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WO2001058878A1 - 2-carboxamide-benzimidazoles utiles dans le traitement et la prevention des lesions ischemiques consecutives a la perfusion - Google Patents

2-carboxamide-benzimidazoles utiles dans le traitement et la prevention des lesions ischemiques consecutives a la perfusion Download PDF

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Publication number
WO2001058878A1
WO2001058878A1 PCT/US2001/004211 US0104211W WO0158878A1 WO 2001058878 A1 WO2001058878 A1 WO 2001058878A1 US 0104211 W US0104211 W US 0104211W WO 0158878 A1 WO0158878 A1 WO 0158878A1
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alkyl
carbon atoms
alkoxy
compound
hydrogen
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Nicholas Nikolaides
Donatella Chianelli
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Procter and Gamble Co
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Procter and Gamble Co
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Priority to EP01909025A priority Critical patent/EP1263736A1/fr
Priority to AU2001236821A priority patent/AU2001236821A1/en
Priority to CA002399795A priority patent/CA2399795A1/fr
Priority to US10/203,246 priority patent/US20030216582A1/en
Priority to IL15052501A priority patent/IL150525A0/xx
Priority to JP2001558429A priority patent/JP2003522759A/ja
Publication of WO2001058878A1 publication Critical patent/WO2001058878A1/fr
Priority to NO20023752A priority patent/NO20023752L/no
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the subject invention relates to 2-carboxamide-benzimidazoles useful for treatment or prevention of ischemic reperfusion injury of myocardial and other tissue and other cardiovascular and inflammatory diseases and disorders.
  • Rl is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy, the alkyl and aryl portions of preferred Rl having from 1 to about 14 carbon atoms;
  • R3 and R4 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, alkyl-aryloxy, alkylthio, amino, and mono- or dialkylaminio, the alkyl portions of preferred R3 and R4 having from 1 to about 8 carbon atoms; except that R3 and R4 are not both hydrogen;
  • each R5 is independently selected from the group consisting of hydrogen, halo, cyano, alkyl, hydroxy, alkoxy, thio, alkylthio, amino, and mono- or dialkylamino, the alkyl portions of preferred R5 having from 1 to about 8 carbon atoms; and
  • optical isomer diastereomer, or enantiomer or mixture thereof; a pharmaceutically- acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.
  • the present invention further relates to pharmaceutical compositions containing such compounds; and methods of using such compounds for treating or preventing reperfusion injuries to tissues.
  • MI myocardial infarction
  • reperfusion Treatment with thrombolytic agents to restore blood flow (reperfusion) is first line treatment in many cases.
  • reperfusion injury the acute inflammatory response associated with it, resulting in a syndrome called reperfusion injury.
  • Inflammation generally serves a protective role.
  • bacterial endotoxins induce the production of inflammatory cytokines which recruit circulating leukocytes, including neutrophils and monocytes, to destroy the bacteria. Once the infection is cleared, the inflammation subsides.
  • inflammatory cytokines which recruit circulating leukocytes, including neutrophils and monocytes, to destroy the bacteria. Once the infection is cleared, the inflammation subsides.
  • ischemia-reperfusion injury there are conditions where the inflammatory signal is sustained (rheumatoid arthritis) or is unnecessarily severe (ischemia-reperfusion injury).
  • PMNs neutrophils
  • This migration is preceded by a cascade of events mediated by adhesion molecules.
  • the adherence of PMNs to vascular endothelial cells requires the interaction of adhesion molecules on the surface of both cell types.
  • These molecules belong to three distinct families: the selectins, the integrins and the immunoglobulin superfamily.
  • Neutrophils first roll along endothelial cells, a process mediated by the selectins.
  • firm adherence is mediated by the interaction of ⁇ 2 integrins on PMNs and ICAM-1 (intercellular adhesion molecule- 1) expressed on the endothelial cells.
  • ischemia-reperfusion injury including, but not restricted to, myocardial infarction, coronary artery bypass grafting, angioplasty, angina, stroke, peripheral vascular disease, inflammatory bowel disease, ulcerative colitis, burns, frostbite, adult respiratory distress syndrome, asthma, tissue and organ transplants, general surgery, replantation, acute renal failure, rheumatoid arthritis, psoriasis, hepatitis, pancreatitis, sunburn, radiation, ulcer, and shock.
  • alkyl means a hydrocarbon chain which is linear, branched or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term may be used alone or as part of another word where it may be shortened to "alk” (e.g., in alkoxy, alkylamino).
  • Preferred linear alkyl have from 1 to about 20 carbon atoms, more preferably from 1 to about 8 carbon atoms, more preferably still from 1 to about 4 carbon atoms; most preferred are methyl or ethyl.
  • Preferred cyclic and branched alkyl have from 3 to about 20 carbon atoms, more preferably from 3 to about 10 carbon atoms, more preferably still from 3 to about 6 carbon atoms.
  • Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused or spirocyclic hydrocarbon rings.
  • Alkyl may be unsaturated only with one or more double bonds ("alkenyl”) (no triple bonds), preferably with one, two, or three double bonds, more preferably with one double bond.
