WO2008024298A1 - Bis(thiohydrazideamides) servant à inhiber l'angiogenèse - Google Patents

Bis(thiohydrazideamides) servant à inhiber l'angiogenèse Download PDF

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WO2008024298A1
WO2008024298A1 PCT/US2007/018353 US2007018353W WO2008024298A1 WO 2008024298 A1 WO2008024298 A1 WO 2008024298A1 US 2007018353 W US2007018353 W US 2007018353W WO 2008024298 A1 WO2008024298 A1 WO 2008024298A1
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methyl
group
disease
optionally substituted
phenyl
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James Barsoum
Kevin Foley
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Synta Phamaceuticals Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Angiogenesis is the growth of new blood vessels, which is an important natural process occurring in the body, both in health and in disease.
  • Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult.
  • the healthy body controls angiogenesis through a series of "on” and “off switches.
  • the main "on” switches are known as angiogenesis-stimulating growth factors.
  • the main “off switches” are known as angiogenesis inhibitors.
  • Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently.
  • Excessive angiogenesis occurs in diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, and more than 70 other conditions. In these conditions, new blood vessels feed diseased tissues, destroy normal tissues, and in the case of cancer, the new vessels allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases). Excessive angiogenesis occurs when diseased cells produce abnormal amounts of angiogenic growth factors, overwhelming the effects of natural angiogenesis inhibitors.
  • the methods include administering to the subject an effective amount of a bis(thio-hydrazide amide) represented by Structural Formula I:
  • R 1 -R4 are independently -H, an optionally substituted aliphatic group, an optionally substituted aryl group, or Ri and R 3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2 and R 4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic ring optionally fused to an aromatic ring.
  • R 7 -Re are independently -H 5 an optionally substituted aliphatic group, or an optionally substituted aryl group.
  • Z is O or S.
  • ocular neovascular disease e.g., age- • related
  • corneal graft rejection neovascular glaucoma
  • retrolental fibroplasias epidemic keratoconjunctivitis
  • Vitamin A deficiency contact lens overwear
  • atopic keratitis superior limbic keratitis
  • pterygium keratitis sicca sjogrens
  • acne rosacea; wartsphylectenulosis
  • lipid degeneration chemical burns
  • Terrien's marginal degeneration mariginal keratolysis
  • polyarteritis Wegener's sarcoidosis
  • scleritis Stevens-Johnson disease
  • pemphigoid radial keratotomy
  • corneal graph rejection sickle cell anemia
  • sarcoid pseudo
  • the present invention relates to methods of inhibiting angiogenesis in a subject in need thereof with an effective amount of a bis(thio-hydrazide amide) represented by a formula selected from Structural Formulas (I)- (IX) (or a compound encompassed by these structural formulas) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising these bis(thio-hydrazide amides) and compositions comprising these bis(thiohydrazide)amides and an additional pharmaceutically active agent(s).
  • the subject is human.
  • Yet another embodiment of the present invention is the use of a bis(thiohydrazide amide) disclosed herein for the manufacture of a medicament for inhibiting angiogenesis in a subject in need thereof or for treating ocular neovascular disease, macular degeneration (e.g., age-related); corneal graft rejection; neovascular glaucoma; retrolental fibroplasias; epidemic keratoconjunctivitis; Vitamin A deficiency; contact lens overwear; atopic keratitis; superior limbic keratitis; pterygium keratitis sicca; sjogrens; acne; rosacea; wartsphylectenulosis; lipid degeneration; chemical burns; Terrien's marginal degeneration; mariginal keratolysis; rheumatoid arthritis; polyarteritis; Wegener's sarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid
  • Angiogenesis can be divided into the following types:
  • Sprouting angiogenesis is a process resulting in the formation of entirely new vessels. Intussusceptive Angiogenesis •
  • Intussusception is known as splitting angiogenesis.
  • existing vessels are split rather than the formation of entirely new vessel as with sprouting angiogenesis.
  • the present invention encompasses methods of treating both types of angiogenesis.
  • Conditions which are characterized by excessive or abnormal growth of new blood vessels and which can be treated with the disclosed bis(thiohydrazide amides) include ocular neovascular disease, macular degeneration (e.g., age-related); corneal graft rejection; neovascular glaucoma; retrolental fibroplasias; epidemic keratoconjunctivitis; Vitamin A deficiency; contact lens overwear; atopic keratitis; superior limbic keratitis; pterygium keratitis sicca; sjogrens; acne; rosacea; wartsphylectenulosis; lipid degeneration; chemical bums; Terrien's marginal degeneration; mariginal keratolysis; rheumatoid arthritis; polyarteritis; Wegener's sarcoidosis; scleritis; Stevens- Johnson disease; pemphigoid; radial keratotomy; corneal graph rejection
  • ocular neovascular disease e.g., age-related
  • neovascular glaucoma acne; rosacea;; lipid degeneration; rheumatoid arthritis; polyarteritis; Wegener's sarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid; radial keratotomy; sickle cell anemia; sarcoid; pseudoxanthoma elasticum; Paget's disease; vein occlusion; chronic uveitis/vitritis; Eales' disease; Behcet's disease; Best's disease; myopia; Stargardt's disease; diseases associated with rubeosis (neovasculariation of the angle); osteoarthritis; ulcerative colitis; Crohn's disease; BartonellosisOsler-
  • Other conditions characterized by excessive or abnormal growth of new blood vessels and which can be treated with the disclosed bis(thiohydrazide amides) include macular degeneration, acne, rosacea, rheumatoid arthritis, sickle cell anemia, myopia, toxoplasmosis, osteoarthritis, Crohn's disease, pre-eclampsia, obesity, laryngitis, pulmonary edema and glomerulonephritis.
