WO2012035436A1 - Analogues de promédicaments à base de plinabuline et utilisations thérapeutiques associées - Google Patents

Analogues de promédicaments à base de plinabuline et utilisations thérapeutiques associées Download PDF

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WO2012035436A1
WO2012035436A1 PCT/IB2011/002730 IB2011002730W WO2012035436A1 WO 2012035436 A1 WO2012035436 A1 WO 2012035436A1 IB 2011002730 W IB2011002730 W IB 2011002730W WO 2012035436 A1 WO2012035436 A1 WO 2012035436A1
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compound
substituted
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alkyl
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Yoshio Hayashi
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Tokyo University Of Pharmacy And Life Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/12—Triazine radicals

Definitions

  • the present invention relates to compounds and methods of synthetic preparation in the fields of chemistry and medicine. More specifically, the present invention relates to compounds and procedures for making compounds useful in the treatment of cancer and the treatment of fungal infections.
  • VDAs Vascular disrupting agents
  • Avastin, Sutent, Nexavar, and Erbitux a number of angiogenesis inhibitors targeted to the VEGF and EGF pathways in standard of care oncology regimens (e.g., Avastin, Sutent, Nexavar, and Erbitux).
  • VDAs target tumor vasculature in a markedly different, and perhaps complimentary mechanism, to previous oncology therapeutics.
  • Tumor blood vessels differ from normal blood vessels in their pathophysiological characteristics, in particular structural disorganization and high dependence on endothelial cells. Tumor blood vessels also lack the structural support of connective tissue, pericytes and smooth muscle, and tumor blood vessels have high permeability (i.e., "leakiness"). VDAs target the tumor vasculature through a different set of molecular targets than angiogenesis inhibitors by exploiting these characteristics. Preclinical and clinical studies indicate that the efficacy and toxicity profiles of VDAs are different from and complimentary to the VEGF targeted agents and standard cytotoxic agents. In particular myelosuppression, mucositis, prolonged hypertension and bleeding events have not appeared to be associated with VDAs. Not only do these agents differ from the angiogenesis inhibitors as well as cytotoxic agents in terms of toxicity profiles, but data suggest the potential for synergy in anti-tumor activity.
  • Plinabulin is a VDA that was derived from a marine microbial source, as opposed to most other VDAs that are derived from terrestrial sources. Plinabulin binds to the colchicine binding site of b-tubulin preventing polymerization and disrupting the cytoplasmic microtubule network. This leads to loss of vascular endothelial cytoskeletal function, morphology and cohesion, as well as cytotoxicity in proliferating immature tumor vascular endothelial cells, resulting in vascular architectural destabilization and selective tumor vascular collapse and necrosis. This vascular collapse commences within minutes of exposure.
  • the tumor neovasculature is particularly susceptible to these effects given the lack of supporting structure and dependence on immature proliferating endothelial cells.
  • Plinabulin has been shown to produce anti-tumor activity in animal models as a single agent and synergistically with other chemotherapy agents including taxanes.
  • Overall, preclinical studies indicate that plinabulin has a favorable safety and activity profile, which has led to the initiation of clinical trials.
  • Favorable data from early clinical studies has lead to the initiation of a Phase 2 clinical trial program utilizing plinabulin.
  • Some embodiments disclosed herein include a compound having the structure of Formula I or ⁇ , and tautomers and pharmaceutically acceptable salts thereof:
  • Ri can be a hydrophilic moiety
  • R 2 can be selected from a hydrogen atom; a halogen atom; mono-substituted, poly- substituted or unsubstituted, straight or branched chain variants of the following residues: Ci-Ci 2 alkyl, CrC 12 alkenyl, acyl, and alkoxy; and mono-substituted, poly- substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl; or R 2 can be a bond to Ar;
  • R 4 and R 6 can each be separately selected from hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: Ci-C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro,
  • Xi can be selected from an oxygen atom, a sulfur atom, and a nitrogen atom substituted with a R5 group;
  • each R 5 can be independently selected from a hydrogen atom, a halogen atom, and saturated CrC 12 alkyl, unsaturated CrC 12 alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl and substituted sulfonyl groups;
  • Y can be selected from a nitrogen atom substituted with R 5 , an oxygen atom, a sulfur atom, a oxidized sulfur atom, a methylene group, and a substituted methylene group;
  • PG can be a protecting group;
  • L can be a linking group
  • n can be 0, 1, 2, 3, or 4;
  • Ar can be a cyclic or polycyclic aryl or heteroaryl ring system comprising between one and three rings, wherein:
  • each ring in said system can be separately a 5, 6, 7, or 8 membered ring;
  • each ring in said system separately can have 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen;
  • each ring in said system can be optionally substituted with one or more substituents selected from hydrogen; halogen; hydroxyl; mono-substituted, poly- substituted or unsubstituted, straight or branched chain variants of the following residues: C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly- substituted or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, carbonyl, amino, aminocarbonyl, amide, aminocarbonyloxy
  • each ring in said system can be optionally fused to a ring selected from dioxole, dithiole, oxathiole, dioxine, dithiine, oxathiine, and indenone.
  • Another embodiment includes a method for treating a condition in an animal, by administering to the animal a compound of formula I or ⁇ in an amount that is effective to reduce vascular proliferation or in an amount that is effective to reduce vascular density.
  • the condition can be selected from immune and non-immune inflammation, rheumatoid arthritis, chronic articular rheumatism, psoriasis, diabetic retinopathy, neovascular glaucoma, retinopathy of prematurity, macular degeneration, corneal graft rejection, retrolental fibroplasia, rubeosis, capillary proliferation in atherosclerotic plaques, and osteoporosis.
  • said condition can be a neoplastic condition.
  • said neoplastic condition can be cancer.
  • the cancer can be selected from one or more of colon cancer, breast cancer, lung cancer, pancreas cancer, prostate cancer, and melanoma.
  • the condition can not be cancer.
  • said condition can be a retinopathy.
  • said retinopathy can be diabetic retinopathy.
  • said retinopathy can be an age-related macular degeneration.
  • said animal can be a human.
  • the condition can be a condition associated with hypervascularization.
  • Another embodiment includes a method of inducing vascular collapse in an animal, comprising treating said animal with a therapeutically effective amount of a compound of formula I or ⁇ , wherein said therapeutically effective amount of said compound causes tubulin depolymerization in said vasculature.
  • said animal can be a human.
  • said human can have a disease selected from a tumor, a diabetic retinopathy, and an age-related macular degeneration.
  • the disease can not be cancer.
  • the tumor can be selected from one or more of a colon tumor, a breast tumor, a lung tumor, a pancreas tumor, and a prostate tumor.