  • Alkyl may be unsaturated with one or more triple bonds (“alkynyl”), preferably with one triple bond. More preferred alkyl are saturated (“alkanyl”).
  • alkylene means an alkyl which is attached to 2 or more moieties.
  • alkyl examples include alkyl, aryl, halo, hydroxy, alkoxy, aryloxy, amino, alkylamino, arylamino, thio, alkylthio, arylthio, acyl, alkylacyl, arylacyl, carboxy, alkylester, arylester, amino, alkylamino, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, nitro, cyano, heterocycle.
  • Preferred alkyl are unsubstituted.
  • aryl means an aromatic hydrocarbon ring which is substituted or unsubstituted. The term may be used alone or as part of another word (e.g., in aryloxy, arylamino). Preferred aryl have from 6 to about 14 carbon atoms in the aromatic ring(s), and a total of from about 6 to about 20, preferably to about 12, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl.
  • arylene means an aryl which is attached to two or more other moieties.
  • Preferred substituents of aryl include alkyl, aryl, halo, hydroxy, alkoxy, aryloxy, amino, alkylamino, arylamino, thio, alkylthio, arylthio, acyl, alkylacyl, arylacyl, carboxy, alkylester, arylester, amino, alkylamino, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, nitro, cyano, heterocycle.
  • heteroatom means a nitrogen, oxygen, or sulfur atom.
  • heterocycle or “heterocyclyl” means a cyclic alkyl or aryl with one or more heteroatoms substituted for carbon atoms in the ring(s), preferably 1, 2 or 3 heteroatoms in the ring(s). Preferred heterocycle substituents are the same as for alkyl.
  • heteroaryl refers to the subset of heterocycele which comprise an aromatic ring. Preferred heteroaryl have from 5 to about 14, more preferably to about 10, more preferably still 5 or 6, carbon plus heteroatoms in the ring(s), and a total of from 5 to about 20, more preferably to about 12, carbon plus heteroatoms.
  • safe and effective amount means an amount of a pharmacologically active compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular condition being treated, the size and age and physical condition of the patient, the severity of condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • pharmaceutically-acceptable carrier or “pharmaceutically-acceptable excipients” means one or more compatible solid or liquid excipients which are suitable for administration to a human or lower animal.
  • compatible means that the excipients are capable of being commingled with the pharmacologically active compound or compounds, and with each other, in a manner such that there is no interaction which substantially reduces the pharmaceutical efficacy of the composition under ordinary use situations.
  • the excipients do not have substantial pharmacological activity themselves, but may function, for example, as diluents, lubricants, disintigration enhancers, dissolution enhancers, encapsulating materials, preservatives, colorants, flavorants, and the like.
  • Pharmaceutical-acceptable excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
  • unit dosage form means a composition comprising an amount of a pharmacologically active compound that is suitable for administration to a human or a lower animal subject in a single dose, according to good medical practice.
  • a “biohydrolyzable ester” is an ester of a carboxylic acid-containing 2-carboxamide benzimidazoles of the present invention that does not interfere with the activity of the 2- carboxamide benzimidazoles or that is readily converted by an animal to yield an active 2- carboxamide benzimidazole of this invention.
  • esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
  • lower alkyl esters such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters
  • lactonyl esters such as phthali
  • the subject invention involves 2-carboxamide benzimidazoles compounds having the structure:
  • Rl is selected from alkyl, aryl, alkoxy, and aryloxy.
  • the alkyl and aryl portions of preferred Rl moieties have from 1 to about 14 carbon atoms.
  • Rl is selected from unsubstituted or substituted alkyl having from 1 to about 12 carbons atoms, and unsubstituted or substituted phenyl or naphthyl.
  • More preferred alkyl Rl include unsubstituted or substituted linear alkyl having from about 2 to about 8 carbon atoms, more preferably still from about 3 to about 6 carbon atoms; still more preferred is n-propyl or n-butyl or n-pentyl. More preferred Rl include branched alkyl having from about 3 to about 8 carbon atoms, more preferably still from about 3 to about 6 carbon atoms; still more preferred is isobutyl or isopentyl. More preferred Rl include cyclic alkyl having from 3 to about 8 carbon atoms, more preferably still from 3 to about 6 carbon atoms.
  • Preferred substituents for such linear, branched or cyclic alkyl include halo, hydroxy, alkoxy, amino, mono- and dialkylamino, thio, alkylthio, aryl (especially phenyl), and heterocycle; more preferred is such alkyl being unsubstituted.
  • Preferred Rl which are linear, branched or cyclic alkyl are saturated or unsaturated with one or more double bonds; more preferred are saturated.
  • More preferred aryl Rl include unsubstituted or substituted phenyl.
  • Preferred substituents for such phenyl include halo, hydroxy, alkoxy, amino, mono- and dialkylamino; also preferred is for such phenyl being unsubstituted.
  • More preferred aralkyl Rl include unsubstituted or substituted benzyl.