  • the present invention is directed to methods of treating or inhibiting angiogenesis in a subject with a condition selected from the group consisting of as acne, rosacea, rheumatoid arthritis, osteoarthritis, Crohn's disease and obesity with a bis(thio-hydrazide amide).
  • the methods of the present invention does not include treating subjects suffering from a condition selected from the group diabetic retinopathy, retinopathy of prematurity, systemic lupus, mycobacteria infections, bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpes zoster infections; protozoan infections toxoplasmosis diseases caused by the abnormal proliferation of fibro vascular or fibrous tissue including all forms of proliferative vitreoretinopathy, interstitial pulmonary fibrosis, eczema; syphilis, Kaposi's sarcoma, trauma, trauma and post-laser complications; artery occlusion, atherosclerosis; endometriosis, wound healing, ulcers (Helicobacter pylori), Mooren's ulcer; periodontal disease, hepatitis, rhinitis, bronchitis, pneumonia, and cancer.
  • the bis(thio-hydrazide amides) employed in the disclosed invention are represented by Structural Formula 1 and pharmaceutically acceptable salts and solvates of the compounds represented by Structural Formula I.
  • Ri-R 4 are as described above for Structural Formula I.
  • Rs and R* are each independently -H, an aliphatic or substituted aliphatic group, or R 5 is -H and R ⁇ is an optionally substituted aryl group, or, R 5 and R_ 5 , taken together, are an optionally substituted C2-C6 alkylene group.
  • the compound of Structural Formula I is in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of Structural Formula I is in the form of a pharmaceutically acceptable salt in combination with one or more pharmaceutically acceptable cations.
  • the pharmaceutically acceptable cations are as described in detail below.
  • certain bis(thio-hydrazide amides) are represented by Structural Formula II:
  • Ring A is substituted or unsubstituted and V is -CH- or -N-.
  • the other variables in Structural Formula II are as described herein for Structural Formula I or Ilia.
  • the bis(thio-hydrazide amides) are represented by
  • R i -R. 8 are as described above for Structural Formula I.
  • and R 2 are the same or different and/or R 3 and R 4 are the same or different; preferably, Ri and R 2 are the same and R 3 and R 4 are the same.
  • Z is preferably O.
  • Ri and R 2 are the same; and R 3 and R 4 are the same. More preferably, Z is O; R
  • the bis(thio-hydrazide amides) are represented by
  • Ri and R 2 are each an optionally substituted aryl group, preferably an optionally substituted phenyl group;
  • R 3 and R 4 are each an optionally substituted aliphatic group, preferably an alkyl group optionally substituted with -OH, halogen, phenyl, benzyl, pyridyl, or C1-C8 alkoxy and R ⁇ is -H or methyl, more preferably, methyl or ethyl group optionally substituted with -OH, halogen, phenyl, benzyl, pyridyl, or C1-C8 alkoxy and R ⁇ is -H or methyl optionally substituted with -OH, halogen or C1-C4 alkoxy; and R 5 and R 6 are as described above, but R 5 is preferably -H and R 6 is preferably —H, an aliphatic or substituted aliphatic group.
  • R] and R 2 are each an optionally substituted aryl group; R 3 and R 4 are each an optionally substituted aliphatic group; R 5 is -H; and R 6 is -H, an aliphatic or substituted aliphatic group.
  • Rj and R 2 are each an optionally substituted aryl group; R 3 and R 4 are each an alkyl group optionally substituted with - OH, halogen, phenyl, benzyl, pyridyl, or C1-C8 alkoxy and R 6 is -H or methyl; and R 5 is -H and R 6 is -H or methyl.
  • Ri and R 2 are each an optionally substituted phenyl group, preferably optionally substituted with -OH, halogen, C 1-4 alkyl or C1-C4 alkoxy; R 3 and R4 are each methyl or ethyl optionally substituted with -OH, halogen or C1-C4 alkoxy; and R 5 is -H and Rg is -H or methyl.
  • Suitable substituents for an aryl group represented by Ri and R 2 and an aliphatic group represented by R 3 ⁇ R 4 and R 6 are as described below for aryl and aliphatic groups.
