WO2014018671A1 - Composés thérapeutiques pour le traitement du cancer - Google Patents

Composés thérapeutiques pour le traitement du cancer Download PDF

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Publication number
WO2014018671A1
WO2014018671A1 PCT/US2013/051885 US2013051885W WO2014018671A1 WO 2014018671 A1 WO2014018671 A1 WO 2014018671A1 US 2013051885 W US2013051885 W US 2013051885W WO 2014018671 A1 WO2014018671 A1 WO 2014018671A1
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Prior art keywords
compound
colomitide
formula
pharmaceutically acceptable
salt
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PCT/US2013/051885
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English (en)
Inventor
Christine Salomon
Yasuhiko KAWAKAMI
Anindya Bagchi
Yudi RUSMAN
Robert BLANCHETTE
Benjamin Held
Aaron SPIKE
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Regents Of The University Of Minnesota
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Publication of WO2014018671A1 publication Critical patent/WO2014018671A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RTK receptor tyrosine kinase
  • FGFR Fibroblast Growth Factor Receptor
  • RTK small molecule receptor tyrosine kinase
  • Natural products represent a validated source of structurally diverse and biologically active compounds that have been historically successful as anti-cancer agents and cellular tools: for example, rapamycin, an immunosuppressant obtained from Streptomyces hygroscopicus is also a potent anticancer agent which acts by specifically inhibiting mammalian target of rapamycin (mTOR) kinase.
  • mTOR mammalian target of rapamycin
  • tumorsphere Treatment of two-week old tumorspheres with colomitide C resulted in the reversal of the transformation process and return to the smaller, hollow "normal" mammosphere state within one day. Staining studies with labeled cellular markers showed that colomitide C treatment leads to upregulation of apoptosis in FGFR activated cells. Pharmacokinetic studies demonstrated that colomitide C is stable in both blood plasma and liver microscomes.
  • R 1 is (C]-C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C C 6 )alkynyl, wherein each (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, and (Q-C ⁇ alkynyl is optionally substituted with one or more groups independently selected from halo, (Ci-C ⁇ alkoxy, (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 )alkanoyloxy;
  • R a is H or (d-C ⁇ alkanoyl
  • R b and R c are each independently selected from H, and (C 1 -C 6 )alkanoyl;
  • R d is hydroxy, (C ! -C )alkoxy, -NR b R c , or (C 1 -C 6 )alkanoyloxy, wherein the (C 1 -C 6 )alkoxy and (C!-C 6 )alkanoyloxy are each optionally substituted with one or more groups independently selected from halo, (Q-C ⁇ alkoxy, (C 1 -C 6 )alkoxycarbonyl, aryl, and (C 1 -C 6 )alkanoyloxy, and wherein each aryl is optionally substituted with one or more groups independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifiuoromethoxy, (C 1 -C 6 )alkoxy, (Q-C ⁇ alkoxycarbonyl, and (Ci- C 6 )alkanoyloxy;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention also provides a method for treating or preventing cancer in an animal comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.
  • the invention also provides a method for modulating the FGF1R pathway in a cell comprising contacting the cell with a compound of formula I or a salt thereof.
  • the invention also provides a method for treating a pathological condition associated with the FGF1R pathway in an animal comprising administering a compound of formula I or a
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of cancer.
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for prophylactic or therapeutic treatment of a condition associated with the FGF1R pathway.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating cancer in an animal (e.g. a mammal such as a human).
  • an animal e.g. a mammal such as a human.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a pathological condition associated with the FGF1R pathway in an animal (e.g. a mammal such as a human).
  • an animal e.g. a mammal such as a human.
  • the invention also provides a whole animal in vivo screen for FGF signaling modulators using a larval zebrafish tail regeneration system as described herein.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.
  • Figure 1 Larvae fin amputation and regeneration
  • A Normal larvae fin at 4 days post fertilization.
  • B Amputation is performed at the bold vertical line red line.
  • C Normal larvae fin at 6 days post fertilization.