  • Preferred substituents for such benzyl include halo, hydroxy, alkoxy, amino, mono- and dialkylamino; also preferred is for such benzyl being unsubstituted.
  • R3 and R4 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, alkyl-aryloxy, alkylthio, amino and mono- or dialkylamino, except that R3 and R4 are not both hydrogen.
  • the alkyl portions of preferred R3 and R4 moieties have from 1 to about 8 carbon atoms.
  • R3 and R4 are independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, alkylthio, and mono- or dialkylamino except that R3 and R4 are not both hydrogen.
  • R3 and R4 include hydrogen, alkoxy having from 1 to about 6, preferably to about 3, carbon atoms; alkylthio having from 1 to about 6, preferably to about 3, carbon atoms; monoalkylamino or dialkylamino each alkyl having from 1 to about 6, preferably to about 3, carbon atoms; and alkyl having from 1 to about 6, preferably to about 3, carbon atoms.
  • Preferred substitutents on the alkyl of such moieties include halo, hydroxy, alkoxy, amino, mono- or dialkylamino, thio, alkythio; more preferred is for such R3 and R4 moieties to be unsubstituted. More preferred still is for at least one of R3 and R4, to be ethoxy or especially methoxy.
  • one of R3 and R4 is hydrogen; more preferably R3 is hydrogen.
  • R5 denotes moieties at positions 4 and 7 of the benzimidazole rings.
  • Each R5 is independently selected from hydrogen, halo, cyano, alkyl, hydroxy, alkoxy, thio, alkylthio, amino, and mono- or dialkylamino.
  • the alkyl portions of preferred R5 moieties have from 1 to about 8 carbon atoms.
  • Preferred R5 include hydrogen, halo, alkyl having from 1 to about 6, preferably to about 3, carbon atoms, alkoxy having from 1 to about 6, preferably about 3, carbon atoms, monoalkyl- or dialkylamino each alkyl having from 1 to about 6, preferably to about 3, carbon atoms, and alkylthio having from 1 to about 6, preferably to about 3, carbon atoms.
  • Preferred substituents on the alkyl of such R5 moieties include alkoxy, amino, and alkyl; more preferred is for the alkyl of such moieties to be unsubstituted.
  • each R5 is independently selected from hydrogen, halo, and unsubstituted alkyl having from 1 to about 3 carbon atoms. More preferred is for no more than one R5 being other than hydrogen. Most preferred is both R5 being hydrogen.
  • Preferred compounds of the subject invention include the following examples having structure (I) and the indicated substituents:
  • Subject invention compounds include all active optical isomers, diastereomers and enantiomers, and mixtures thereof, of the above compounds.
  • Subject invention compounds include pharmaceutically-acceptable salts, hydrates, and biohydrolizable esters, amides, and imides of such compounds.
  • CDCI3 Spectra taken in CDCI3 are referenced to solvent (78 ppm), those in CD3OD are referenced to solvent (49 ppm), those in (CD3)2SO are referenced to solvent (39.7 ppm), and those in (CD3)2CO are referenced to solvent (206.5, 29.8 ppm).
  • Mass spectra are determined on a Fision's Trio 2000 equipped with a robotic probe or a Fisons Platform II Mass Spectrometer. Chemical ionization spectra are obtained using methane and/or ammonia as a reagent gas.
  • ESI compound introduction is via Hewlett Packard 1050 HPLC autosampler using methanol, 0.2% formic acid, and 0.2 mM ammonium acetate as the eluting solvent.
  • Thin layer chromatography is performed on silica gel 60-F254 precoated plates. Flash chromatography is performed using silica gel 60 (Merck, 230-400 mesh). Melting points are obtained with an Electrothermal 1A9200 or a MelTemp II capillary melting point apparatus and are uncorrected.
  • Scheme I is a general scheme useful for synthesizing many subject invention compounds:
  • B a NaNO2, propionic acid; b: HNO 3 ; c: Tf O/Et3N, toluene; d: R1-NH ; e: HCOOH, 10% Pd/C; f: n-BuLi, ECF; g: NH 3 , MeOH, KCN.
  • Tf2 ⁇ triflic anhydride
  • reaction mixture is stirred at 0°C for 5 minutes; the amine (RI-NH2) (0.12 mol) is added and the reaction mixture is heated to reflux for 5.5 hrs. After cooling to room temperature, the reaction content is filtered through a plug of silica gel (eluted with 90:10 hexane:ethyl acetate) and concentrated via rotary evaporation to provide crude N-alkyl-5-methoxy-2-nitroaniline. The material is used as is in the next synthetic step.
  • K L h (CH2 ⁇ ) n , KCN, HOAc, ZnCl2; j: EtOH, KOH; k: R2-OH, DEAD, Ph 3 P, THF; m:KOH, t-BuOH.
  • 2-cyano-6-methoxybenzimidazole-N-oxide 457mg, 2.41 mmol
  • THF tetrahydorfuran
  • P13P triphenylphosphine
  • DEAD diethylazodicarboxylate
  • Scheme III is another general scheme useful for synthesizing many subject invention compounds: Scheme III
  • the ethyl acetate layer is dried over magnesium sulfate and evaporated to dryness.