  • the bis(thio-hydrazide amides) are represented by Structural Formula HIa: Ri and R 2 are each. an optionally substituted aliphatic group, preferably a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group, more preferably cyclopropyl or 1-methylcyclopropyl; R 3 and R 4 are as described above for Structural Formula I, preferably both an optionally substituted alkyl group; and R 5 and R 6 are as described above, but R 5 is preferably -H and R 6 is preferably -H, an aliphatic or substituted aliphatic group, more preferably -H or methyl.
  • the bis(thio-hydrazide amides) are represented by Structural Formula HIa: R] and R 2 are each an optionally substituted aliphatic group; R3 and R 4 are as described above for Structural Formula I, preferably both an optionally substituted alkyl group; and R 5 is -H and R 6 is — H or an optionally substituted aliphatic group.
  • Ri and R 2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group;
  • R 3 and R 4 are both as described above for Structural Formula I, preferably an alkyl : group; and
  • R 5 is -H and R 6 is -H or an aliphatic or substituted aliphatic group.
  • Ri and R 2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group;
  • R 3 and R 4 are both an alkyl group optionally substituted with -OH, halogen, phenyl, benzyl, pyridyl, or C1-C8 alkoxy and R 6 is -H or methyl; and
  • R 5 is — H and R 6 is -H or methyl.
  • and R 2 are both cyclopropyl or 1-rriethylcyclopropyl; R 3 and R 4 are both an alkyl group, preferably methyl or ethyl optionally substituted with -OH, halogen or C1-C4 alkoxy; and R 5 is — H and R 6 is — H or methyl.
  • the bis(thio-hydrazide amides) are represented by Structural Formula IHb:
  • Rj, R 2 , R 3 , R 4 , R 7 , Rg, and Z are as defined above for Structural Formula Ilia.
  • the bis(thio-hydrazide amides) are represented by Structural Formula IVa:
  • Rj and R 2 are both p'fifenyl, R 3 and R 4 are both methyl, and R 5 and R$ are both -H; Ri and R 2 are both phenyl, R 3 and R 4 are both ethyl, and R 5 and R ⁇ are both -H; Ri and R 2 are both 4-cyanophenyl, R 3 and R 4 are both methyl, R5 is methyl, and R 6 is -H; Ri and R 2 are both 4-methoxyphenyl, R 3 and R 4 are both methyl, and R 5 and R 6 are both -H; Rj and R 2 are both phenyl, R 3 and R 4 are both methyl, R 5 is methyl, and R 6 is -H; Ri and R 2 are both phenyl, R 3 and R 4 are both ethyl, R 5 is methyl, and R 6 is -H; Ri and R 2 are both 4-cyanophenyl, R 3 and R 4 are both methyl, and R 5 and R 6 are both -
  • Ri and R 2 are both 2,3-dimethoxyphenyl, R 3 and R 4 are both methyl, and R 5 and Re are both -H; Ri and R 2 are both 2,3-dimethoxyphenyl, R 3 and R4 are both methyl, R 5 is methyl, and R 6 is -H; Ri and Ro.are both 2,5-difluorophenyl, R 3 and R 4 are both methyl, and R 5 and R_s are both -H; Ri and R 2 are both 2,5-difluorophenyl, R 3 5 and R 4 are both methyl, Rs is methyl, and Re is -H; Ri and R 2 are both
  • and R 2 are both cyclopentyl, R 3 and R 4 are both methyl, and R 5 and Re are both -H; R 1 and R 2 are both cycl
  • the bis(thio-hydrazide amides) are represented by Structural Formula IVb:
  • the bis(thio-hydrazide amides) are represented by Structural Formula V: *" .
