WO1993001203A1 - Antifungal amphotericin derivative - Google Patents
Antifungal amphotericin derivative Download PDFInfo
- Publication number
- WO1993001203A1 WO1993001203A1 PCT/GB1992/001209 GB9201209W WO9301203A1 WO 1993001203 A1 WO1993001203 A1 WO 1993001203A1 GB 9201209 W GB9201209 W GB 9201209W WO 9301203 A1 WO9301203 A1 WO 9301203A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- decarboxy
- ascorbate salt
- hydroxymethylamphotericin
- amphotericin
- ascorbate
- Prior art date
Links
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
Definitions
- 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.
- the present invention further provides the L- ascorbate salt of 16- decarboxy-16-hydroxymethylamphotericin B in substantially pure form.
- the L- ascorbate salt or 16-decarboxy-16- hydroxymethylamphotericin 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.
- a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
- 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.
- 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
- a compound for use as an active therapeutic substance is intended for use in the treatment of disorders in animals including humans.
- the L- ascorbate salt of 16-decarboxy-16- hydroxymethylamphotericin B has anti-fungal activity and is potentially useful in combating fungal infections in animals including humans.
- the present invention further provides the L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B for use in the treatment of fungal infections.
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
ANTIFUNGAL AMPHOTERICIN DERIVATIVE
This invention relates to the L-ascorbate salt of 16-decarboxy-16- hydroxymethylamphotericin 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-16- hydroxymethylamphotericm B is particularly stable and has improved solubility in aqueous media.
Accordingly, the present invention provides the L- ascorbate salt of 16- decarboxy-16-hydroxymethylamphotericin B.
The present invention further provides the L- ascorbate salt of 16- decarboxy-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 L- ascorbate 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 L- ascorbic 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
the 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
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 R^ 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 R-j_', 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, R ' is preferably 9- Fluoroenylmethyoxy-carbonyl and R4 is most preferably triethylsilyl.
Compounds 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. Trichophvton. Microsporum or Epidermophvton. 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 Blastomvces spp. It may also be of use in treating eumycotic mycetoma, chromoblastomycosis, and phycomycosis.
The invention further provides a pharmaceutical composition comprising the It- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B together with a pharmaceutically acceptable diluent or carrier. The composition is preferably for human use in tablet, capsule, injectable or cream form.
For human use, the L- ascorbate salt or 16-decarboxy-16- hydroxymethylamphotericin 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
that the daily dosage level of the L- ascorbate salt of 16-decarboxy-16- hydroxymethylamphotericin 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-16- hydroxymethylamphotericin 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-16- hydroxymethylamphotericin 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 16- decarboxy-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-16- hydroxymethylamphotericin B has anti-fungal activity and is potentially useful in combating fungal infections in animals including humans.
Accordingly 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 16- decarboxy-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-16- hydroxymethylamphaterin 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.
Description 1
N-(9-Fluorenylmethoxycarbonyl)-16-decarboxy-16-hvdroxymethyl amphotericin B (DP
A solution of N-(9-fluorenylmethoxycarbonyl)-16-decarboxy-16- hydroxymethyl-lS-O-methyl-S.δ^.θ.ll.lδ.Sδ^'^'-nona-O- triethylsilylamphotericin B (prepared as described in EP- 375223) (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-toluenesulphonate (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-hvdroxymethylamphotericin B (D2)
The title compound of Description 1 (9.720g, 8.59mmoles) was stirred at
room 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 C 7H75NOχgNa 932.5.
Example 1
16-Decarboxy-16-hvdroxymethylamphotericin 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 (IH, dd, J 8.6, 15.2Hz), 5.44-5.31 (2H,m), 4.64 (lH,s), 4.35 (IH, d, J 3.3 Hz), 4.34 (lH,m), 4.24 (lH,m), 4.15 (IH, tt, J 3.4, 9.2 Hz), 3.94 (IH, dt, J
4.7. 10.8 Hz), 3.90 (IH, 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 (IH, dd, J
9.3. 16.9 Hz), 2.19 (IH, dd, J 3.1, 16.8 Hz), 1.98 (IH, 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
1. The L- ascorbate salt of 16-decarboxy-16-hydroxymethyl- amphotericin 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-hydroxymethyl- amphotericin B in greater than 95% purity.
4. The L- ascorbate salt of 16-decarboxy-16-hydroxymethyl- amphotericin B in greater than 90% purity.
5. The L- ascorbate salt of 16-decarboxy-16-hydroxymethyl- amphotericin B in greater than 80% purity.
6. A process for the preparation of the L- ascorbate 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 L- ascorbic acid and isolating the resulting product.