  • the product is chromatographed on a silica gel column using 30% ethyl acetate -hexane as the eluant to give a mixture of the title compound (and the bis Boc protected compound).
  • Scheme IV is another general scheme useful for synthesizing many subject compounds: Scheme IV
  • AA v R6-COC1, CH 2 C1 2 ; w: B 2 H 6 , THF; x: 10% Pd/C, EtOH; y: (CHO-COOEt) n , I 2 /EtOH, z: NH4OH, THF.
  • DCM dichloro methane
  • Scheme V and VI are two general schemes useful for synthesizing many subject invention compounds: aa: R7PhCHO/AcOH, NaCNBH 3; MeOH
  • reaction mix is cooled at room temperature and sodiumcyanoborohydrate (O.lg) is added portion wise.
  • the reaction mixture is stirred at room temperature room temperature for 4 hour.
  • the mixture is then evaporated to dryness and the residue is dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate, water, and brine.
  • the organic layer is dried over sodium sulfate and evaporated to dryness.
  • the residue is chromatographed on a silica gel column using 25% ethyl acetate-hexane as eluant to give the title compound.
  • the subject invention includes pharmaceutical compositions comprising a safe and effective amount of a 2-carboxamide benzimidazole compound described hereinabove and pharmaceutically-acceptable excipients.
  • the compositions may also optionally include other pharmacologically active compounds, particularly those having activity as thrombolytics (e.g., reteplase, streptokinase or tissue plasminogen activators), anticoagulents (e.g., heparin), beta-blockers (e.g., carvedilol, propanalol), calcium channel blockers (e.g., verapamil, nifedipine), and anti-platelet compounds (e.g., aspirin, abciximab).
  • thrombolytics e.g., reteplase, streptokinase or tissue plasminogen activators
  • anticoagulents e.g., heparin
  • beta-blockers e.g., carvedilol, propan
  • pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose, and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; or calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; excipients; tableting agents; stabilizers; antioxidants; preservatives; pyr
  • a pharmaceutically-acceptable carrier to be used in conjunction with a compound is basically determined by the way the compound is to be administered.
  • the compounds and compositions of the present invention may be administered systemically.
  • Routes of administration include topical or transdermal (patch, ointment, cream, powder, etc.); oral; parenteral, including subcutaneous, intramuscular, or intravenous injection; topical; rectal; colonic; intraperitoneal; intraoccular; sublingual; buccal; inhalation; and/or intranasal.
  • the preferred route of administration is parenteral, especially intravenous injection on a daily or as needed basis.
  • the appropriate amount of the compound to be used may be determined by routine experimentation with animal models. Such models include, but are not limited to the ferret, canine, and non human primate models. Generally, an amount between 0.01 ⁇ g/kg to 100 mg/kg of body weight per day is administered dependent on the potency of the compound or compositions used.
  • Preferred unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereof.
  • Parenteral unit dosage form compositions may be in the form of solutions ready for injection or dry (e.g. lyophilized) compositions which are reconstituted with water or saline solutions prior to injection.
  • the pH of said solutions should be adjusted to about 7.4.
  • Suitable carriers for injection or surgical implants include hydrogels, controlled- or sustained release devises, polylactic acid, and collagen matrices.
  • Other suitable carriers for injection include dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, and the like.
  • compositions of the subject invention are preferably provided in unit dosage form.
  • a unit dosage form composition preferably contains from about 50mg, more preferably from about 200mg, also preferably from about 500mg, preferably to about 2000mg, more preferably to about lOOOmg, also preferably to about 500mg, of a 2-carboxamide benzimidazole compound disclosed hereinabove.
  • compositions may be in a variety of forms suitable (for example) for peroral, topical, or parenteral administration.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface- active agents, and encapsulating substances.
  • the amount of carrier components employed in conjunction with the active compound is sufficient to provide a practical quantity of the material for administration per unit dose of the active compound. Techniques and compositions for making the subject unit dosage forms are described in the following references: Modern Pharmaceutics, vol. 7, chapters 9 & 10, Banker and Rhodes, editors, 1979; Lieberman et al., Pharmaceutical Dosage Forms: Tablets, 1981; and Ansel, Introduction to Pharmaceutical Dosage Forms. 2d edition, 1976.
  • a preferred dosage form of the subject invention is intended for parenteral administration.
  • Preferred pharmaceutically-acceptable excipients for such compositions include sterile, pyrogen-free water and physiological saline solution.
  • Parenteral unit dosage form compositions may be in the form of solutions ready for injection or dry (e.g., lyophilized) compositions which are reconstituted with water or saline solution prior to injection.
  • compositions of the subject invention include those intended for peroral administration, such as tablets, capsules, powders and liquids.
  • Suitable pharmaceutically- acceptable excipients, and anti-platelet compounds (e.g., aspirin, abciximab)nts for such compositions include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, magnesium sulfate, vegetable oils, synthetic oils, polyols, algenic acid, phosphate buffers, emulsifiers, alcohols, and water.