  • D Regenerated larvae fin at 6 days post fertilization, 2 days after amputation.
  • Vertical dotted line indicates the amputated level.
  • the shape of the fin is outlined by a curved dotted line.
  • FIG. 2 Images of regenerating fins after treating with DMSO (A, Control) and BIO (B). Dotted and solid vertical lines represent the amputation plane and the distal edge of the regenerating fin, respectively. Horizontal arrows represent the length to be measured.
  • Figure 3 Colomitide C can reverse the proliferative phenotype in iFGFRl mammary epithelial cells.
  • Figure 4 shows that Colomitide C can inhibit proliferation and induce apoptosis in iFGFRl mammary epithelial cells.
  • the top panel shows the total number of iFGFRl cells seen by using a using a dye (Hoechst33342) that has been untreated or treated with Colomitide C. While all four untreated iFGFRl cells can take up EdU, which suggests that they are proliferating, only 2 out of 20 iFGFRl cells treated with Colomitide C are shown to take up EdU, suggesting that majority of these cells are not proliferating following the treatment of Colomitide C (middle panel). Also, most of the Colomitide C treated iFGFRl cells are shown to undergo apoptosis as shown by TUNEL assay, while none of the control untreated cells are undergoing apoptosis.
  • FIG. 5 Colomitide C inhibits phosphorylation of AKT and affects the downstream targets of AKT signaling pathway.
  • Colomitide C can inhibit proliferation and induce apoptosis in human breast cancer cell lines.
  • Three breast cancer cell lines, MDA-MB-361, CAMA1 and HCC38 were treated with or without Colomitide C and tested for proliferation (EdU incorporation) and apoptosis (TUNEL).
  • EdU incorporation proliferation
  • TUNEL apoptosis
  • FIG. 7 Colomitide C targets phosphorylation of AKT in HCC38 human breast cancer cells.
  • a known inhibitor SU5402 is used as a control.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho- fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • (Ci-C ⁇ alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 1 -C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso- butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C 2 -C 6 )alkyn
  • the compound of formula I is a compound of formula (la):
  • the compound of formula I is a compound of formula (lb):
  • the compound of formula I is a compound of formula (Id):
  • the compound of formula I is a compound of formula (Ie):
  • R 1 is (C 1 -C 6 )alkyl.
  • R 1 is 1-methylpropyl.
  • R 2 is H and R 3 is -OH or NH 2 .
  • R d is hydroxy
  • R d is (C 1 -C 6 )alkoxy optionally substituted with one or more groups independently selected from halo, (CrC 6 )alkoxy, (CrC ⁇ alkoxycarbonyl, aryl, and (Ci- C 6 )alkanoyloxy, wherein each aryl is optionally substituted with one or more groups independently selected from halo.
  • R d is (C 1 -C 6 )alkanoyloxy, optionally substituted with one or more groups independently selected from halo,
  • R d is benzyloxy, phenylcarbonyloxy, amino, or a-trifluoromethyl-a- methoxybenzyl.
  • the compound of formula I is not colomitide C.
  • the invention provides colomotide C in isolated or purified form (e.g. at least about 80, 90, 95, or 99% pure).
  • the compound of formula I is not colomitide A. In another embodiment the compound of formula I is not colomitide B. In one embodiment the compound of formula I is not colomitide A or colomitide B. In one embodiment the compound of formula I is not colomitide A, colomitide B or colomitide C.
  • An intermediate useful for preparing a compound of formula I is a compound of the following formula
  • Another intermediate useful for preparing a compound of formula I is a compound of the following formula
  • An intermediate useful for preparing a compound of formula 1(b), is a compound of the following formula
  • An intermediate useful for preparing a compound of formula 1(c), 1(d) or 1(e), is a compound of the following formula
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a- glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as
  • compositions or formulations in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the biological activity of a compound of the invention may be determined using pharmacological models which are well known to the art, or using Test A described below.
  • Regeneration of the tail fin of zebrafish larvae was used as one of biological assays.
