydrofuran) in a plastic conical flask. Methanol (50ml) was added and the mixture was stirred at room temperature. After 20 hours, the mixture was poured into diethyl ether/n-hexane (9L, 1:1). The precipitated product was collected by filtration, washed with diethyl ether and dried to give a yellow powder.
This product was stirred at room temperature in tetrahydrofuran (360ml)/water (60ml) with pyridinium p-toluepesulphonate (18.4g, 73.1mmoles). After 1.5 hours, triethylamine (9.66g, 13.3ml, 95.4mmoles) was added and the tetrahydrofuran was removed on the rotary evaporator. The aqueous concentrate was diluted with water (2L) and the solid product was collected by filtration, washed with water and dried under suction. The solid product was stirred in tetrahydrofuran/water (4:3, 100ml) and then filtered. This wash procedure was repeated twice more and the product was then dried to give the title compound as a bright yellow powder (9.72g) (Dl).
HPLC: Reverse phase ODS 4m Nova-Pak 8mmxl0cm, radial compression column; eluant 82% methanol-18% pH 3.5 phosphate buffer - lml.min‘1; detection wavelength 350nm; Retention time 10.5 minutes.
Description 2 16-Decarboxy-16-hydroxymethylamphotericin B (D2) The title compound of Description 1 (9.720g, 8.59mmoles) was stirred at P30120 -7room temperature in DMSO (140ml)/methanol (40ml) and piperidine (1.17g, 1.36ml, 13.7mmoles) was added. After 1.25 hours, the mixture was diluted with methanol (100ml), filtered and added to diethyl ether (10L). The precipitated product was collected by filtration, washed with diethyl ether/ethyl acetate (1:1, 3x250ml) and dried to give the title compound as a yellow powder (7.49g) (D2).
Mass spectrum: FAB (Thiodiethanol/sodium matrix) observed mass 932.5, calculated mass for C47H75NOieNa 932.5.
Example 1 16-Decarboxy-16-hydroxymethyIamphotericin B-L-ascorbate (El) A suspension of the title compound of Description 2 (18.80g, 20.7mmoles) in distilled water (1.25L) was stirred at room temperature and L- ascorbic acid (3.46g, 19.6mmoles) was added portionwise at such a rate that the pH did not fall below 5. After all the ascorbic acid had been added (1.25 hours), the mixture was stirred for a further 30 minutes at room temperature, filtered and then freeze dried to give the title compound as a yellow/orange solid (22.3g) (El). dH 400MHz (CD3OD/D6-DMSO, 3:1): 6.51-6.12 (12H, series of m), 6.05 (1H, dd, J 8.6, 15.2Hz), 5.44-5.31 (2H,m), 4.64 (lH,s), 4.35 (1H, d, J 3.3 Hz), 4.34 (lH,m), 4.24 (lH,m), 4.15 (1H, tt, J 3.4, 9.2 Hz), 3.94 (1H, dt, J 4.7, 10.8 Hz), 3.90 (1H, m), 3.77 (3H,m), 3.67 (lH,m), 3.64-3.55 (3H,m), 3.32 (lH,m), 3.17 (2H,m), 2.99 (lH,m), 2.44-2.33 (2H,m), 2.27 (1H, dd, J 9.3, 16.9 Hz), 2.19 (1H, dd, J 3.1, 16.8 Hz), 1.98 (1H, dd, J 4.8, 12.1 Hz), 1.82-1.28 (14H, series of m), 1.26 (3H, d, J 5.9 Hz), 1.18 (3H, d, J 6.4 Hz), 1.10 (3H, d, J 6.4 Hz), 0.99 (3H, d, J 7.1 Hz) ppm. 2 protons masked by solvent.
Claims (20)
1.Claims 1. The L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B.
2. The L- ascorbate salt of 16-decarboxy-16-hydroxymethy-l amphotericin B in substantially pure form.
3. The L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B in greater than 95% purity.
4. The L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B in greater than 90% purity.
5. The L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B in greater than 80% purity.
6. A process for the preparation of the L- ascorbate salt of 16decarboxy-16-hydroxymethylamphotericin B which comprises reacting the free base or a salt other than the L- ascorbate of 16decarboxy-16-hydroxymethylamphotericin B in solution with Lascorbic acid and isolating the resulting product.
7. A process for the preparation of the L-ascorbate salt of 16decarboxy-16-hydroxymethyl- amphotericin B or its free base which comprises the selective reduction of a compound of formlula (II): Me NH (II) P30120 -9wherein R]_' is an activated carboxylic acid derivative; R2' is C^.g alkyl; R3' is an amine protection group; and each R4' is a silyl protecting group; and thereafter, optionally or as necessary and in any appropriate order converting R2' to hydrogen removing any amine protection group and removing any R4' silyl protecting group and thereafter if required carrying out the process as defined in claim 6.
8. A process according to claim 6 or 7 wherein the the L- ascorbate salt of 16-decarboxy-16-hydroxymethyl- amphotericin B is isolated by freeze drying.
9. A pharmaceutical composition comprising the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B together with a pharmaceutically acceptable diluent or carrier.
10. A method of treatment of fungal infections in animals, which comprises administering an effective anti-fungal amount of the Lascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B to the animal.