  • the 2-carboxamide-benzimidazoles compounds of the subject invention are useful for the treatment of ischemia-reperfusion injury. Although not limited to any specific mechanism, it is believed that the compounds act via modulation of adhesion molecule metabolism. Therefore, the subject compounds are potentially useful for the treatment of ischemia-reperfusion injury including: cardiovascular disease (myocardial ischemia, angina, cardiac arrhythmia, heart failure, hypertension); for treatment to a reduce neurotoxic injury associated with anoxia or ischemia which typically follows stroke, cardiac arrest, or perinatal asphyxia; for treatment to reduce reperfusion injury following organ transplantation; for treatment of frostbite, inflammatory valve disease, psoriasis, asthma, adult respiratory distress syndrome; for treatment of chronic inflammatory lung diseases including emphysema, bronchitis; and for treatment of fibrosis, urticaria, angioedema, vasculitis, migarine, rheumatoid arthritis, gout, and allergy.
  • cardiovascular disease
  • a key event in the reperfusion injury damage process is the up-regulation, expression, activation of intracellular adhesion molecule- 1 (ICAM-1) on endothelial cells.
  • ICAM-1 intracellular adhesion molecule- 1
  • ICAM-1 can then interact with neutrophils resulting in the transmigration of the neutrophils into the tissue with subsequent release of deleterious enzymes and destructive reactive oxygen molecules.
  • compounds which can interfere with the up-regulation, expression, or activation of ICAM-1 are likely to have a beneficial effect for ischemic reperfusion events.
  • These compounds can be administered via oral, intra- vascular, subcutaneous, intra-musclar, intra-nasal, intra-rectal, intra-occular, sublingual/buccal, inhalation, and topical (patch, ointment, powder, or cream) routes, as long as an effective dose is delivered to the source of the ICAM-1.
  • Subject invention 2-carboxamide-benzimidazoles, significantly reduce ICAM-1 up-regulation, expression, or activation.
  • subject compounds demonstrate activity which correlates with protection to the heart. The following are test methods useful for determining such activities of compounds.
  • Tissue The expression of adhesion of molecules (ICAM-1 in particular) is performed on Human Umbilical Vein Endothelial Cells (HUVEC) obtained from Clonetics Corp. (Cat# CC2519), San Diego, CA.
  • VEC Human Umbilical Vein Endothelial Cells
  • Endpoint Concentration of material that inhibits 50% of the expression of ICAM-1 on the surface of HUVECs upregulated with 300U/ml of TNF-alpha (IC50).
  • Method Thaw 1 vial of frozen HUVEC ( rapidly at 37°C for ⁇ 2 min (5 x 10 5 -1 x l ⁇ 6 cells in 1 ml medium), then transfer cells to 45 ml pre- warmed growth medium ( EGM for HUVEC) in a 225 cm 2 flask (seeded at 2500 - 5000 cells/cm 2 ) and place in a humidified 37°C incubator with 5% CO2. Change medium after 24-30h (to remove dead cells and cytopreservatives), and change every 2-3 days thereafter - cells should be confluent after 5-7 days of growth.
  • EGM pre- warmed growth medium
  • HVEO/Neutrophil Adhesion Tissue Adhesion is performed on Human Umbilical Vein Endothelial Cells (HUVEC) obtained from Clonetics (Cat# CC2519).
  • Endpoint Concentration of material that inhibits 20% of the PMN adhesion to HUVECs upregulated with 300 U/ml of TNFalpha (IC20)
  • Human umbilical vein endothelial cells are purchased as frozen cells in 1 ml aliquots (Clonetics Corporation, San Diego, CA). Endothelial Growth Media-Umbilical Vein (EGM-UV), bullet kit additives, trypsinization reagents (trypsin neutralizing solution and HEPES buffer) are also purchased from Clonetics.
  • EMM-UV Endothelial Growth Media-Umbilical Vein
  • trypsinization reagents trypsin neutralizing solution and HEPES buffer
  • the flask is placed at 37°C in a 5% CO2 + 95% air, 100% humidity incubator.
  • One vial of liquid N2 frozen cell is thawed in the 37°C water bath, the whole vial placed in a T-275 flask with 50 mis of fresh media and placed in the CO2 incubator. The media is replaced 24-48 hrs later.
  • Confluency should occur within 4-5 days. Media is changed at least once during that period. The monolayer in the flask is detached using the trypsin solution, after the monolayer is washed with Hanks balanced salt solution (HBSS). The trypsinized cells are centrifuged at 200xGs for 5 minutes and resuspended in approximately 150 mis of media. 100 ul aliquots are placed in each well of 96-well plate that had been previously coated with collagen. The monolayer in the plate should be confluent within 48 hrs.
  • HBSS Hanks balanced salt solution
  • PMNs Peripheral blood polymorphonuclear neutrophils
  • Human blood is obtained from the cubital vein by conventional venipucture performed by qualified phlebotomist.
  • the blood is collected in heparinized vacutainers (Vacutainer #6489, green cap, 15 ml draw, VWR). Thirty ml of blood is used for each assay.