  • Ri and R 2 are both phenyl, and R 3 and R 4 are both o-CH 3 -phenyl; Ri and R 2 are both o-CH 3 C(O)O-phenyl, and R 3 and R 4 are phenyl; Ri and R 2 are both phenyl, and R 3 and R 4 are both methyl; Rj and R 2 are both phenyl, and R 3 and R 4 are both ethyl; R) and R 2 are both phenyl, and R 3 and R 4 are both M-propyl; Ri and R 2 are both /7-cyanophenyl, and R 3 and R 4 are both methyl; Rj and R 2 are both/7-nitro phenyl, and R 3 and R 4 are both methyl; R) and R 2 are both 2,5-dimethoxyphenyl, and R 3 and R 4 are both methyl; Ri and R 2 are both phenyl, and R 3 and R 4 are both n-butyl; Ri and R 2 are both/7-
  • Ri and R 2 are both 3-cyanophenyl, and R 3 and R 4 are both methyl;
  • Rj and R 2 are both 3-fluorophenyl, and R 3 and R 4 are both methyl;
  • Ri and R 2 are both 2-furanyl, and R 3 and R 4 are both phenyl;
  • and R 2 are both 2-methoxyphenyl, and R 3 and R 4 are both methyl;
  • R] and R 2 are both 3-methoxyphenyl, and R 3 and -R 4 are both methyl;
  • Rj and R 2 are both 2,3-dimethoxyphenyl, and R 3 and R 4 are both methyl;
  • Rj and R 2 are both 2-methoxy-5-chlorophenyl, and R 3 and R 4 are both ethyl;
  • Ri and R 2 are both 2,5-difluorophenyl, and R 3 and R 4 are both methyl;
  • R] and R 2 are both 2,5-dichlorophenyl,
  • R 3 and R are both phenyl; R] and R 2 are both H-butyl, and R 3 and R 4 are both phenyl; R] and R 2 are both /7-pentyl, R 3 and R 4 are both phenyl; Ri and R 2 are both methyl, and R 3 and R 4 are both 2-pyridyl; Ri and R 2 are both cyclohexyl, and R 3 and R 4 are both phenyl; Ri and R 2 are both methyl, and R 3 and R 4 are both 2-ethylphenyl; Ri and R 2 are both methyl, and R 3 and R 4 are both 2,6-dichlorophenyl; Ri-R 4 are all methyl; Ri and R 2 are both methyl, and R 3 and R 4 are both /-butyl; Ri and R 2 are both ethyl, and R 3 and R 4 are both methyl; R] and R 2 are both /-butyl, and R 3 and R 4 are both methyl; R] and R
  • Preferred examples of bis(thio-hydrazide amides) include Compounds (I)-(18) and pharmaceutically acceptable salts and solvates thereof:
  • bis(thio-hydrazide amide) and references to the Structural Formulas of this invention also include pharmaceutically acceptable salts and solvates of these compounds and Structural Formulas.
  • acceptable salts and solvates are described in US Publication No.: 20060135595 and US Patent Application Serial No.: 1 1/432,307 filed 1 l- May-2006, titled Synthesis Of Bis(Thio- Hydrazide Amide) Salts, the entire contents of each of which are incorporated herein by reference.
  • These compounds can have one or more sufficiently acidic proton that can react with a suitable organic or inorganic base to form a base addition salt.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases such as alkoxides, alkyl amides, alkyl and aryl amines, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
  • pharmaceutically acceptable salts of bis(thio-hydrazide) amides employed herein are those formed by the reaction of the compound with one equivalent of a suitable base to form a monovalent salt (i.e., the compound has single negative charge that is balanced by a pharmaceutically acceptable counter cation, e.g., a monovalent cation) or with two equivalents of a suitable base to form a divalent salt (e.g., the compound has a two-electron negative charge that is balanced by two pharmaceutically acceptable counter cations, e.g., two pharmaceutically acceptable monovalent cations or a single pharmaceutically acceptable divalent cation).
  • Divalent salts of the bis(thio-hydrazide amides) are preferred.
  • “Pharmaceutically acceptable” means that the cation is suitable for administration to a subject. Examples include Li + , Na + , K + , Mg 2+ , Ca 2+ and NR/, wherein each R is independently hydrogen, an optionally substituted aliphatic group (e.g., a hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group) or optionally substituted aryl group, or two R groups, taken together, form an optionally substituted non-aromatic heterocyclic ring optionally fused to an aromatic ring.
  • an optionally substituted aliphatic group e.g., a hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group
  • optionally substituted aryl group or two R groups, taken together, form an optionally substituted non-aromatic heterocyclic ring optionally fused to an aromatic ring.
  • the pharmaceutically acceptable cation is Li + , Na + , K + , NH 3 (C 2 H 5 OH) + or N(CH 3 ) S (C 2 H 5 OH) + , and more typically, the salt is a disodium or dipotassium salt, preferably the disodium salt.
  • Bis(thio-hydrazide) amides employed herein having a sufficiently basic group, such as an amine can react with an organic or inorganic acid to form an acid addition salt.
  • Acids commonly employed to form acid addition salts from compounds with basic groups are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citrte'acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citrte'acid, benzoic acid, acetic acid, and the like.
  • salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenyl
  • Salts of the disclosed bis(thiohydrazide amides) may have tautomeric forms.
  • one tautomeric form for the disalt is is:
  • Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group.
  • R 1 -R4 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or Ri and R 3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R 2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non- aromatic heterocyclic ring optionally fused to an aromatic ring.
  • Z is -O or — S.
  • M + is a pharmaceutically acceptable monovalent cation and M 2+ is a pharmaceutically acceptable divalent cation.
  • M + is a pharmaceutically acceptable monovalent cation.
  • M 2+ is a pharmaceutically acceptable divalent cation.
  • “Pharmaceutically acceptable” means that the cation is suitable for administration to a subject.
  • M + or M 2+ include Li + , Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ , and NR 4 + , wherein each R is independently hydrogen, a substituted or unsubstituted aliphatic group (e.g., a hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group) or substituted or unsubstituted aryl group, or two R groups, taken together, form a substituted or unsubstituted non- aromatic heterocyclic ring optionally fused to an aromatic ring.