  • Another embodiment includes a method of preferentially targeting tumor vasculature over non-tumor tissue vasculature, comprising administering to an animal a compound of formula I or ⁇ .
  • the non-tumor tissue can be selected from skin, muscle, brain, kidney, heart, spleen, and gut.
  • the tumor vasculature can be preferentially targeted over non-tumor tissue vasculature by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%.
  • the animal can be a human.
  • Another embodiment includes a pharmaceutical composition comprising a compound of formula I or ⁇ together with a pharmaceutically acceptable carrier.
  • Another embodiment includes a method for treating a tumor in an animal, comprising irradiating the tumor with radiation and administering to the animal a compound of Formula (I) and/or ( ⁇ ).
  • Still further embodiments relate to pharmaceutical compositions for treating or preventing vascular proliferation comprising a pharmaceutically effective amount of a compound disclosed herein together with a pharmaceutically acceptable carrier therefor.
  • the vascular proliferation can be a symptom of a disease, for example, cancer, age-related macular degeneration and diabetic retinopathy.
  • Other embodiments relate to methods of preferentially targeting tumor vasculature over non-tumor tissue vasculature, which methods can include administering to an animal an agent that preferentially targets tumor vasculature over non-tumor tissue vasculature.
  • the condition can be any other that is associated with hypervascularization, associated with vasculature or which relies upon vasculature.
  • Examples include immune and non-immune inflammation, rheumatoid arthritis, chronic articular rheumatism, psoriasis, diabetic retinopathy, neovascular glaucoma, retinopathy of prematurity, macular degeneration, corneal graft rejection, retrolental fibroplasia, rubeosis, capillary proliferation in atherosclerotic plaques, osteoporosis, and the like.
  • Figure 1 shows the conversion of prodrug Compound 6 into active
  • Figure 2 shows the conversion of prodrug Compound 9 into active
  • Figure 3 shows the conversion of prodrug Compound 12 into active
  • the disclosure provides methods for producing pharmaceutically acceptable cell cycle inhibitors, antitumor agents and antifungal agents in relatively high yield, wherein said compounds and/or their derivatives are among the active ingredients in these cell cycle inhibitors, antitumor agents and antifungal agents.
  • Other objects include providing novel compounds not obtainable by currently available, non- synthetic methods. It is also an object to provide a method of treating cancer, particularly human cancer, comprising the step of administering an effective tumor-growth inhibiting amount of a member of a class of new anti-tumor compounds.
  • This invention also provides a method for preventing or treating a pathogenic fungus in a subject which involves administering to the subject an effective anti-fungal amount of a member of a class of new anti-fungal compounds, e.g., administering a Plinabulin prodrug or its analog in an amount and manner which provides the intended antifungal effect.
  • an effective anti-fungal amount of a member of a class of new anti-fungal compounds e.g., administering a Plinabulin prodrug or its analog in an amount and manner which provides the intended antifungal effect.
  • Ri can be a hydrophilic moiety selected from a straight or branched chain Ci-C 6 alkyl or a C 5 -C 6 heterocyclyl; and wherein the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl moiety can be substituted with one or more groups selected from a carboxylic acid, a carboxylate, a hydroxyl, and a sulfonate.
  • the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl can be substituted with one or more carboxylic acid groups.
  • the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl can be further substituted with one or more hydroxyl groups.
  • the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl can be substituted with one or more carboxylate groups. In some embodiments, the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl can be further substituted with one or more hydroxyl groups. In some embodiments, the Ci-C 6 alkyl or C 5 -C 6 heterocyclyl can be substituted with one or more hydroxyl groups.
  • Ri can be selected from - CH 2 CH(OH)CH 2 C0 2 H, -CH 2 CH(OH)CH 2 C0 2 Na, -CH(CH 2 OH)C0 2 H, CH(CH 2 OH)C0 2 Na, -CH(CH 2 CH 2 C0 2 H)C0 2 H, -CH(CH 2 CH 2 C0 2 H)C0 2 Na, - CH(CH 2 CH 2 C0 2 Na)C0 2 H, -CH(CH 2 CH 2 C0 2 Na)C0 2 Na, -CH(C0 2 H)CH 2 C0 2 H, - CH(C0 2 H)CH 2 C0 2 Na, -CH(C0 2 Na)CH 2 C0 2 H, -CH(C0 2 Na)CH 2 C0 2 Na,
  • R can be a bond.
  • L can be a divalent mono-substituted, poly- substituted or unsubstituted radical comprising from 1 to 10 linked atoms between the linking divalent bonds, wherein the linked atoms can be part of linear or ring structures.
  • L can be a mono-substituted, poly-substituted or unsubstituted, straight or branched chain variant of Ci-Cio alkyl, Ci-Cio alkenyl, Ci-Cio alkynyl, or Ci- C heteroalkyl.
  • L can have the following formula: , wherein r and t can be independently selected from 0, 1, 2, 3,
  • r can be 3 and t can be 0.
  • Ar can be selected from:
  • substituents selected from hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, CrC 12 haloalkyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly- substituted or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, amino, aminocarbonyl,
  • Ar can be selected from:
  • substituents selected from hydrogen; halogen; hydroxyl; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of C 1 -C 24 alkyl, Ci-Ci 2 haloalkyl and C 1 -C 12 alkoxy.
  • Ar can be selected from:
  • Ar can be any organic compound [0030]
  • Y can be selected from a nitrogen atom substituted with R 5 , an oxygen atom, and a sulfur atom.
  • Y can be a nitrogen atom substituted with R5.
  • R5 can be a hydrogen atom or a saturated C 1 -C 12 alkyl.
  • R 5 can be a hydrogen atom.
  • Y can be an oxygen atom.
  • R 4 can be a mono-substituted, poly- substituted or unsubstituted, straight or branched chain variant of CrC 12 alkyl or CrC 12 alkenyl. In some embodiments, R 4 can be 3,3-dimethylpropyl-l-ene or tert-butyl. In some embodiments, R 4 can be 3,3-dimethylpropyl-l-ene. In some embodiments, R 4 can be tert- butyl.
  • Xi can be oxygen
  • n can be 0.
  • the compound can have the structure of Formula I.
  • the compound can have the structure of Formula ⁇ .
  • Formula I can have the structure of Formula ⁇
  • Formula ⁇ can have the structure of Formula ⁇ ' :
  • Formula I can have the structure of Formula ⁇
  • Formula ⁇ can have the structure of Formula ⁇ ' :
  • Li and L 2 are linking groups that can react with each other to produce L, and the remaining variable groups are as defined herein.
  • a compound of Formula (IV) is reacted with X-PG-Li to produce a compound of Formula (V).