  • the heparinized blood is diluted with approximately '/. volume of phosphate buffered saline containing 0.2% glucose (PBS-G).
  • PBS-G phosphate buffered saline containing 0.2% glucose
  • Histopaque-1119 in the bottom and 3 ml of Histopaque- 1077 on top) (Sigma Chemical Co., St. Louis, MO) is prepared in 6, 15-ml conical centrifuge tubes. The diluted blood is carefully layered on top of the Histopaque- 1077. The tubes are centrifuged at 800 x G for 30 min at room temperature. After the centrifugation step the PMNs are removed by aspiration from the area between Histopaque-1077/Histopaque-1119 interface and the top of the pelleted red blood cells. The PMNs are collected from all the tubes, further diluted to a total volume of 30 ml and centrifuged at 600 x G for 15 min.
  • the pellet (containing PMNs and some red blood cells) is treated with 6 ml of cold water for 30 seconds to lyse contaminating RBC. Normal osmolarity is reestablished by adding 3 ml of 2.7% saline. The PMNs are washed an additional 2 times with PBS-G. The viability and number of the PMNs is determined using the trypan blue exclusion test in a hemocytometer counting chamber. Occasionally, a small aliquot of the PMNs suspension is used for a Cytofuge preparation. The Cytofuge slide is stained with Wright's blood stain (Sigma Chemical Co.) and a differential court performed to evaluate the percent of PMNs in the preparation.
  • TNF Tumor Necrosis Factor
  • the neutrophil pellet is resuspended in 5 mis of PBS-G (approximately 1-3 x 10°7ml). 5 (and 6) carboxyfluorescein diacetate succinimidyl ester (CFSE, Molecular Probes, Eugene, OR).
  • a 20 mM stock of the CFSE is prepared by dissolving 25 mg into 2.24 mis (MW557.5) of DMSO. 5 ⁇ l of the stock is added to the 5 ml suspension of PMNs for a final concentration of 2 uM. The mixture is incubated in the ' refrigerator for 20 minutes. At the end of this period the PMNs are washed 4 times with PBS-G. After the final wash the PMNs are resuspended in complete EGM-UV media to the desired concentration (usually each well of a 96-well plate receives 0.6-1.2 x 10 ⁇ PMNs). .
  • One hundred ⁇ l of media containing the compounds with TNF is used to replace the media in the wells containing the monolayers of endothelial cells 4 hours prior to the addition of the PMNs.
  • CFSE-labeled neutrophils (.7 to 1.5 x 10 ⁇ ) in 10 ⁇ l volumes (see III) are added to the HUVEC monolayers.
  • the plates are incubated at 37°C in a 5% CO2 + 95% air, 100% humidity incubator for 30 min.
  • Non-adherent cells are removed by centrifugation according to the following protocol:.
  • the plates are removed and any empty wells recorded.
  • the lid and the folded paper towel are removed (maintaining the plate upside-down).
  • the Sealing Film is then removed over the biological material disposal bin and the media shaken out.
  • the plate is then blotted on the paper towel and any excess fluid aspirated.
  • the EXCEL spreadsheet calculates a) the percent of PMNs adhering to the monolayer, b) the percent PMNs adhering to the monolayer minus background (PMNs adherent to unstimulated endothelial cells) and c) the percent adhesion inhibition considering the wells receiving TNF alone to the 0% inhibition (negative numbers indicate increase in adhesion).
  • mice Male, Sprague-Dawley rats are anesthetized with urethane, 1.25 g/kg ip.
  • a carotid artery and jugular vein are exteriorized and cannulated with PE-50 tubing for recording blood pressure and to facilitate intravenous administration of dye or drug.
  • a Tracheotomy is performed.
  • the animals are connected to a Harvard Rodent Ventilator (Model 683, Harvard Apparatus, South Natick, MA) and ventilated at 1.5 ml/100 g body weight at 50 strokes/min. Needle electrodes are placed for a lead II electrocardiogram.
  • the animals are maintained at 37°C by means of electric heating pads adjusted to the desired temperature and controlled via a rectal thermistor probe and controller.
  • the heart is carefully isolated by a left thoracotomy at the fifth intercostal space, and the left anterior descending coronary artery (LAD) is located.
  • LAD left anterior descending coronary artery
  • a ligature of 6-0 silk is placed around the LAD, with the ends threaded through a small length of PE-320 tubing to facilitate rapid occlusion and reperfusion of the artery.
  • the LAD is occluded by clamping the suture and tubing tight against the heart surface using 25 mm Schwarz aneurysm clip. Occlusion lasts for 90 min and is followed by reperfusion for 3.0-4.5 hour. Animals are dosed with drug or vehicle 10 min prior to reperfusion of the affected area of the heart by intravenous delivery via a jugular vein.
  • Sham-operated rats are not subjected to ischemia or reperfusion.
  • the LAD is permanently re-occluded and a 10 mg/ml solution of Evans Blue Stain is administered via the jugular cannula to identify the area affected by ischemia, i.e., the area-at-risk (AAR).