  • a substituted or unsubstituted aliphatic group e.g., a hydroxyalkyl group, aminoalkyl group or ammoniumalkyl group
  • the pharmaceutically acceptable cation is Li + , Na + , K + , NHs(C 2 HsOH) + , N(CHs) 3 (C 2 HsOH) + , arginine or lysine. More preferably, the pharmaceutically acceptable cation is Na + or K + . Na + is even more preferred.
  • Preferred examples of bis(thio-hydrazide amide) disalts of the present invention are the following:
  • 2 M + and M 2+ are as described above for Structural Formula (VI).
  • the pharmaceutically acceptable cation is 2 M + , wherein M + is Li + , Na + , K + , NH 3 (C 2 H 5 OH) + or N(CH 3 MC 2 H 5 OH) + . More preferably, M + is Na + or-K + . Even more preferably, M + is Na + .
  • Certain compounds of the invention may be obtained as different stereoisomers (e.g., diastereomers and enantiomers).
  • the invention includes all isomeric forms and racemic mixtures of the disclosed compounds and methods of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures.
  • Stereoisomers can be separated and isolated using any suitable method, such as chromatography.
  • alkyl group is saturated straight or branched chain linear or cyclic hydrocarbon group.
  • a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10
  • a cyclic alkyl group has from 3 to about 10 carbon atoms, preferably from 3 to about 8.
  • An alkyl group is preferably a straight chained or branched alkyl group, e.g, methyl, ethyi, w-propyl, wo-propyl, n-butyl, sec-butyl, tor ⁇ -butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group with 3 to about 8 carbon atoms.
  • a C1-C8 straight chained or branched alkyl group or a C3-C8 cyclic alkyl group is also referred to as a "lower alkyl" group.
  • Suitable substitutents for an alkyl group are those which do not substantially interfere with the biological activity of the disclosed compounds. Suitable substituents are as described below for aliphatic groups. Preferred substituents on alkyl groups include, - OH, -NH 2 . -NO 2 , -CN, -COOH, halogen, aryl, C1-C8 alkoxy, C1-C8 haloalkoxy and — CO(Cl -C8 alkyl). More preferred substituents on alkyl groups include -OH, halogen, phenyl, benzyl, pyridyl, and C1-C8 alkoxy. More preferred substituents on alkyl groups include -OH, halogen, and C1-C4 alkoxy.
  • a “straight chained hydrocarbyl group” is an alkylene group, i.e., -(CH 2 ) y -, with one or more (preferably one) internal methylene groups optionally replaced with a linkage group, y is a positive integer (e.g., between 1 and 10), preferably between 1 and 6 and more preferably 1 or 2.
  • a “linkage group” refers to a functional group which replaces a methylene in a straight chained hydrocarbyl.
  • linkage groups examples include a ketone (-C(O)-), alkene, alkyne, phenylene, ether (-O-), thioether (-S-), or amine (-N(R 8 )-), wherein R a is defined below.
  • a preferred linkage group is -C(R S R O )-, wherein R 5 and R$ are defined above.
  • Suitable substitutents for an alkylene group and a hydrocarbyl group are those which do not substantially interfere with the biloogical activity of the disclosed compounds.
  • R5 and Re are preferred substituents for an alkylene or hydrocarbyl group represented by Y.
  • An aliphatic group is a straight chained, branched or cyclic non-aromatic hydrocarbon which is completely saturated or which contains one or more units of unsaturation.
  • a straight chained or branched aliphatic group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, and a cyclic aliphatic group has from 3 to about 10 carbon atoms, preferably from 3 to about 8.
  • An aliphatic group is preferably a straight chained or branched alkyl group, e.g, methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec-butyl, /er/-butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group with 3 to about 8 carbon atoms.
  • a C1-C8 straight chained or branched alkyl group or a C3-C8 cyclic alkyl group is- also referred to as a "lower alkyl" group.
  • aromatic group may be used interchangeably with “aryl,” “aryl ring,” “aromatic ring,” “aryl group” and “aromatic group.”
  • Aromatic groups include carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl, and heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrroyl, pyrazinyl, thiazole, oxazolyl, and tetrazole.
  • heteroaryl group may be used interchangeably with “heteroaryl,” “heteroaryl ring,” “heteroaromatic ring” and “heteroaromatic group.”
  • Heteroaryl groups are aromatic groups that comprise one or more heteroatom, such as sulfur, oxygen and nitrogen, in the ring structure. Preferably, heteroaryl groups comprise from one to four heteroatoms.
  • Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • Non-aromatic heterocyclic rings are non-aromatic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring.
  • the ring can be five, six, seven or eight-membered.
  • heterocyclic groups comprise from one to about four heteroatoms.
  • Examples include tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, and thiazolidinyl.
  • Suitable substituents on an aliphatic group (including an alkylene group), non- aromatic heterocyclic group, benzylic or aryl group (carbocyclic and heteroaryl) are those which. do not substantially interfere with the biological activity of the disclosed compounds.
