WO2008140214A1 - Utilisation d'un dérivé d'aminothiophène pour prévenir ou traiter des maladies ischémiques - Google Patents

Utilisation d'un dérivé d'aminothiophène pour prévenir ou traiter des maladies ischémiques Download PDF

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Publication number
WO2008140214A1
WO2008140214A1 PCT/KR2008/002594 KR2008002594W WO2008140214A1 WO 2008140214 A1 WO2008140214 A1 WO 2008140214A1 KR 2008002594 W KR2008002594 W KR 2008002594W WO 2008140214 A1 WO2008140214 A1 WO 2008140214A1
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WIPO (PCT)
Prior art keywords
thiophene
carboxylic acid
methyl ester
acetylamino
acid methyl
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PCT/KR2008/002594
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English (en)
Inventor
Jeehee Suh
Sung-Eun Yoo
Kyu Yang Yi
Nakjeong Kim
Eunhee Kim
Yong-Sam Jung
Yun-Suk Lee
Haeyoung Suh-Kim
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Korea Research Institute Of Chemical Technology
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Publication of WO2008140214A1 publication Critical patent/WO2008140214A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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 present invention relates to a use of an aminothiophene derivative for preventing or treating an ischemic disease, a composition for preventing or treating an ischemic disease comprising said compound, and a method of preventing or treating an ischemic disease in a mammal comprising administering to the mammal said compound.
  • Ischemia a symptom of reduced blood supply to organs or tissues is caused by contraction or occlusion of the blood vessel. Once ischemia occurs, subsequent reperfusion causes various sequelae due to the damaged nerve cells.
  • Ischemia is frequently associated with coronary artery diseases, cardiovascular diseases, angina pectoris, headache or other symptoms related to such reduced blood supply, which ultimately leads to necrosis of the cells or tissues involved.
  • Ischemic diseases such as myocardial infarction, arrhythmia or heart failure caused by the cell damage and cell dysfunction induced by ischemia- reperfusion are accompanied by high morbidity and mortality rates, and therefore, they have been the subject of extensive researches and clinic studies for the last fifty years (Wang, Q. D. et al., Cardiovasc. Res. 55:25-37, 2002).
  • ROS reactive oxygen species
  • Ischemia leads to cell death, especially after reperfusion, which is the main cause of various ischemic diseases involving brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, and ischemic acute renal failure. It has been reported that in the case of brain ischemia, the depletion of the energy supply caused by reduced blood supply induces ischemic cell death, which excessively activates cell membrane receptors, leading to various biochemical alterations, e.g., the accumulation of glutamic acid on the outside and calcium on the inside of the cells, to injure the brain tissues (Liu, P. K., J. Biomed. Sci. 10:4- 13, 2003; Lipton, P., Physiol.
  • the retinal ischemia has been reported to be caused by cell death of retinal cells caused by glutamate salt in combination with ischemic cell death (Napper, G. A. et al., Vis. Neurosci. 16:149-158, 1999). Insufficient blood supply to the colon results in ischemic cell death, causing occlusive artery injuries and hemodynamic disorders, and ultimately ischemic colitis (Saegesser, F. et al., Pathobiol. Annu. 9:303-337, 1979).
  • Minocycline a tetracycline antibiotic for inhibiting ischemic cell death
  • ischemic diseases such as cerebral infarction (Yrjanheikki, J. et al., Proc. Natl. Acad. Sci. USA 96:13496-13500, 1999), myocardial infarction (Scarabelli, T. M. et al., J. Am. Coll. Cardiol. 43:865-874, 2004), and ischemic acute renal failure (Wang, J. et al., J. Biol. Chem. 279:19948-19954, 2004), which suggests that the above-mentioned diseases are caused by ischemic cell death.
  • nerve cells damage or death induced by ischemia is involved in various nerve diseases such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma, or diabetic neuropathy (G. J. Zoppo et al., Drugs 54, 9 (1997); and I. Sziraki et al., Neurosci. 85, 1101 (1998)).
  • the present inventors have therefore endeavored to develop a compound which has improved activity in treating ischemic diseases, and have found that an aminothiophene derivative inhibits ischemic cell death, and thus, can be used for preventing and treating ischemic diseases such as brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma, and diabetic neuropathy.
  • ischemic diseases such as brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma, and diabetic neuropathy.
  • an object of the present invention to provide a use of an aminothiophene derivative for preventing or treating an ischemic disease; a composition for preventing or treating an ischemic disease comprising said compound; and a method of preventing or treating an ischemic disease in a mammal comprising administering said compound to a mammal.