  • X is a halogen.
  • Li contains an alkynyl group.
  • the compound of Formula (V) is reacted with L 2 -Ri to produce a compound of Formula (I).
  • L 2 contains an azide group.
  • Ri contains a carboxylic acid or carboxylate group. In some embodiments, Ri contains a carboxylic acid or carboxylate group that is substituted with either a hydroxyl or a hydroxymethyl group.
  • Exemplary L 2 -Ri species include the following compounds: N 3 -CH(CH 2 OH)-C0 2 H and N 3 -CH 2 -CH(OH)-CH 2 -C0 2 H, wherein is N 3 - , and Ri is -CH(CH 2 OH)-C0 2 H and -CH 2 -CH(OH)-CH 2 -C0 2 H , respectively.
  • L ⁇ -Ri species include, but are not limited to, the following compounds: N 3 - CH(CH 2 CH 2 C0 2 H)C0 2 H, N 3 -CH(C0 2 H)CH 2 C0 2 H, N 3 -CH(C0 2 H)CH(OH)CH 3 , -
  • variable groups are as defined herein.
  • Compounds of Formula I and ⁇ can serve as a water-soluble prodrug for compounds of Formula IV and IV, respectively.
  • the polarity of the Ri group increases the aqueous solubility of the compounds of Formula I and ⁇ as compared to the relative aqueous solubility of compounds of Formula IV and IV' .
  • the protecting group of Formula I and ⁇ can be removed under appropriate in vitro or in vivo deprotection conditions, as shown in Scheme 3.
  • an enzyme capable of removing the protecting group can cleave the -PG-L-Ri portion of Formula I and ⁇ to produce the physiologically active form of Formula IV and IV', respectively.
  • variable groups are as defined herein.
  • Deprotection of Formula I and ⁇ can be via hydrolysis. Hydrolysis can occur spontaneously in an aqueous or biological environment. Hydrolysis can be catalyzed by acid, base, or biocatalytically. Hydrolysis can be catalyzed enzymatically. Enzymes capable of deprotecting Formula I and ⁇ include, but are not limited to, esterases, hydrolases, proteases, and lipases.
  • any "R” group(s) such as, without limitation, R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 represent substituents that can be attached to the indicated atom.
  • An R group may be substituted or unsubstituted. If two "R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R la and R lb of an NR la R lb group are indicated to be "taken together," it means that they are covalently bonded to one another to form a ring:
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • C a to C b in which "a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.
  • the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from "a" to "b", inclusive, carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no "a” and "b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.
  • hydrophilic moiety refers to a chemical moiety with the capacity to favorably interact with polar groups and polar solvents, such as water and aqueous solutions.
  • protecting group refers to a group that can be cleaved by hydrolysis or enzymatically in an in vivo environment. In the context of a prodrug, a protecting group can be cleaved in a biological environment to release the drug.
  • linking group refers to a bond, or a divalent mono-substituted, poly-substituted or unsubstituted radical that links two portions of a molecule together. Such radicals may include both linear and/or ring portions.
  • the "linking group” is a divalent mono-substituted, poly-substituted or unsubstituted radical comprising from 1 to 10 linked atoms between the linking divalent bonds, wherein the linked atoms can be part of linear or ring structures.
  • pharmaceutically acceptable salt especially when referring to a pharmaceutically acceptable salt of the compound of Formula (I), ( ⁇ ), ( ⁇ ), ( ⁇ ), ( ⁇ ') or ( ⁇ '), refers to any pharmaceutically acceptable salts of a compound.
  • exemplary salts include an acid addition salt of a compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, C 1 -C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, C 1 -C7 alkylamine, cyclohe
  • Exemplary pharmaceutically acceptable salt are the alkali metal salts (sodium or potassium), the alkaline earth metal salts (calcium or magnesium), or ammonium salts derived from ammonia or from pharmaceutically acceptable organic amines, for example C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine or tris- (hydroxymethyl)-aminomethane.
  • exemplary pharmaceutically acceptable salts are acid addition salts of pharmaceutically acceptable inorganic or organic acids, for example, hydrohalic, sulfuric, phosphoric acid or aliphatic or aromatic carboxylic or sulfonic acid, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, p-toluensulfonic or naphthalenesulfonic acid.
  • hydrohalic sulfuric, phosphoric acid or aliphatic or aromatic carboxylic or sulfonic acid
  • acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, p-toluensulfonic or naphthalenesulfonic acid for example, hydrohalic, sulfuric, phosphoric acid or aliphatic or aromatic carboxylic or sulfonic acid, for example acetic, succ
  • compositions disclosed herein include pharmaceutically acceptable salts of the compounds of Formula (I), (II), ( ⁇ ), ( ⁇ ), ( ⁇ ') or ( ⁇ '). Accordingly, if the manufacture of pharmaceutical formulations involves intimate mixing of the pharmaceutical excipients and the active ingredient in its salt form, then the pharmaceutical excipients which are non-basic, that is, either acidic or neutral excipients, can be used.
  • halogen or "halogen atom,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, i.e., fluorine, chlorine, bromine, or iodine.
  • alkyl means any unbranched or branched, saturated hydrocarbon.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • exemplary alkyl groups include CrC 6 unbranched, saturated, unsubstituted hydrocarbons, such as methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec -butyl, tert- butyl, pentyl, hexyl, perfluromethyl, perchloromethyl, perfluoro-tert-butyl, and perchloro- tert-butyl.
  • cycloalkyl refers to any non-aromatic hydrocarbon ring, preferably having five to twelve atoms comprising the ring.
  • acyl refers to -C(0)R, where R is an alkyl or aryl group.
  • esters refers to -C(0)OR, where R is an alkyl or aryl group.
  • alkenyl means any unbranched or branched, unsaturated hydrocarbon including polyunsaturated hydrocarbons, with C 2 -C6 unbranched, mono-unsaturated and di-unsaturated, hydrocarbons being preferred.
  • cycloalkenyl refers to any non-aromatic hydrocarbon ring, preferably having five to twelve atoms comprising the ring.
  • alkynyl as used herein, means any unbranched or branched, unsaturated hydrocarbon including polyunsaturated hydrocarbons, that contain at least one carbon-carbon triple bond.
  • aryl refers to aromatic hydrocarbon rings, preferably having five, six, or seven atoms, and most preferably having six atoms comprising the ring.
  • heteroaryl and “substituted heteroaryl,” refer to aromatic hydrocarbon rings in which at least one heteroatom, e.g., oxygen, sulfur, or nitrogen atom, is in the ring along with at least one carbon atom.