  • a substituent substantially interferes with biological activity when the biological activity is reduced by more than about 50% in a compound with the substituent compared with a compound without the substituent.
  • R a -R d are each independently an alkyl group, aromatic group, non-aromatic heterocyclic group or -N(R a R b ), taken together, form a non-aromatic heterocyclic group.
  • the alkyl, aromatic and non-aromatic heterocyclic group represented by R a -R d and the non-aromatic heterocyclic group represented by -N(R a R b ) are each optionally and independently substituted with one or more groups represented by R*.
  • R a -R d are unsubstituted.
  • R" is R + , -OR + , -O(haloalkyl), -SR + , -NO 2 , -CN, -NCS, -N(R + ) 2 , -NHCO 2 R + ,
  • R + is unsubstituted.
  • the group -N(R + ) 2 is a non-aromatic heterocyclic group, provided that non-aromatic heterocyclic groups represented by R + and -N(R + ) 2 that comprise a secondary ring amine are optionally acylated or alkylated.
  • Preferred substituents for a phenyl group include C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, benzyl, pyridyl, -OH, -NH 2 , -F, -Cl, -Br, -I, -NO 2 or -CN. More preferred for a phenyl group, including phenyl groups represented by Ri-R 4 , include R] and R 2 are optionally substituted with -OH, -CN, halogen, Cl -4 alkyl or C1-C4 alkoxy
  • Preferred substituents for a cycloalkyl group are alkyl groups, such as a methyl or ethyl group.
  • the bis(thiohydrazide amides) described herein can be administered in combination with anti-angiogenesis agents, including, but not limited to, Dalteparin, Suramin, ABT- 510, Combretastatin A4 Phosphate, Lenalidomide, LY317615 (Enzastaurin), Soy Isoflavone (Genistein; Soy Protein Isolate), Thalidomide, AMG-706, Anti-VEGF Antibody (Bevacizumab; AvastinTM), AZD2171, Bay 43-9006 (Sorafenib tosylate), PI-88, PTK787/ZK 222584 (Vatalanib), SUl 1248 (Sunitinib malate), VEGF-Trap, XLl 84, ZD6474, ATN-161, EMD 121974 (Cilenigtide), Celecoxib, Angiostatin, Endostatin,
  • the bis(thiohydrazide amides) described herein can be administered to a subject in the form of a pharmaceutical composition.
  • a "pharmaceutical composition” can be a formulation containing the disclosed compounds, in a form suitable for administration to a subject.
  • the pharmaceutical composition can be in bulk or in unit dosage form.
  • the unit dosage form can be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (i.e., a formulation of the disclosed compound or salts thereof) in a unit dose of composition can be an effective amount and can be varied according to the particular treatment involved. It may be appreciated that it can be necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage can also depend on the route of administration.
  • Suitable dosages are those described in PCT/US2006/014531 filed 13-Apr-2006, titled Combination Cancer Therapy With Bis[Thiohydrazide] Amide Compounds, the entire contents of which are incorporated herein by reference.
  • routes including topical, oral, pulmonary, rectal, vaginal, parenternal, including transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal. -o,
  • the compounds described herein, and the pharmaceutically acceptable salts thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compounds can be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • Techniques for formulation and administration of the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy , 19 th edition, Mack Publishing Co., Easton,.PA (1995).
  • the bis(thio-hydrazide amide) disclosed herein can be prepared by the methods described in U.S. Provisional Patent No.: 60/708,977 filed 16- Aug-2005, titled Bis(Thio-Hydrazide Amide) Formulation, the entire teachings of which is incorporated herein by reference.
  • the disclosed compounds or salts thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions, or the like.
  • the tablets, pills, capsules, and the like can contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • the bis(thio-hydrazide) amides can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds may also be formulated as a depot preparation.
  • Suitable formulations of this type include biocompatible and biodegradable polymeric hydrogel formulations using crosslinked or water insoluble polysaccharide formulations, polymerizable polyethylene oxide formulations, impregnated membranes, and the like.
  • Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch.
  • they can be implanted in, or applied to, the microenvironment of an affected organ or tissue, for example, a membrane impregnated with the disclosed compound can be applied to an open wound or burn injury.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials, for example, as an emulsion in an acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, a cream formulation can be administer to a wound site, or a bandage may be impregnated with a formulation, and the like.
  • suitable pharmaceutical compositions are, for rectal administration, for rectal administration, for rectal administration, suitable pharmaceutical compositions are, for
  • topical preparations ⁇ example, topical preparations, suppositories or enemas.
  • suitable pharmaceutical compositions are, for example, topical preparations, pessaries, tampons, creams, gels, pastes, foams or sprays.
  • the compounds may also be formulated to deliver the active agent by pulmonary administration, e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • pulmonary administration e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • pulmonary refers to any part, tissue or organ whose primary function is gas exchange with the external environment, i.e., CVCO? exchange, within a patient. "Pulmonary” typically refers to the tissues of the respiratory tract.