  • an aminothiophene derivative of formula (I) or (II), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating an ischemic disease; a composition for preventing or treating an ischemic disease comprising said compound, and a method of preventing or treating an ischemic disease in a mammal comprising administering said compound to the mammal:
  • R 1 is H, -CO 2 R , -CH 2 OR 2 , -CONR 2 2 R 3 3 , or , R 2 2 and R 3 being each independently H, or C 1 -C 6 alkyl optionally substituted with halogen or hydroxy;
  • B is H, or phenyl optinally substituted with C 1 -C 3 alkyl or halogen; n is an integer ranging from 0 to 2; Y is S, O, SO, or SO 2 ;
  • Z is H, halogen, NO 2 , NH 2 , C 1 -C 3 alkyl, or OR 4 , R 4 being H, or Cj-C 3 alkyl;
  • A is CH, N 5 or N-O.
  • FIG. 1 inhibitory effects of the aminothiophene derivatives of the present invention against hypoxemia-induced ischemic cell death
  • FIGs. 2 and 3 inhibitory effects of the aminothiophene derivatives obtained in Examples 1 and 2, respectively, against cerebral ischemia-induced cerebral infarction.
  • the present invention provides the compound of formula I, wherein:
  • R 1 is H, -CO 2 R 2 , -CH 2 OR 2 , -CONR 2 2 R 3 3 or ⁇ - ⁇ ⁇ > , R 2 2 and R 3 3 being each independently H or methyl;
  • B is H, or phenyl optionally substituted with C 1 -C 3 alkyl or halogen; n is O or 1 ; Y is S, O, SO, or SO 2 ;
  • Z is H, halogen, NO 2 , NH 2 , C 1 -C 3 alkyl, or OR 4 , R 4 being H, or C 1 -C 3 alkyl;
  • A is CH 5 N, or N-O.
  • the aminothiophene derivative of the present invention may exist in the form of a pharmaceutically acceptable salt, a solvate, a hydrate or an enantiomer thereof.
  • the pharmaceutically acceptable salt of the aminothiophene derivative of the present invention may be an acid addition salt formed with a pharmaceutically acceptable inorganic acid or an organic acid.
  • organic acid include citric acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid
  • the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, or phosphoric acid, preferably methane sulfonic acid or hydrochloric acid.
  • the acid addition salt of the present invention may be prepared by a conventional method, for example, by dissolving the aminothiophene derivative of formula (I) or (II) in a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess amount of the organic acid or an aqueous solution of the inorganic acid, to induce the precipitation of the salt from the resulting mixture, removing the solvent and remaining free acid therefrom, and isolating the precipitated salts.
  • a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile
  • aminothiophene derivative examples include: 1) 3-[2-(4-bromo-phenylsulfanyl)-acetylamino]-thiophene-2-carboxylic acid methyl ester;
  • the aminothiophene derivative of formula (I) may be prepared by performing a nucleophilic substitution reaction of a compound of formula (III) with a compound of formula (V) in the presence of a solvent and a base:
  • R 1 , B, n, Z, Y and A have the same meanings as defined in formula (I); and L is a leaving group selected from the group consisting of halogen, methanesulfonyloxy, and toluenesulfonyloxy.
  • the base which may be an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, and l,8-diazabicyclo[5,4,0]-unde-7- cene(DBU), or an inorganic base such as NaOH, Na 2 CO 3 , K 2 CO 3 and Cs 2 CO 3 , is used in an equivalent or excess amount based on the compound of formula F.
  • the solvent used in the above reaction may be tetrahydrofuran, dioxane, 1,2- dimethoxyethane, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide, or a mixture thereof.
  • the reaction may be conducted at a temperature ranging from 0 °C to the boiling point of the solvent used.
  • aminothiophene derivative of formula (II) may be prepared by performing a nucleophilic substitution reaction of a compound of formula (IV) with a compound of formula (V) in the presence of a solvent and a base:
  • R 1 , B, n, Z, Y and A have the same meanings as defined in formula (I); and L is a leaving group selected from the group consisting of halogen, methanesulfonyloxy, and toluenesulfonyloxy.
  • the base and the solvent used may be those used in the preparation of the compound of formula (I), respectively.
  • a compound of formula (Ilia) which is the compound of formula (III) wherein R 1 is ester, may be prepared by amidation of the 3- aminothiophene carboxylic acid alkyl ester derivative of formula (VI), as shown in Reaction Scheme I, and the compound of formula (IV) may be prepared in a similar manner.