  • alkoxy refers to any unbranched, or branched, saturated or unsaturated ether, with Ci-C 6 unbranched, saturated, ethers being preferred, with methoxy being preferred, and also with dimethyl, diethyl, methyl-isobutyl, and methyl-tert-butyl ethers also being preferred.
  • purified refers to the compound being free of other, dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% of the mass, by weight, of a given sample.
  • sucrose refers to a natural or an unnatural monosaccharide, disaccharide, oligosaccharide, or polysaccharide comprising one or more triose, tetrose, pentose, hexose, heptose, octose, and nonose saccharides.
  • Sugars may include alditols resulting from reduction of the saccharide carbonyl group; aldonic acids resulting from oxidation of one or more terminal groups to carboxylic acids of the saccharide; deoxy sugars resulting from replacement of one or more hydroxyl group(s) by a hydrogen in the saccharide; amino sugars resulting from replacement of one or more hydroxyl group(s) by an amino group in the saccharide; thio sugars resulting from replacement of one or more hydroxyl group(s) by a thiol group, or other analogous compounds resulting from the replacement of, for example, one or more hydroxyl group(s) by an acylamino group, a sulfate group, a phosphate group, or similar heteroatomic group; or any combination of the foregoing modifications.
  • sugar also includes analogs of these compounds (i.e., sugars that have been chemically modified by acylation, alkylation, and formation of glycosidic bonds by reaction of sugar alcohols with aldehydes or ketones, etc).
  • Sugars may be present in cyclic (oxiroses, oxetosesm furanoses, pyranoses, septanoses, octanoses, etc) form as hemiacetals, hemiketals, or lactones; or in acyclic form.
  • the saccharides may be ketoses, aldoses, polyols and/or a mixture of ketoses, aldoses and polyols.
  • Sugars may include, but are not limited to glycerol, polyvinylalcohol, propylene glycol, sorbitol, ribose, arabinose, xylose, lyxose, allose, altrose, mannose, mannitol, gulose, dextrose, idose, galactose, talose, glucose, fructose, dextrates, lactose, sucrose, starches (i.e., amylase and amylopectin), sodium starch glycolate, cellulose and cellulose derivatives (i.e., methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, croscarmellose, hypomellose, and hydroxypropyl methyl cellulose), carrageenan, cyclodextrins, dextrin, polydextrose, and
  • amino acid refers to any amino acid (both standard and non-standard amino acids), including, but limited to, oc-amino acids, ⁇ - amino acids, ⁇ -amino acids and ⁇ -amino acids.
  • suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
  • suitable amino acids include, but are not limited to, ornithine, hypusine, 2- aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.
  • substituted refers to the substitution of at least one hydrogen atom with a substituent selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, oxo, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl,-SO-aryl, -SO-heteroaryl, -S0 2 -alkyl, -S0 2 -aryl and -S0 2
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise.
  • a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless expressly stated otherwise.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • the compounds described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Prodrugs are molecules capable of being converted to drugs (active therapeutic agents) in vivo by certain chemical or enzymatic modifications to the structure of the prodrug. Such modifications to the prodrug include hydrolysis or enzymatic cleavage of protecting groups to release an active agent. In some embodiments, a prodrug is deprotected in vivo to release the active agent.
  • compounds of Formula I and ⁇ that are prodrugs of an active agent having the structure of Formula IV or IV' .
  • Prodrugs can address some of the limitations associated with certain therapeutic agents, such as poor water solubility, cardiotoxicity, development of drug resistance, lack of selectivity, and metabolic inactivation of the agent. Therefore, it is of considerable interest to prepare prodrugs of antitumor therapeutic agents, including compounds of Formula IV or IV', such as plinabulin.
  • compounds of Formula IV and IV can benefit from being formulated as a compound of Formula I and ⁇ to increase the water solubility and serum half-life of the active agent.
  • the compounds of Formula I and ⁇ can provide a high specificity of action, and/or reduced toxicity and/or an improved stability in the serum and blood, when compared to the corresponding compound of Formula IV or IV.
  • compounds of Formula I and ⁇ can provide improved pharmacological properties relative to the corresponding therapeutic agent of Formula IV or IV .
  • the present invention also encompasses the compounds disclosed herein, optionally and preferably produced by the methods disclosed herein, in pharmaceutical compositions comprising a pharmaceutically acceptable carrier prepared for storage and subsequent administration, which have a pharmaceutically effective amount of the products disclosed above in a pharmaceutically acceptable carrier or diluent.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985).
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • the compounds and compositions disclosed herein may be formulated and used as tablets, capsules, or elixirs for oral administration; suppositories for rectal administration; sterile solutions, suspensions for injectable administration; patches for transdermal administration, and sub-dermal deposits and the like.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection or infusion, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, human serum albumin and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.
  • compositions for parenteral administration include aqueous solutions of the compounds in water-soluble form. Additionally, suspensions of the compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions for oral use may be obtained by combining the compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Such formulations can be made using methods known in the art (see, for example, U.S. Patent Nos.
  • compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery.
  • Pharmaceutical formulations include aqueous ophthalmic solutions of the compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et al., 2001 Clin Ther 23(3):440-50) or hydrogels (Mayer et al., 1996 Ophthalmologica 210:101-3); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, A., 1994 J Ocul Pharmacol 10:29-45), lipid-soluble formulations (Aim et al., 1989 Prog Clin Biol Res 312:447-58), and microspheres (Mordenti, 1999 Toxicol Sci 52:101-6); and ocular inserts.
  • Such suitable pharmaceutical formulations are most often and preferably formulated to be sterile, isotonic and buffered for stability and comfort.
  • Pharmaceutical compositions may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure maintenance of normal ciliary action.
  • suitable formulations are most often isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often include antimicrobial preservatives and appropriate drug stabilizers.
  • Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.
  • the compound of Formula (I) or ( ⁇ ) can be administered by either oral or a non-oral pathways.
  • it can be administered in capsule, tablet, granule, spray, syrup, or other such form.
  • it can be administered as an aqueous suspension, an oily preparation or the like or as a drip, suppository, salve, ointment or the like, when administered via injection or infusion, subcutaneously, intreperitoneally, intravenously, intramuscularly, or the like.
  • the compound may be administered topically, rectally, or vaginally, as deemed appropriate by those of skill in the art for bringing the compound into optimal contact with a tumor, thus inhibiting the growth of the tumor.
  • Local administration at the site of the tumor is also contemplated, either before or after tumor resection, as are controlled release formulations, depot formulations, and infusion pump delivery.
  • the present invention also encompasses methods for administering the disclosed chemical compounds and the disclosed pharmaceutical compositions.