  • pulmonary administration refers to administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharynx, larynx, trachea, carina, bronchi, bronchioles, alveoli).
  • pulmonary is also meant to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.
  • a drug delivery device for delivering aerosols can comprise a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • a solid or a liquid carrier can be used for nasal administration.
  • the solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages.
  • the formulation may be administered as a nasal spray or drops and may include oil or aqueous solutions of the active ingredients.
  • a formulation can optionally include, or be co-administered with one or more additional drugs.
  • the formulation may also contain preserving agents, solubilizing agents, chemical buffers, surfactants, emulsifiers, colorants, odorants and sweeteners.
  • a "subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e g., rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e g., rats, mice, guinea pigs, and the like).
  • the term "effective amount” is the quantity of compound in which a beneficial clinical outcome is achieved when the compound is administered to a subject in need thereof.
  • a "beneficial clinical outcome” includes a partial or significant reduction in formation of blood vessels; a reduction in the severity of the symptoms associated with the condition and/or an increase in the longevity
  • Effective amounts of the disclosed compounds typically range between about 10 g/kg per day to about 1 mg/kg per day, 5 g/kg per day to about 5 mg/kg per day, 3 g/kg per day to about 10 mg/kg per day 2 g/kg per day to about 50 mg/kg per day.
  • an "effective amount" of the therapeutic agent will depend on the type of drug used.
  • the bis(thio-hydrazide amide).disclosed herein can be prepared by the methods described in U.S. Publication ' Nos. 20060135595, 2003/0045518 and
  • HUVEC human umbilical vein endothelial cell migration assay
  • HUVEC cells passage number 4
  • time-lapse imaging is performed with the live cell imaging system on an inverted microscope supplied with 6-7% CO 2 .
  • the temperature is kept at 37°C. Images are taken every 30 minutes using the 2X objective for up to 106 hr or every 60 seconds using the 2OX objective for 30 min.
  • Confluent HUVEC cultures are scraped similarly to make a blank area, followed by culturing in HUVEC medium for 15 hr without treatment.
  • the migration areas which are imaged as time-lapse sequences for each well, are used as a basis to standardize/correct migration rates. Then, migration of cells under different treatments is imaged at the same time to generate time-lapse image sequences for each well. Time-lapse movies are further analyzed by measuring areas that are covered by migrating cells.
  • HUVEC cells are activated by the presence of VEGF and basic FGF.
  • Compounds of the invention e.g. 100 nM and 1 ⁇ M are expected to completely block migration of HUVEC cells to the blank area, indicating that compounds of the invention possesses potent inhibitory effect on the migration of activated HUVEC cell in vitro induced by VEGF and basic FGF.
  • HUVEC cells are treated with DMSO or a compound of the invention (e.g. 10, 100 and 100OnM) for 24 hrs and fixed for immunostaining.
  • DMSO concentration is 1 :100 for all treatments.
  • cells are stained with a mixture of 2 polyclonal anti-human VE-cadherin Abs followed by staining with a mixture of fluorescent secondary antibodies. It is expected that with compounds of the invention, VE-cadherin staining"will be extremely strong in cell-cell junction regions, but not the non-contacted regions compared to that in DMSO treated cultures.
  • Compounds of the invention are expected to enhance the assembly of cell -cell junctions of activated human endothelial cells, likely through induction of the accumulation of VE-cadherin molecules at the junctions. This effect could result in limited motility of the cells and reducing permeability of the endothelium', thus contributing to the cell migration inhibition and the potential anti-angiogenesis effect of compounds of the invention. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

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Abstract

L'invention concerne des procédés d'inhibition de l'angiogenèse chez un sujet qui en a besoin avec des bis(thiohydrazideamides) représentés par une formule sélectionnée parmi les formules de structure (I)-(IX) ou des sels acceptables du point de vue pharmaceutique de ceux-ci.