  • the assay was a modification of a procedure reported by Kawakami A, et al., Dev Dyn. 2004, 231(4): 693-699.
  • Zebrafish housing, mating, embryo collection, and raising larvae are performed by following standard procedures in the Zebrafish Book (Westerfield, M. (2000). The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). 4th ed., Univ. of Oregon Press, Eugene). Zebrafish larvae used in the assay were not given any food during the assay period (up to 6 days post fertilization). Embryos and larvae were developed at 28°C in the embryo media. For anesthetizing, approximately 1% volume of tricaine (MS-222) solution (40 mg/ml) was added to larvae.
  • MS-222 tricaine
  • a larva was placed on a transparent plastic dish, and associated liquid was removed by absorbing it using Kimwipe, so that the larva attached to the dish.
  • the tail was cut with a razor blade at the immediately caudal level of the neural tube (Fig. 1). The cutting was made perpendicular to the neural tube.
  • magnification of the Zeiss V8 Discovery stereomicroscope was x8.
  • the longest length of regenerated area was determined by i Solution software by measuring the pixel number of the line that was drawn perpendicular to the amputation plane (Fig. 2).
  • the average of regenerated lengths of the control group was set as 1.00, and regenerated length of each larva was calculated.
  • the regenerated length by treating larvae with a compound was evaluated in comparison to a control group, and statistical significance was determined by Student's t-test. If the p value was smaller than 0.05, it was considered that the compound has significant activity of either enhancing or inhibiting regeneration. If more than three larvae of a control group (treated by DMSO) were dead, it was considered that the quality of the larvae of the specific batch was bad, and the entire data of the assay was not used to evaluate any compound in the assay.
  • BIO has been shown to impair larvae fin regeneration in a similar, but not identical assay (Lijoy K. Mathew, et al., FASEB J. 2008 August; 22(8): 3087-3096). Thus, if larvae treated by BIO did not show statistically significant inhibition of fin regeneration, it was considered that the quality of the larvae of the specific batch was bad, and the entire data of the assay was not used to evaluate any compound in the assay. If more than three larvae of a treated group were dead, the compound in the assay was not evaluated.
  • the biological activity of a compound of the invention may also be determined using pharmacological models which are well known to the art, or using Test B described below.
  • Colomitide C was tested for the fin regeneration assay. As shown in Table 1, at 10 ug/ml, colomitide C inhibited fin regeneration. The degree of regenerated lengths was 74.8 ⁇ 1.9%, compared to DMSO treated control larvae.
  • BIO (0.5 nM) 40 51.6 41 47 0 44.90 5.43 0.656 0.846 0.672 0.771 0.736 0.089 0.004
  • Benzyl-colomitide C was tested in the larvae fin regeneration assay. As shown in Table 2, it showed toxicity at 10 ug/ml. However, as shown in Table 3, at lower concentrations, it exhibited an inhibitory activity on fin regeneration.
  • Colomitide C can have any effect on specific signaling pathways which are found to be upregulated in cancer.
  • a mouse model system where the FGFRl signaling pathway can be induced via a FGFRl dimerizer, AP20187 was used.
  • Upregulation of FGFRl in the mammary epithelial cells results into uncontrolled proliferation of these cells which can be assayed by transformed acinar structure in the matrigel ( Figure 3 A).
  • Colomitide C can prevent the transformation of these cells upon FGFRl activation. Additionally, it can reverse the phenotype when applied to the FGFRl mediated transformed acinar structures.
  • Colomitide C can inhibit transformation of iFGFRl mammary epithelial cells, proliferation and apoptosis assays of these cells in presence and absence of Colomitide C was carried out. As shown in Figure 4, Colomitide C can inhibit the iFGFRl mammary epithelial cells to incorporate 5-ethynyl-2'-deoxyuridine (EdU), which suggest that Colomitide C inhibits proliferation of these cells. More strikingly, TUNEL assay shows that iFGFRl mammary epithelial cells undergo apoptosis in presence of Colomitide C when FGFR1 is upregulated ( Figure 4).