  • AAR area-at-risk
  • the stained heart is rapidly excised and placed into 0.9% saline at 4°C prior to the determination of creatine phosphokinase activity (CPK).
  • the left ventricular free wall (LVFW) is dissected free from the heart and weighed.
  • the AAR as defined by the absence of stain, is dissected from the LVFW and also weighed.
  • the AAR is homogenized for 5 sec in 4 ml of 0.25 M sucrose containing 1 mM EDTA and 10 mM mercaptoethanol at 4°C.
  • the homogenate is centrifuged at 3000 x g for 30 min at 4°C.
  • the supernatant is decanted for determination of CPK activity and the pellet is stored frozen for the isolation and assay of myeloperoxidase activity.
  • CPK activity is assayed spectrophotometrically with a commercially supplied substrate, CPK Assay Vial® (Sigma Diagnostics), at a wavelength of 340 nm at 24-26°C. Determination of Myeloperoxidase Activity:
  • MPO Myeloperoxidase
  • HTAB hexadecyltrimefhylammonium bromide
  • CPK and MPO activity are expressed as units/g tissue, where 1 unit of CPK activity is defined as the quantity of CPK utilizing 1 ⁇ mol phosphoceatine per minute and 1 unit of MPO activity is that quantity that degrades 1 ⁇ mol peroxide per minute.
  • the AAR is quantified as a percentage of the LVFW based on weight.
  • Mean arterial blood pressure (MABP) is calculated as one-third the difference between systolic and diastolic blood pressure added to diastolic blood pressure. Data are analyzed for statistical significance of treatment effects at the 95%) confidence level by a pooled t-test or by one-way analysis of variance.
  • the subject invention involves methods of treating or preventing any of the diseases and disorders provided hereinabove, especially reperfusion injury, by administering a safe and effective amount of a 2-carboxamide benzimidazole compound disclosed above.
  • Such methods of treatment can involve administering a unit dosage form of such compounds parenterally, perorally, or topically.
  • Parenteral administration includes intravenous, intramuscular, subcutaneous, intraperitoneal, or other injection of the dosage form.
  • Peroral administration involves ingestion of the dosage form and absorption of the active from the gastrointestinal tract.
  • Topical administration involves contacting the dosage form with the surface of the skin or mucosal tissues, including, but not limited to, those of the alimentaryl canal and the respiratory system.
  • the amount of 2-carboxamide benzimidazole compound typically administered is preferably from about 2 mg/kg, more preferably from about 5 mg/kg, preferably to about 2 mg/kg, more preferably to about 10 mg/kg.
  • the frequency of such administration is typically once or twice daily.
  • a treatment regimen typically is a single dose, or lasts from about 1 day, preferably from about 5 days, to about 30 days, preferably to about 15 days.
  • the amount of 2-carboxamide benzimidazole compound typically administered is preferably from about 5 mg/kg, more preferably from about 10 mg/kg, preferably to about 25 mg/kg, more preferably to about 15 mg/kg.
  • the frequency of such administration is typically from once to about 4 times daily.
  • a treatment regimen typically lasts from about 1 day, preferably from about 5 days, to about 30 days, preferably to about 15 days.
  • composition and method examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the invention. In each case other compounds within the invention may be substituted for the example compound shown below with similar results.
  • compositions in the form of an intravenous solution are prepared by conventional methods, such as mixing the following:
  • tissue damage event aneurysm repair, coronary bypass, transplant surgery, traumatic hemorrhage, organ ischemia due to hypoperfusion, sepsis, etc.
  • Example B Pharmaceutical compositions in liquid form are prepared by conventional methods, formulated as follows:
  • tissue damage event aneurysm repair, coronary bypass, transplant surgery, traumatic hemorrhage, organ ischemia due to hypoperfusion, sepsis, etc.
  • Example 1 can be substituted with any of Examples 2-14.
  • 2 Compound of Example 1 can be substituted with any of Examples 2-14.

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Abstract

L'invention concerne des composés ayant la structure (I) ci-après. Dans cette structure: (a) R1 peut être alkyle, aryle, alcoxy, et aryloxy, sachant que les parties alkyle et aryle de la configuration préférée pour R1 ont entre 1 et environ 14 atomes de carbone; (b) R3 et R4 peuvent être indépendamment hydrogène, halo, alkyle, alcoxy, alkyl-aryloxy, alkylthio, amino, et mono- ou dialkylaminio, sachant que les parties alkyle de la configuration préférée pour R3 et R4 ont entre 1 et environ 8 atomes de carbone; à condition toutefois que R3 et R4 ne soient pas ensemble hydrogène; (c) chaque R5 peut être indépendamment hydrogène, halo, cyano, alkyle, hydroxy, alcoxy, thio, alkylthio, amino, et mono- ou dialkylamino, sachant que les parties alkyle de la configuration préférée pour R5 ont entre 1 et environ 8 atomes de carbone. L'invention concerne en outre des compositions renfermant ce type de composé. Les composés considérés sont utiles pour la prévention ou le traitement des lésions consécutives à la perfusion qui affectent une variété de tissus.