  • Such disclosed methods include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, suppository, salve, ointment or the like; administration via injection or infusion, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, or the like; as well as (c) administration topically, (d) administration rectally, or (e) administration vaginally, as deemed appropriate by those of skill in the art for bringing the compound into contact with living tissue; and (f) administration via controlled released formulations, depot formulations, and infusion pump delivery.
  • modes of administration and as further disclosure of modes of administration, disclosed herein are various methods for administration of the disclosed chemical compounds and pharmaceutical compositions including
  • the pharmaceutically effective amount of the compounds and compositions disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the products or compositions can be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents.
  • the compounds disclosed herein are effective in the treatment of cancer when used in combination with other actives, specifically other chemotherapeutics, for example biologies and the specific chemo therapeutics CPT-11, Taxotene (docataxel) and paclitaxel.
  • the compounds disclosed herein are also effective in the treatment of cancer when used in combination with other actives, including anti-vascular agents, anti-angiogenenic agents, such as Erbuitux (Imclone/bristol-Myers) and Iressa (AstraZeneca), other VEGF inhibitors and biologies, more specifically, at least one anti-VEGF antibodies, especially monoclonal antibodies to the VEGF receptor, including DC 101, a rat monoclonal antibody, which blocks the mouse VEGF receptor 2 (flk-1).
  • actives including anti-vascular agents, anti-angiogenenic agents, such as Erbuitux (Imclone/bristol-Myers) and Iressa (AstraZeneca), other VEGF inhibitors and biologies, more specifically, at least one anti-VEGF antibodies, especially monoclonal antibodies to the VEGF receptor, including DC 101, a rat monoclonal antibody, which blocks the mouse VEGF receptor 2 (flk-1).
  • the disclosed compounds in employing them in vivo, may be administered to the mammal in a variety of ways, including parenterally, intravenously, via infusion or injection, subcutaneously, intramuscularly, colonically, rectally, vaginally, nasally or intraperitoneally, employing a variety of dosage forms. Such methods may also be applied to testing chemical activity in vivo.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved.
  • acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
  • dosages may range broadly, depending upon the desired affects and the therapeutic indication. Typically, dosages may be between about 10 microgram/kg and 100 mg/kg body weight, preferably between about 100 microgram/kg and 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Administration may be oral on an every third day, every other day, daily, twice daily, or thrice daily basis.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See for example, Fingl et ah, in The Pharmacological Basis of Therapeutics, 1975. It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Suitable agent may be formulated and administered systemically or locally.
  • Suitable administration routes may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, via infusion, intraperitoneal, intranasal, or intraocular injections.
  • the agents may be formulated in aqueous solutions, for example, in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention. With proper choice of carrier and suitable manufacturing practice, the compositions disclosed herein, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection or infusion.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes, then administered as described above. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. Additionally, due to their hydrophobicity, small organic molecules may be directly administered intracellularly.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • the pharmaceutical compositions may be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several art recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • the compounds disclosed herein may be administered by either oral or a non- oral pathways.
  • it can be administered in capsule, tablet, granule, spray, syrup, or other such form.
  • it can be administered as an aqueous suspension, an oily preparation or the like or as a drip, suppository, salve, ointment or the like, when administered via injection or infusion, subcutaneously, intreperitoneally, intravenously, intramuscularly, intradermally, or the like.
  • the compound may be administered topically, rectally, or vaginally, as deemed appropriate by those of skill in the art for bringing the compound into optimal contact with a tumor, thus inhibiting the growth of the tumor.
  • Local administration at the site of the tumor or other disease condition is also contemplated, either before or after tumor resection, or as part of an art-recognized treatment of the disease condition. Controlled release formulations, depot formulations, and infusion pump delivery are similarly contemplated.
  • the compounds and compositions disclosed herein may be orally or non-orally administered to a human patient in the amount of about .0007 mg/day to about 7,000 mg/day of the active ingredient, and more preferably about 0.07 mg/day to about 70 mg/day of the active ingredient at, preferably, one time per day or, less preferably, over two to about ten times per day.
  • Compounds of Formula I and ⁇ can be orally or non-orally administered to a human patient in any of the aforementioned amounts.
  • the compounds disclosed herein may be administered in the stated amounts continuously by, for example, an intravenous drip.
  • the preferred daily dose of the active anti-tumor ingredient would be about 0.0007 mg/kg/day to about 35 mg/kg/day including 1.0 mg/kg/day and 0.5 mg/kg/day, and more preferable, from 0.007 mg/kg/day to about 0.050 mg/kg/day, including 0.035 mg/kg/day. Nonetheless, as will be understood by those of skill in the art, in certain situations it may be necessary to administer the anti-tumor compound in amounts that exceed, or even far exceed, the above-stated, preferred dosage range to effectively and aggressively treat particularly advanced or lethal tumors.
  • the preferable amount of the compounds and compositions disclosed herein effective in the treatment or prevention of a particular fungal pathogen will depend in part on the characteristics of the fungus and the extent of infection, and can be determined by standard clinical techniques. In vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Effective doses may be extrapolated from dose-response curves derived from in vitro analysis or preferably from animal models. The precise dosage level should be determined by the attending physician or other health care provider and will depend upon well known factors, including route of administration, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the infection; the use (or not) of concomitant therapies.
  • the effective dose of the compounds and compositions disclosed herein will typically be in the range of about 0.01 to about 50 mg/kgs, preferably about 0.1 to about 10 mg/kg of mammalian body weight per day, administered in single or multiple doses.
  • the compound may be administered to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient.
  • ком ⁇ онентs to formulate the dosage including the compounds disclosed herein as a tumor- growth-inhibiting compound, known surface active agents, excipients, smoothing agents, suspension agents and pharmaceutically acceptable film-forming substances and coating assistants, and the like may be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a
  • compositions disclosed herein in a pharmaceutical composition may also comprise a pharmaceutically acceptable carrier.
  • Such compositions may be prepared for storage and for subsequent administration.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985).
  • such compositions may be formulated and used as tablets, capsules or solutions for oral administration; suppositories for rectal or vaginal administration; sterile solutions or suspensions for injectable administration.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection or infusion, or as emulsions.
  • Suitable excipients include, but are not limited to, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • absorption enhancing preparations for example, liposomes
  • the pharmaceutically effective amount of the composition required as a dose will depend on the route of administration, the type of animal being treated, and the physical characteristics of the specific animal under consideration.
  • the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the products or compositions, as described above, may be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents.
  • the compounds can be administered or used in combination with treatments such as chemotherapy, radiation, and biologic therapies.
  • the compounds can be administered or used with a chemotherapeutic agent.
  • chemotherapeutic s include Alkaloids, alkylating agents, antibiotics, antimetabolites, enzymes, hormones, platinum compounds, immuno therapeutics (antibodies, T-cells, epitopes), BRMs, and the like.