  • EdU 5-ethynyl-2'-deoxyuridine
  • Colomitide C affects AKT phosphorylation in iFGFRl mammary epithelial cells
  • GFR1 can mediate activation of several sinaling pathways, including induction of ERK1/2 and AKT signaling pathways. These are marked by phosphorylation of the ERK1/2 and/or AKT. Aberrant phosphorylation of these two proteins are found in many cancers. Western analysis of these two proteins was carried out. Whereas phosphorylation of ERKl/2 remains unaffected,
  • Colomitide C can inhibit proliferation and induce apoptosis in human breast cancer cells
  • Colomitide C can have therapeutic potential in human cancers.
  • MDA-MB 361, CAMA 1, and HCC 38 All these cell lines are known to have aberrant FGFR signaling.
  • All the three breast cancer cell lines have dramatic reduction in proliferation and induction of apoptosis, as seen previously in the iFGFRl mammary epithelial cells ( Figure 6).
  • the AKT phosphorylation was reduced in the Colomitide C treated HCC38 cells, suggesting that for this breast cancer cell line, Colomitide C is likely affecting the AKT signaling pathway (Figure 7).
  • the above experiments provide strong proof of principle that
  • Colomitide C can have anti-cancer activity and can be of therapeutic value.
  • the strain was cultured in 20 erlenmeyer flask containing 100 g rice media at room temperature. After 30 days, the culture was extracted with two times 4 liters of methanol and two times 4 liters of ethylacetate, consecutively. The extracts were combined and dried in the vacuum. Dried extract was suspensed in 500 ml of water and then partitioned with 500 ml of ethylacetete. Dried ethylacetate extract was then dissolved in 500 ml of 90 % methanol (v/v in water) and extracted with 250 ml of n-hexane. Methanol extracts (later called as ethylacetate extracts) was dried and further processed for the isolation of colomitide C (1)
  • fraction 24.53 The next fractions (called fraction 24.53 ; 3324.5 mg)was re-separated using 50 g silica with linear gradient elution of 100 % to 0 % of n-hexane/ethylacetate to obtain more colomitide C (1) (970.2 mg).
  • Total colomitide C (1) isolated from this culture was 2773 mg.
  • Colomitide C (1) (28 mg ; 0.12 mmol) and cerium chloride heptahydrate (92 mg ; 0.32 mmol) were dissolved in 1 ml methanol. While stirring at 0°C, sodium borohydride (9.3 mg ; 0.24 mmol) was added into solution and the reaction was continued at 0°C for 1 hr. After the mixture was kept at -20° C for 24 hr, it was then dried out and portioned between water and EtOAC. Ethylacetate fraction (25.6 mg) was then subjected to a separation using preparative HPLC with gradient elution 35% - 100 % of acetonitrile/H 2 0. Three isomers of products 2 (70 %), 3 (15%) and 4 (8%) were isolated as white solid.
  • Example 2 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

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Abstract

La présente invention concerne un composé représenté par la formule (I) dans laquelle R1 à R3 ont l´une quelconque des valeurs définies dans la description, ou un sel correspondant. Les composés modulent l'activité de la voie de FGF1R et se révèlent utiles pour le traitement du cancer.
PCT/US2013/051885 2012-07-24 2013-07-24 Composés thérapeutiques pour le traitement du cancer WO2014018671A1 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2015177668A1 (fr) * 2014-05-19 2015-11-26 Pfizer Inc. Composes de 6,8-dioxabicyclo [3.2.1] octane -2,3-diol substitues utilises en tant qu'agents de ciblage d'asgpr
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
CN106459120A (zh) * 2014-05-19 2017-02-22 辉瑞大药厂 作为asgpr靶向剂的被取代的‑6,8‑二氧杂双环[3.2.1]辛烷‑2,3‑二醇化合物
US9617293B2 (en) 2014-05-19 2017-04-11 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10039778B2 (en) 2014-05-19 2018-08-07 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US10376531B2 (en) 2014-05-19 2019-08-13 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
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