11. The use of the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B for the manufacture of a medicament for use as an active therapeutic substance in the treatment of fungal infections in animals.
12. A pharmaceutical composition for use in the treatment of fungal infections in animals which comprises an effective amount of the Lascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B and a pharmacetically acceptable carrier.
13. The use of the L- ascorbate salt of 16-decarboxy-16hydroxymethylamphotericin B in the treatment of fungal infections in animals. S, 21 2 6 4 -10
14. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
15. A compound as claimed in claim 1, whenever prepared by a process claimed in any one of claims 6, 7, 8 or 14.
16. A process according to claim 7 for the preparation of an L-ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B or its free base, substantially as hereinbefore described and exemplified.
17. An L-ascorbate salt of 1 6-decarboxy-16-hydroxymethylamphotericin B or its free base, whenever prepared by a process claimed in any one of claims 7, 8 or 16.
18. A pharmaceutical composition according to claim 9, substantially as hereinbefore described.
19. Use according to claim 11, substantially as hereinbefore described.
20. Use according to claim 13, substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919114949A GB9114949D0 (en) | 1991-07-11 | 1991-07-11 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE922264A1 true IE922264A1 (en) | 1993-01-13 |
Family
ID=10698172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE922264A IE922264A1 (en) | 1991-07-11 | 1992-07-10 | Novel compounds |
Country Status (7)
| Country | Link |
|---|---|
| AU (1) | AU2230892A (en) |
| GB (1) | GB9114949D0 (en) |
| IE (1) | IE922264A1 (en) |
| MX (1) | MX9204031A (en) |
| PT (1) | PT100671B (en) |
| TW (1) | TW199894B (en) |
| WO (1) | WO1993001203A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7192713B1 (en) | 1999-05-18 | 2007-03-20 | President And Fellows Of Harvard College | Stabilized compounds having secondary structure motifs |
| EP2094721B1 (en) | 2006-12-14 | 2018-02-14 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US7981998B2 (en) | 2006-12-14 | 2011-07-19 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| CA2939778C (en) | 2007-01-31 | 2019-01-29 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
| ES2648687T3 (en) | 2007-02-23 | 2018-01-05 | Aileron Therapeutics, Inc. | Triazole-linked macrocyclic peptides |
| CN101730708B (en) | 2007-03-28 | 2013-09-18 | 哈佛大学校长及研究员协会 | Stitched polypeptides |
| AU2010204648B2 (en) | 2009-01-14 | 2016-09-01 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| CA2774973A1 (en) | 2009-09-22 | 2011-03-31 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| SI2603600T1 (en) | 2010-08-13 | 2019-04-30 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| WO2013059525A1 (en) | 2011-10-18 | 2013-04-25 | Aileron Therapeutics, Inc. | Peptidomimetic macrocyles |
| SG11201404648PA (en) | 2012-02-15 | 2014-09-26 | Aileron Therapeutics Inc | Peptidomimetic macrocycles |
| CN108912211A (en) | 2012-02-15 | 2018-11-30 | 爱勒让治疗公司 | Triazole crosslinking and thioether crosslinking peptidomimetic macrocyclic compound |
| EP2914256B1 (en) | 2012-11-01 | 2019-07-31 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
| EP3197478A4 (en) | 2014-09-24 | 2018-05-30 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| BR112017005736A2 (en) | 2014-09-24 | 2017-12-12 | Aileron Therapeutics Inc | peptidomimetic macrocycles and formulations thereof |
| US10253067B2 (en) | 2015-03-20 | 2019-04-09 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| US10059741B2 (en) | 2015-07-01 | 2018-08-28 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10023613B2 (en) | 2015-09-10 | 2018-07-17 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles as modulators of MCL-1 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8829592D0 (en) * | 1988-12-19 | 1989-02-08 | Beecham Group Plc | Novel compounds |
| GB8829593D0 (en) * | 1988-12-19 | 1989-02-08 | Beecham Group Plc | Novel compounds |
| EP0431874A1 (en) * | 1989-12-08 | 1991-06-12 | Beecham Group p.l.c. | Novel compounds |
| EP0431870A1 (en) * | 1989-12-08 | 1991-06-12 | Beecham Group p.l.c. | Amphotericin B derivatives |
-
1991
- 1991-07-11 GB GB919114949A patent/GB9114949D0/en active Pending
-
1992
- 1992-07-03 WO PCT/GB1992/001209 patent/WO1993001203A1/en active Application Filing
- 1992-07-03 AU AU22308/92A patent/AU2230892A/en not_active Abandoned
- 1992-07-09 PT PT10067192A patent/PT100671B/en not_active IP Right Cessation
- 1992-07-09 MX MX9204031A patent/MX9204031A/en unknown
- 1992-07-10 IE IE922264A patent/IE922264A1/en not_active Application Discontinuation
- 1992-07-13 TW TW81105515A patent/TW199894B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| PT100671B (en) | 1999-07-30 |
| PT100671A (en) | 1993-10-29 |
| AU2230892A (en) | 1993-02-11 |
| MX9204031A (en) | 1993-01-01 |
| TW199894B (en) | 1993-02-11 |
| GB9114949D0 (en) | 1991-08-28 |
| WO1993001203A1 (en) | 1993-01-21 |
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| FA9A | Application withdrawn section 33(1) |