  • Examples include, Vincristine, Vinblastine, Vindesine, Paclitaxel (Taxol), Docetaxel, topoisomerase inhibitors epipodophyllotoxins (Etoposide (VP- 16), Teniposide (VM-26)), Camptothecin, nitrogen mustards (cyclophosphamide), Nitrosoureas, Carmustine, lomustine, dacarbazine, hydroxymethylmelamine, thiotepa and mitocycin C, Dactinomycin (Actinomycin D), anthracycline antibiotics (Daunorubicin, Daunomycin, Cerubidine), Doxorubicin (Adriamycin), Idarubicin (Idamycin), Anthracenediones (Mitoxantrone), Bleomycin (Blenoxane), Plicamycin (Mithramycin, Antifolates (Methotrexate (Folex, Mexate)), purine antimetabolites (6
  • agents that can be administered in combination with a compound of Formula I or ⁇ include, but are not limited to, 6-mercaptopurine, 6-thioguanine, Chlorodeoxyadenosine, Pentostatin (2'- deoxycoformycin), pyrimidine antagonists, fluoropyrimidines (5-fluorouracil (Adrucil), 5- fluorodeoxyuridine (FdUrd) (Floxuridine)), Cytosine Arabinoside (Cytosar, ara-C), Fludarabine, L-ASPARAGINASE, Hydroxyurea, glucocorticoids, antiestrogens, tamoxifen, nonsteroidal antiandrogens, flutamide, aromatase inhibitors Anastrozole (Arimidex), Cisplatin, Thioguanine, Methotrexate, Cytoxan, Cytarabine, L- Asparaginase, and Steroids (e.g., Prednisone and De
  • proteasome inhibitors such as bortezomib can be used in combination with the instant compounds, for example.
  • biologies can include agents such as TRAIL antibodies to TRAIL, integrins such as alpha- V-beta-3 ( ⁇ 3) and/or other cytokine/growth factors that are involved in angiogenesis, VEGF, EGF, FGF and PDGF, immunotherapeutics, such as proteasome inhibitors, T cells, T cells vaccines, and the like.
  • the compounds can be conjugated to or delivered with an antibody.
  • Radiation therapy includes, but is not limited to, treatment with X-ray radiation and proton beam therapy. The above-described combination methods can be used to treat a variety of conditions, including cancer and neoplastic diseases, inflammation, and microbial infections.
  • compositions can be utilized in vivo or in vitro.
  • the useful dosages and the most useful modes of administration will vary depending upon the age, weight and animal treated, the particular compounds employed, and the specific use for which these composition or compositions are employed.
  • the magnitude of a dose in the management or treatment for a particular disorder will vary with the severity of the condition to be treated and to the route of administration, and depending on the disease conditions and their severity, the compositions may be formulated and administered either systemically or locally.
  • a variety of techniques for formulation and administration may be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990).
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methyiacetate- methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.
  • the vascular disrupting agents and the antifungal agents disclosed herein can be orally or non-orally administered to a human patient at once every three days on a cyclic basis, once every other day, one time per day, twice per day, or over two to about ten times per day.
  • the compound may preferably be administered continuously by, for example, an intravenous drip.
  • the compound inhibits the progression of the cell cycle when it is dissolved in an organic solvent or hydrous organic solvent and it is directly applied to any of various cultured cell systems.
  • Usable organic solvents include, for example, methanol, methylsulfoxide, and the like.
  • the formulation can, for example, be a powder, granular or other solid inhibitor, or a liquid inhibitor prepared using an organic solvent or a hydrous organic solvent. While a preferred concentration of the compound for use as a cell cycle inhibitor is generally in the range of about 1 to about 100 ⁇ g/ml, the most appropriate use amount varies depending on the type of cultured cell system and the purpose of use, as will be appreciated by persons of ordinary skill in the art. Also, in certain applications it may be necessary or preferred to persons of ordinary skill in the art to use an amount outside the foregoing range.
  • certain embodiments provide methods for preventing or treating fungal infections and/or a pathogenic fungus in a subject, involve administering to the subject a compound or composition disclosed herein in an amount and manner which provides the intended antifungal effect.
  • Other embodiments include the treatment or prevention of infection in a patient by a pathogenic fungus such as those listed above or referred to below.
  • Another embodiment relates to the treatment or prevention of infection in a patient by a pathogenic fungus which is resistant to one or more other antifungal agents, especially an agent other than dehydrophenylahistin or its analog, including e.g.
  • amphotericin B or analogs or derivatives thereof including 14(s)-hydroxyamphotericin B methyl ester, the hydrazide of amphotericin B with l-amino-4-methylpiperazine, and other derivatives
  • other polyene macrolide antibiotics including, e.g., nystatin, candicidin, pimaricin and natamycin; flucytosine; griseofulvin; echinocandins or aureobasidins, including naturally occurring and semi-synthetic analogs; dihydrobenzo[a]napthacenequinones; nucleoside peptide antifungals including the polyoxins and nikkomycins; allylamines such as naftifine and other squalene epoxidase inhibitors; and azoles, imidazoles and triazoles such as, e.g., clotrimazole, miconazole, ketoconazole,
  • Another embodiment involves the treatment or prevention of infection in a patient by a pathogenic fungus in cases in which the patient is allergic to, otherwise intolerant of, or nonresponsive to one or more other antifungal agents or in whom the use of other antifungal agents is otherwise contra-indicated.
  • Those other antifungal agents include, among others, those antifungal agents disclosed above and elsewhere herein.
  • a compound or composition disclosed herein is administered to the subject in an effective antifungal amount.
  • Other embodiments relate to the treatment or prevention of infection by a pathogenic fungus in a patient by administration of a compound or composition disclosed herein, in conjunction with the administration of one or more other antifungal agents, including for example, any of the previously mentioned agents or types of agents (e.g. in combination with treatment with amphotericin B, preferably in a lipid or liposome formulation; an azole or triazole such as fluconazole, for example; an aureobasidin; dihydrobenzo[alnapthacenequinone]; or an echinocardin) as well as with a different dehydrophenylahistin or its analog.
  • agents e.g. in combination with treatment with amphotericin B, preferably in a lipid or liposome formulation
  • an azole or triazole such as fluconazole, for example; an aureobasidin; dihydrobenzo[alnapthacenequinone]; or an echinocardin
  • the compounds or compositions disclosed herein may be administered before, after or at the same time the other agent is administered.
  • the combination therapy will permit the use of reduced amounts of one or both components, relative to the amount used if used alone.