PCT/US2007/018353 2006-08-21 2007-08-20 Bis(thiohydrazideamides) servant à inhiber l'angiogenèse Ceased WO2008024298A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579503B2 (en) 2004-06-23 2009-08-25 Synta Pharmaceuticals Corp. BIS (thio-hydrazide amide) salts for treatment of cancers
US7645904B2 (en) 2006-09-15 2010-01-12 Synta Pharmaceuticals Corp. Purification of bis(thiohydrazide amides)
US7652168B2 (en) 2001-07-10 2010-01-26 Synta Pharmaceuticals Corp. Synthesis of taxol enhancers
US7671092B2 (en) 2001-07-10 2010-03-02 Synta Pharmaceuticals Corp. Paclitaxel enhancer compounds
US7678832B2 (en) 2005-08-16 2010-03-16 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) formulation
US7750042B2 (en) 2001-07-10 2010-07-06 Synta Pharmaceuticals Corp. Paclitaxel enhancer compound
US7763658B2 (en) 2003-01-15 2010-07-27 Synta Pharmaceuticals Corp. Treatment for cancers
US7939564B2 (en) 2006-08-31 2011-05-10 Synta Pharmaceuticals Corp. Combination with bis(thiohydrazide amides) for treating cancer
US8017654B2 (en) 2005-04-15 2011-09-13 Synta Pharmaceuticals Corp. Combination cancer therapy with bis(thiohydrazide) amide compounds
CN103948784A (zh) * 2014-04-30 2014-07-30 郭如英 甲状腺肿大行滞散结制剂及制备方法
CN104352567A (zh) * 2014-11-25 2015-02-18 何朋飞 一种用于治疗甲状腺肿大的中药
US9156783B2 (en) 2006-08-21 2015-10-13 Synta Pharmaceuticals Corp. Compounds for treating proliferative disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064826A1 (fr) * 2003-01-15 2004-08-05 Synta Pharmaceuticals Corp. Composes bis (thio-hydrazide amide) destines au traitement de cancer resistant a des medicaments multiples
WO2006033913A2 (fr) * 2004-09-16 2006-03-30 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amides) pour le traitement de l'hyperplasie
WO2006055747A2 (fr) * 2004-11-19 2006-05-26 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amides) pour augmenter l'expression de hsp70
WO2006062732A2 (fr) * 2004-11-19 2006-06-15 Synta Pharmaceuticals Corp. Composes agissant sur le centrosome
WO2006113572A1 (fr) * 2005-04-15 2006-10-26 Synta Pharmaceuticals Corp. Methodes d'accroissement de l'activite des cellules tueuses naturelles a des fins therapeutiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064826A1 (fr) * 2003-01-15 2004-08-05 Synta Pharmaceuticals Corp. Composes bis (thio-hydrazide amide) destines au traitement de cancer resistant a des medicaments multiples
WO2006033913A2 (fr) * 2004-09-16 2006-03-30 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amides) pour le traitement de l'hyperplasie
WO2006055747A2 (fr) * 2004-11-19 2006-05-26 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amides) pour augmenter l'expression de hsp70
WO2006062732A2 (fr) * 2004-11-19 2006-06-15 Synta Pharmaceuticals Corp. Composes agissant sur le centrosome
WO2006113572A1 (fr) * 2005-04-15 2006-10-26 Synta Pharmaceuticals Corp. Methodes d'accroissement de l'activite des cellules tueuses naturelles a des fins therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CARMELIET PETER: "Angiogenesis in health and disease", NATURE MEDICINE, NATURE PUBLISHING GROUP, NEW YORK, NY, US, vol. 9, no. 6, June 2003 (2003-06-01), pages 653 - 660, XP002422112, ISSN: 1078-8956 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9107955B2 (en) 2001-07-10 2015-08-18 Synta Pharmaceuticals Corp. Paclitaxel enhancer compounds
US7652168B2 (en) 2001-07-10 2010-01-26 Synta Pharmaceuticals Corp. Synthesis of taxol enhancers
US7671092B2 (en) 2001-07-10 2010-03-02 Synta Pharmaceuticals Corp. Paclitaxel enhancer compounds
US7750042B2 (en) 2001-07-10 2010-07-06 Synta Pharmaceuticals Corp. Paclitaxel enhancer compound
US7763658B2 (en) 2003-01-15 2010-07-27 Synta Pharmaceuticals Corp. Treatment for cancers
US8048925B2 (en) 2004-06-23 2011-11-01 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) salts for treatment of cancers
US7579503B2 (en) 2004-06-23 2009-08-25 Synta Pharmaceuticals Corp. BIS (thio-hydrazide amide) salts for treatment of cancers
US7795313B2 (en) 2004-06-23 2010-09-14 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) salts for treatment of cancers
US8461208B2 (en) 2004-06-23 2013-06-11 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) salts for treatment of cancers
US8017654B2 (en) 2005-04-15 2011-09-13 Synta Pharmaceuticals Corp. Combination cancer therapy with bis(thiohydrazide) amide compounds
US8623921B2 (en) 2005-08-16 2014-01-07 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) formulation
US7678832B2 (en) 2005-08-16 2010-03-16 Synta Pharmaceuticals Corp. Bis(thio-hydrazide amide) formulation
US9156783B2 (en) 2006-08-21 2015-10-13 Synta Pharmaceuticals Corp. Compounds for treating proliferative disorders
US7939564B2 (en) 2006-08-31 2011-05-10 Synta Pharmaceuticals Corp. Combination with bis(thiohydrazide amides) for treating cancer
US7645904B2 (en) 2006-09-15 2010-01-12 Synta Pharmaceuticals Corp. Purification of bis(thiohydrazide amides)
CN103948784A (zh) * 2014-04-30 2014-07-30 郭如英 甲状腺肿大行滞散结制剂及制备方法
CN104352567A (zh) * 2014-11-25 2015-02-18 何朋飞 一种用于治疗甲状腺肿大的中药

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