7. A process for the preparation of the L-ascorbate salt of 16- decarboxy-16-hydroxymethyl- amphotericin B or its free base which comprises the selective reduction of a compound of formlula (II):
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 L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B to the animal.
11. The use of the L- ascorbate salt of 16-decarboxy-16- hydroxymethylamphotericin 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 L- ascorbate salt of 16-decarboxy-16-hydroxymethylamphotericin B and a pharmacetically acceptable carrier.
13. The use of the L- ascorbate salt of 16-decarboxy-16- hydroxymethylamphotericin B in the treatment of fungal infections in animals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9114949.2 | 1991-07-11 | ||
| GB919114949A GB9114949D0 (en) | 1991-07-11 | 1991-07-11 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993001203A1 true WO1993001203A1 (en) | 1993-01-21 |
Family
ID=10698172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1992/001209 WO1993001203A1 (en) | 1991-07-11 | 1992-07-03 | Antifungal amphotericin derivative |
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) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7960506B2 (en) | 2006-12-14 | 2011-06-14 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US7981998B2 (en) | 2006-12-14 | 2011-07-19 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US7981999B2 (en) | 2007-02-23 | 2011-07-19 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US9096684B2 (en) | 2011-10-18 | 2015-08-04 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US9527896B2 (en) | 2007-01-31 | 2016-12-27 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
| US9604919B2 (en) | 2012-11-01 | 2017-03-28 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
| US9951099B2 (en) | 1999-05-18 | 2018-04-24 | President And Fellows Of Harvard College | Stabilized compounds having secondary structure motifs |
| US9957299B2 (en) | 2010-08-13 | 2018-05-01 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10022422B2 (en) | 2009-01-14 | 2018-07-17 | Alleron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10023613B2 (en) | 2015-09-10 | 2018-07-17 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles as modulators of MCL-1 |
| US10059741B2 (en) | 2015-07-01 | 2018-08-28 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10213477B2 (en) | 2012-02-15 | 2019-02-26 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10227380B2 (en) | 2012-02-15 | 2019-03-12 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
| US10253067B2 (en) | 2015-03-20 | 2019-04-09 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| US10301351B2 (en) | 2007-03-28 | 2019-05-28 | President And Fellows Of Harvard College | Stitched polypeptides |
| US10300109B2 (en) | 2009-09-22 | 2019-05-28 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10471120B2 (en) | 2014-09-24 | 2019-11-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| US10905739B2 (en) | 2014-09-24 | 2021-02-02 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and formulations thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0375223A2 (en) * | 1988-12-19 | 1990-06-27 | Beecham Group Plc | Novel compounds |
| EP0375222A2 (en) * | 1988-12-19 | 1990-06-27 | Beecham Group Plc | Amphotericin B derivatives |
| 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 AU AU22308/92A patent/AU2230892A/en not_active Abandoned
- 1992-07-03 WO PCT/GB1992/001209 patent/WO1993001203A1/en active Application Filing
- 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
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0375223A2 (en) * | 1988-12-19 | 1990-06-27 | Beecham Group Plc | Novel compounds |
| EP0375222A2 (en) * | 1988-12-19 | 1990-06-27 | Beecham Group Plc | Amphotericin B derivatives |
| 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 |
Cited By (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10487110B2 (en) | 1999-05-18 | 2019-11-26 | President And Fellows Of Harvard College | Stabilized compounds having secondary structure motifs |
| US9951099B2 (en) | 1999-05-18 | 2018-04-24 | President And Fellows Of Harvard College | Stabilized compounds having secondary structure motifs |
| US7981998B2 (en) | 2006-12-14 | 2011-07-19 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US8609809B2 (en) | 2006-12-14 | 2013-12-17 | Aileron Thraputics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US10328117B2 (en) | 2006-12-14 | 2019-06-25 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US7960506B2 (en) | 2006-12-14 | 2011-06-14 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US9175056B2 (en) | 2006-12-14 | 2015-11-03 | Alleron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US9675661B2 (en) | 2006-12-14 | 2017-06-13 | Aileron Therapeutics, Inc. | Bis-sulfhydryl macrocyclization systems |
| US9527896B2 (en) | 2007-01-31 | 2016-12-27 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