  • Still other embodiments relate to administration of a compound or composition disclosed herein to a subject for the treatment or prevention of infection by a pathogenic fungus, where the subject is immunosuppressed or immunocompromised, e.g. as the result of genetic disorder, disease such as diabetes or HIV or other infection, chemotherapy or radiation treatment for cancer or other disease, or drug- or otherwise induced immunosuppression in connection with tissue or organ transplantation or the treatment of an autoimmune disorder.
  • immunosuppressed or immunocompromised e.g. as the result of genetic disorder, disease such as diabetes or HIV or other infection, chemotherapy or radiation treatment for cancer or other disease, or drug- or otherwise induced immunosuppression in connection with tissue or organ transplantation or the treatment of an autoimmune disorder.
  • a dehydrophenylahistin or its analog may be co-administered with the immunosuppressive agent(s) to treat or prevent a pathogenic fungal infection.
  • Another aspect of this invention is the treatment or prevention of infection by a pathogenic fungus in a patient infected, or suspected of being infected, with HIV, by administration of an antifungal compound or composition disclosed herein, in conjunction with the administration of one or more anti-HIV therapeutics (including e.g. HIV protease inhibitors, reverse transcriptase inhibitors or anti- viral agents).
  • an antifungal compound or composition disclosed herein in conjunction with the administration of one or more anti-HIV therapeutics (including e.g. HIV protease inhibitors, reverse transcriptase inhibitors or anti- viral agents).
  • anti-HIV therapeutics including e.g. HIV protease inhibitors, reverse transcriptase inhibitors or anti- viral agents.
  • the compounds or compositions disclosed herein may be administered before, after or at the same time as administration of the anti-HIV agent(s).
  • Another aspect of this invention is the treatment or prevention of infection by a pathogenic fungus in a patient by administration of an antifungal compound or composition disclosed herein, in conjunction with the administration of one or more other antibiotic compounds, especially one or more antibacterial agents, preferably in an effective amount and regiment to treat or prevent bacterial infection.
  • the compound or composition disclosed herein may be administered before, after or at the same time as administration of the other agent(s).
  • Pathogenic fungal infections which may be treated or prevented by the disclosed methods include, among others, Aspergillosis, including invasive pulmonary aspergillosis; Blastomycosis, including profound or rapidly progressive infections and blastomycosis in the central nervous system; Candidiasis, including retrograde candidiasis of the urinary tract, e.g. in patients with kidney stones, urinary tract obstruction, renal transplantation or poorly controlled diabetes mellitus; Coccidioidomycosis, including chronic disease which does not respond well to other chemotherapy; Cryptococcosis; Histopolasmosis; Mucormycosis, including e.g.
  • compositions comprising an antifungal amount of one or more compound disclosed herein may be particularly useful for treating or preventing a pathogenic fungal infection in a mammalian subject where the fungus is resistant to one or more other antifungal therapies, or where the use of one or more other antifungal therapies is contraindicated, e.g., as mentioned above.
  • Antifungal pharmaceutical compositions containing at least one antifungal compound disclosed herein are also provided for use in practicing the disclosed methods. Those pharmaceutical compositions may be packaged together with an appropriate package insert containing, inter alia, directions and information relating to their antifungal use. Pharmaceutical compositions are also provided which contain one or more compound disclosed herein together with a second antifungal agent.
  • Certain embodiments disclosed herein relate to methods for treating or preventing a pathogenic fungal infection, including for example Aspergillosis, including invasive pulmonary aspergillosis; Blastomycosis, including profound or rapidly progressive infections and blastomycosis in the central nervous system; Candidiasis, including retrograde candidiasis of the urinary tract, e.g. in patients with kidney stones, urinary tract obstruction, renal transplantaion or poorly controlled diabetes mellitus; Coccidioidomycosis, including chronic disease which does not respond well to other chemotherapy; Cryptococcosis; Histopolasmosis; Mucormycosis, including e.g.
  • Aspergillosis including invasive pulmonary aspergillosis
  • Blastomycosis including profound or rapidly progressive infections and blastomycosis in the central nervous system
  • Candidiasis including retrograde candidiasis of the urinary tract, e.g. in patients with kidney stones, urinary tract obstruction, renal transplant
  • the methods may involve administering at least one antifungal compound or composition disclosed herein, as described above, to a human subject such that the fungal infection is treated or prevented.
  • the compound or composition disclosed herein may be administered in conjunction with administration of one or more non-dehydrophenylahistin or its analog antifungal agents such as amphotericin B, or an imidazole or triazole agent such as those mentioned previously.
  • the pathogenic fungal infection may be topical, e.g., caused by, among other organisms, species of Candida, Trichophyton, Microsporum or Epiderinophyton or mucosal, e.g., caused by Candida albicans (e.g. thrush and vaginal candidiasis).
  • the infection may be systemic, e.g., caused by Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Coccidiodes, Paracocciciodes, Histoplasma or Blastomyces spp.
  • the infection may also involve eumycotic mycetoma, chromoblastomycosis, cryptococcal meningitits or phycomycosis.
  • Further embodiments relate to methods for treating or preventing a pathogenic fungal infection selected from Candida spp. including C albicans, C tropicalis, C kefyr, C krusei and C. galbrata; Aspergillus spp. including A. fumigatus and A. flavus; Cryptococcus neoibrmans; Blastomyces spp. including Blastomyces dermatitidis; Pneumocystis carinii; Coccidioides immitis; Basidiobolus ranarum; Conidiobolus spp.; Histoplasma capsulatum; Rhizopus spp. including R. oryzae and R.
  • the method may involve administering a non-immunosuppressive antifungal compound or composition disclosed herein to a patient in need thereof such that the fungal infection is treated or prevented without inducing an untoward immunosuppressive effect.
  • Further embodiments relate to methods for treating or preventing a pathogenic fungal infection which is resistant to other antifungal therapy, including pathogenic fungal infections which are resistant to one or more antifungal agents mentioned elsewhere herein such as amphotericin B, flucytosine, one of the imidazoles or triazoles (including e.g. fluconazole, ketoconazole, itraconazole and the other previously mentioned examples).
  • the methods may involve administering to the patient one or more antifungal compound or composition disclosed herein, in an amount and dosing regimen such that a fungal infection resistant to another antifungal therapy in the subject is treated or prevented.
  • Further embodiments relate to methods for treating or preventing a pathogenic fungal infection in a patient who is allergic to, intolerant of or not responsive to another antifungal therapy or in whom the use of other antifungal agents is otherwise contra-indicated, including one or more other antifungal agents mentioned elsewhere herein such as amphotericin B, flucytosine, one of the imidazoles or triazoles (including e.g. fluconazole, ketoconazole, itraconazole and the other previously mentioned examples).