PCT/US2001/004211 2000-02-09 2001-02-08 2-carboxamide-benzimidazoles utiles dans le traitement et la prevention des lesions ischemiques consecutives a la perfusion Ceased WO2001058878A1 (fr)

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EP01909025A EP1263736A1 (fr) 2000-02-09 2001-02-08 2-carboxamide-benzimidazoles utiles dans le traitement et la prevention des lesions ischemiques consecutives a la perfusion
AU2001236821A AU2001236821A1 (en) 2000-02-09 2001-02-08 2-carboxamide-benzimidazoles useful in the treatment and prevention of ischemic reperfusion injury
CA002399795A CA2399795A1 (fr) 2000-02-09 2001-02-08 2-carboxamide-benzimidazoles utiles dans le traitement et la prevention des lesions ischemiques consecutives a la perfusion
US10/203,246 US20030216582A1 (en) 2001-02-08 2001-02-08 2-carboxamide-benzimidazoles useful in the treatment and prevention of ischemic reperfusion injury
IL15052501A IL150525A0 (en) 2000-02-09 2001-02-08 2-carboxamide-benzimidazoles useful in the treatment and prevention of isochemic reperfusion injury
JP2001558429A JP2003522759A (ja) 2000-02-09 2001-02-08 ２−カルボキサミド−ベンズイミダゾール類
NO20023752A NO20023752L (no) 2000-02-09 2002-08-08 2-karboksamid-benzimidazoler som er nyttige ved behandling og forebygging av iskemisk reperfusjonsskade

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6872827B2 (en) 2002-04-26 2005-03-29 Chembridge Research Laboratories, Inc. Somatostatin analogue compounds
CN108456171A (zh) * 2018-03-16 2018-08-28 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种flt3/itd突变体抑制剂及其在防治肿瘤药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062908A2 (fr) * 1998-06-04 1999-12-09 Abbott Laboratories Composes anti-inflammatoires inhibant l'adhesion cellulaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999062908A2 (fr) * 1998-06-04 1999-12-09 Abbott Laboratories Composes anti-inflammatoires inhibant l'adhesion cellulaire

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
CHEM. COMMUN. (1967), (3), 129-31 *
CHEMICAL ABSTRACTS, vol. 55, no. 17, 21 August 1961, Columbus, Ohio, US; abstract no. 16520i, TAFFS, K. H. ET AL: "Preparation and oxidation of some bisbenzimidazoles and benzimidazolylhydroxypropionic acids" XP002167213 *
CHEMICAL ABSTRACTS, vol. 66, no. 21, 22 May 1967, Columbus, Ohio, US; abstract no. 94954b, GARNER, ROBERT ET AL: "Synthesis of 1,2-disubstituted benzimidazoles involving an N-heteroparaffinic ring cleavage" XP002167212 *
CHEMICAL ABSTRACTS, vol. 80, no. 7, 18 February 1974, Columbus, Ohio, US; abstract no. 37040r, BUKOWSKI, L.: "Nitriles of benzimidazolylalkanecarboxylic acids" XP002167211 *
CHEMICAL ABSTRACTS, vol. 82, no. 17, 28 April 1975, Columbus, Ohio, US; abstract no. 112000z, BUKOWSKI, LUDWIK ET AL: "Synthesis of some derivatives of benzimidazol-2-ylalkanoic acids. III. Structure of Mannich bases obtained in a reaction with benzimidazol-2-ylalkanoic acid amides" XP002167210 *
CHEMICAL ABSTRACTS, vol. 89, no. 3, 17 July 1978, Columbus, Ohio, US; abstract no. 24218r, SERAFIN, BARBARA ET AL: "Synthesis and reactions of 1,2-disubstituted benzimidazoles" XP002167209 *
CHEMICAL ABSTRACTS, vol. 97, no. 19, 8 November 1982, Columbus, Ohio, US; abstract no. 162893y, GUPTA, RAJENDER P. ET AL: "Potential radiosensitizing agents. 5. 2-Substituted benzimidazole derivatives" XP002167208 *
J. MED. CHEM. (1982), 25(11), 1342-6 *
J. ORG. CHEM., vol. 26, 1961, pages 462 - 7 *
POL. J. CHEM. (1978), 52(1), 51-62 *
ROCZ. CHEM. (1973), 47, 1719-24 *
ROZPR. WYDZ. 3: NAUK MAT.-PRZYR., GDANSK. TOW. NAUK. (1973), 7, 145-58 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6872827B2 (en) 2002-04-26 2005-03-29 Chembridge Research Laboratories, Inc. Somatostatin analogue compounds
CN108456171A (zh) * 2018-03-16 2018-08-28 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种flt3/itd突变体抑制剂及其在防治肿瘤药物中的应用
CN108456171B (zh) * 2018-03-16 2021-07-27 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种flt3/itd突变体抑制剂及其在防治肿瘤药物中的应用

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AU2001236821A1 (en) 2001-08-20
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