| US9957296B2 (en) | 2007-02-23 | 2018-05-01 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US10030049B2 (en) | 2007-02-23 | 2018-07-24 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US7981999B2 (en) | 2007-02-23 | 2011-07-19 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US9493509B2 (en) | 2007-02-23 | 2016-11-15 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US8637686B2 (en) | 2007-02-23 | 2014-01-28 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US9023988B2 (en) | 2007-02-23 | 2015-05-05 | Aileron Therapeutics, Inc. | Triazole macrocycle systems |
| US10301351B2 (en) | 2007-03-28 | 2019-05-28 | President And Fellows Of Harvard College | Stitched polypeptides |
| US10022422B2 (en) | 2009-01-14 | 2018-07-17 | Alleron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10300109B2 (en) | 2009-09-22 | 2019-05-28 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US9957299B2 (en) | 2010-08-13 | 2018-05-01 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US9522947B2 (en) | 2011-10-18 | 2016-12-20 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10308699B2 (en) | 2011-10-18 | 2019-06-04 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US9096684B2 (en) | 2011-10-18 | 2015-08-04 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US10227380B2 (en) | 2012-02-15 | 2019-03-12 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
| US10213477B2 (en) | 2012-02-15 | 2019-02-26 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
| US9845287B2 (en) | 2012-11-01 | 2017-12-19 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
| US9604919B2 (en) | 2012-11-01 | 2017-03-28 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
| US10669230B2 (en) | 2012-11-01 | 2020-06-02 | Aileron Therapeutics, Inc. | Disubstituted amino acids and methods of preparation and use thereof |
| US10471120B2 (en) | 2014-09-24 | 2019-11-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| US10905739B2 (en) | 2014-09-24 | 2021-02-02 | 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| MX9204031A (en) | 1993-01-01 |
| AU2230892A (en) | 1993-02-11 |
| TW199894B (en) | 1993-02-11 |
| GB9114949D0 (en) | 1991-08-28 |
| PT100671B (en) | 1999-07-30 |
| PT100671A (en) | 1993-10-29 |
| IE922264A1 (en) | 1993-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO1993001203A1 (en) | Antifungal amphotericin derivative | |
| CA1057754A (en) | Antihypertensive agents | |
| US5958951A (en) | Modified form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride | |
| KR20010072080A (en) | Phenylazole compounds, process for producing the same and drugs for hyperlipemia | |
| US4724238A (en) | Method of treating inflammatory diseases with labdan derivatives | |
| EP0375222B1 (en) | Amphotericin B derivatives | |
| US4340760A (en) | Monophenylamine derivatives | |
| KR0185200B1 (en) | Polyene macrolide derivatives | |
| CN112812099B (en) | Compound for treating peptic ulcer and preparation method and application thereof | |
| EP0906309B1 (en) | Modified form of the r(-)-n-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride | |
| US7049301B2 (en) | Quercetin derivatives and their medical usages | |
| WO1998043638A1 (en) | Therapeutic agent for autoimmune diseases | |
| KR20010040292A (en) | (E)-3-[1-N-Butyl-5-[2-(2-carboxyphenyl)methoxy-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-prop-2-enoic acid monoargininyl salt | |
| KR880001865B1 (en) | Process for preparing 4-(1-imidazolyl methyl)cinnamic acid hydro-chloride hydrate | |
| EP1118324A1 (en) | Analgesic agent comprising a cyclobutanedicarboxylic acid derivative | |
| US4322555A (en) | Nonaprenylamine derivatives | |
| EP0003286B1 (en) | Derivatives of ergopeptide alkaloids, process for their preparation and pharmaceutical compositions containing them | |
| US4857529A (en) | Interferon inducing, anti-vaccinia, and/or anti-influenza compositions | |
| JP3117251B2 (en) | 14-Op-chlorobenzoyl aconine and analgesic / anti-inflammatory agent | |
| US4297487A (en) | Phosphonium salts | |
| HU201082B (en) | Enolethers of 6-chloro-4-hydroxy-2-methyl-N-(2-pyridyl)-2H-thieno(2,3-e)-1,2-thiazin-3-carboxylic acid amide-1,1-dioxide, a process for their preparation and their use. | |
| DE2004301A1 (en) | Phenylserine derivatives | |
| EP0418655B1 (en) | Conjugated gamma-hydroxybutenolide compounds and antiulcer agents containing the same as an effective ingredient | |
| JPH062748B2 (en) | Novel hydantoin derivative and pharmaceutical composition containing the compound as an active ingredient | |
| HUT62579A (en) | Process for producing 5,7-dihydroxy-2-methyl-8-/4-(3-hydroxy)-1-(1-propyl)-piperidinyl/-4h-benzopyran-4-one and pharmaceutical compositions comprising such compound as active ingredient |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |
|
| 122 | Ep: pct application non-entry in european phase |