  • the methods may involve administering to such patient one or more antifungal compound or composition disclosed herein, in an amount such that a fungal infection is treated or prevented.
  • Certain embodiments relate to packaged compounds of Formula (I), ( ⁇ ), ( ⁇ ), ( ⁇ ), ( ⁇ ') or ( ⁇ ), as described above, wherein the package contains instructions for administering the compound as an anti-cancer or antifungal agent without causing a untoward immunosuppressive effects within a human subject.
  • the non-immunosuppressive an anti-cancer or antifungal compound is a member of one of the preferred subsets of compounds described above.
  • the compound or composition described herein can be packaged alone with the instructions or can be packaged with another compound or another ingredient or additive, e.g., one or more of the ingredients of the pharmaceutical compositions, such as rapamycin.
  • the package can contain one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • Compound 3 was reacted with glutamic acid derivative 10 to obtain compound 11 via Huisgen reaction conditions.
  • the solubility of compound 11 was increased by converting the carboxylic acid group into the corresponding sodium salt 12 via ion exchange resin.
  • Compound 9 was evaluated as a prodrug. Under physiological conditions (37 °C, PBS pH 7.4), the in vitro hydrolysis of compound 9 was measured in the presence of an esterase enzyme. As shown in Figure 2, compound 9 was converted into the active parent compound 1 (Plinabulin) as verified by HPLC analysis.
  • Compound 12 was evaluated as a prodrug. Under physiological conditions (37 °C, PBS pH 7.4), the in vitro hydrolysis of compound 12 was measured in the presence of an esterase enzyme. As shown in Figure 3, compound 12 was converted into the active parent compound 1 (Plinabulin) as verified by HPLC analysis.
  • HT29 human colon tumor; ATCC; HTB-38
  • PC3 human prostate tumor; ATCC; CRL-1435
  • MDA-MB-231 human breast tumor; ATCC; HTB-26
  • NCI-H292 human non-small cell lung tumor; ATCC; CRL-1848
  • OVCAR-3 human ovarian tumor; ATCC; HTB-161
  • B16-F10 murine melanoma; ATCC; CRL-6475
  • CCD-27sk normal human fibroblast; ATCC; CRL-1475.
  • Cells were maintained at subconfluent densities in their respective culture media and cytotoxicity assays were performed as described in WO 2005/077940, using Resazurin fluorescence as an indicator of cell viability. The resulting data is displayed in Table 1.
  • Compound 3 can be reacted with threonine derivative 15 to obtain compound 16 according to the procedure of Example 3.
  • the solubility of compound 16 can be increased by converting the carboxylic acid group into the corresponding sodium salt 17 ia ion exchange resin.
  • Compound 3 can be reacted with aspartic acid derivative 18 to obtain compound 19 according to the procedure of Example 3.
  • the solubility of compound 19 can be increased by converting the carboxylic acid group into the corresponding sodium salt 20 via ion exchange resin.
  • Compound 27 can be prepared according to the procedures of Examples 1 and 2. The solubility of compound 27 can be increased by converting the carbox lic acid group into the corresponding sodium salt 28 via ion exchange resin.
  • Compound 31 can be prepared according to the procedures of Examples 1 and 3. The solubility of compound 31 can be increased by converting the carboxylic acid group into the corresponding sodium salt 32 via ion exchange resin.
  • Compound 35 can be prepared according to the procedures of Examples 1 and 4. The solubility of compound 35 can be increased by converting the carboxylic acid group into the corresponding sodium salt 36 via ion exchange resin.

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Abstract

La présente invention concerne des composés de formule (I) et de formule (I'), ainsi que des procédés de fabrication de ces composés. La présente invention concerne en outre des compositions et des procédés destinés au traitement de différents états pathologiques comprenant des maladies cancéreuses et non cancéreuses associées à la prolifération vasculaire (formules (I) & (I')).
PCT/IB2011/002730 2010-09-15 2011-09-14 Analogues de promédicaments à base de plinabuline et utilisations thérapeutiques associées WO2012035436A1 (fr)

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EP2887413A1 (fr) * 2013-12-20 2015-06-24 Solvay SA Utilisation de composés comprenant un élément structural de pipérazine dans des dispositifs électroniques organiques et composés et polymères comprenant un élément structural de pipérazine
WO2016130839A1 (fr) * 2015-02-12 2016-08-18 Beyondspring Pharmaceuticals, Inc. Utilisation de plinabuline en combinaison avec des inhibiteurs du point de contrôle immunitaire
WO2016192586A1 (fr) * 2015-06-02 2016-12-08 青岛海洋生物医药研究院股份有限公司 Composé de type déhydrophénylahistine substitué par du deutérium, son procédé de préparation et utilisation dans la préparation d'un médicament antitumoral
WO2017011399A1 (fr) * 2015-07-13 2017-01-19 Beyondspring Pharmaceuticals, Inc Compositions de plinabuline
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EP2887413A1 (fr) * 2013-12-20 2015-06-24 Solvay SA Utilisation de composés comprenant un élément structural de pipérazine dans des dispositifs électroniques organiques et composés et polymères comprenant un élément structural de pipérazine
WO2016130839A1 (fr) * 2015-02-12 2016-08-18 Beyondspring Pharmaceuticals, Inc. Utilisation de plinabuline en combinaison avec des inhibiteurs du point de contrôle immunitaire
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JP7356677B2 (ja) 2019-05-22 2023-10-05 学校法人東京薬科大学 複合体
CN113613654A (zh) * 2019-10-15 2021-11-05 大连万春布林医药有限公司 治疗铁紊乱的组合物和方法
CN113613654B (zh) * 2019-10-15 2024-01-26 大连万春布林医药有限公司 普那布林在制备增加非转移性乳腺癌患者触珠蛋白的药物中的用途
WO2022144002A1 (fr) * 2020-12-31 2022-07-07 大连万众益生大健康有限公司 Dérivé d'un composé de 2,5-dicétopipérazine, son procédé de préparation, composition pharmaceutique de celui-ci et son utilisation
CN114349740A (zh) * 2022-01-17 2022-04-15 中国海洋大学 一种微管蛋白抑制剂普那布林异构体杂质的制备方法及其应用
CN114456085A (zh) * 2022-02-11 2022-05-10 四川大学 2-叠氮基-3-羟基丙酸的制备方法及其应用
CN114456085B (zh) * 2022-02-11 2023-03-14 四川大学 2-叠氮基-3-羟基丙酸的制备方法及其应用
WO2023232113A1 (fr) * 2022-06-02 2023-12-07 上海旭成医药科技有限公司 Composé de pipérazinone, son procédé de préparation et son utilisation

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