  • n and B have the same meanings as defined in formula (I);
  • L is a leaving group selected from the group consisting of a halogen, methanesulfonyloxy, and tolunenesulfonyloxy; and D is OH, Br, or Cl.
  • the amidation may be conducted in the presence of a base in a manner similar to that described for the preparation of the compound of formula (I).
  • the amidation may be conducted in the presence of a condensation agent such as 1,3- dicyclohexylcarbodiimide(DCC), l,3-diisopropylcarbodiimide(DIC), l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide(EDC), and 1 , 1 -carbonyldiimidazole (CDI), in a solvent such as dichloromethane, chloroform, tetrahydrofuran and DMF, at a temperature in the range of room temperature to the boiling point of the solvent used.
  • a condensation agent such as 1,3- dicyclohexylcarbodiimide(DCC), l,3-diisopropylcarbodiimide(DIC), l-(3- dimethylaminopropyl)-3 -eth
  • the compound of formula (I) in which n is 1 may be prepared by conducting a 1,4-addition reaction of the compound of formula (VII) with an equivalent or excess amount of a compound of formula (V) in the presence of a suitable solvent and a base, as shown in Reaction Scheme II.
  • the base and the reaction conditions may be those used in the preparation of the compound of formula (I).
  • R 1 , Y, Z, A and B have the same meanings as defined in formula (I).
  • the compound of formula (VII) may be prepared by a conventional method of reacting the compound of formula (III) in which n is
  • aminothiophene derivatives of the present invention may be prepared from the aminothiophene derivative of formula (I) in which R 1 is ester (a compound of formula (Ia)), as shown in Reaction Scheme III.
  • R 2 , Y, Z, A and B are the same as defined in formula I.
  • the carboxylic acid derivative of formula (Ib) is prepared by hydrolyzing the ester group of the compound of formula (Ia) using 1 to 5 equivalent amount of a base in a solvent, e.g., an alcohol such as methanol, an ether such as tetrahydrofuran and dioxane, and a mixture thereof.
  • a base e.g., an alcohol such as methanol, an ether such as tetrahydrofuran and dioxane, and a mixture thereof.
  • the base used in the above reaction is preferably sodium hydroxide or potassium hydroxide, and the reaction is conducted at a temperature in the range of 0 ° C to the boiling point of the solvent used.
  • the compound of formula (Ic) is prepared by reacting the compound of formula (Ib) with a condensation agent such as 1,3- dicyclohexylcarbodiimide(DCC), l,3-diisopropylcarbodiimide(DIC) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide(EDC), and then with 2- chloroethylamine hydrochloride in the presence of an equivalent or excess amount of a base.
  • a condensation agent such as 1,3- dicyclohexylcarbodiimide(DCC), l,3-diisopropylcarbodiimide(DIC) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide(EDC)
  • the solvent which can be used in this reaction is an ether such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, dimethylformamide(DMF), dimethylsulfoxide, or a mixture thereof
  • the base may be an organic base such as pyridine, triethylamine, N 5 N- diisopropylethylamine, and DBU(1, 8-diazabicyclo[5,4,0]-unde-7-cene) or an inorganic base such as NaOH, Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 .
  • the reaction is conducted at a temperature in the range of 0 °C to the boiling point of the solvent used.
  • the compound of formula (Id) is prepared by subjecting the compound of formula (Ic) to an oxazolidine heterocycle formation in the presence of a base such as DBU in a solvent such as tetrahydrofurane, benzene and toluene, at a temperature in the range of O ° C to the boiling point of the solvent used.
  • a base such as DBU
  • a solvent such as tetrahydrofurane, benzene and toluene
  • the alcohol derivative of formula (Ie) may be prepared by reducing the ester group of the compound of formula (Ia) with an equivalent or excess amount of a reducing agent such as sodium borohydride in an alcohol such as methanol or lithium borohydride in tetrahydrofuran at a temperature in the range of 0 ° C to the boiling point of the solvent used.
  • a reducing agent such as sodium borohydride in an alcohol such as methanol or lithium borohydride in tetrahydrofuran at a temperature in the range of 0 ° C to the boiling point of the solvent used.
  • composition of the present invention comprising the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is potently effective in inhibition of the ischemic cell death.
  • the composition of the present invention can be used for the prevention or treatment of ischemic diseases caused by the ischemic cell death, including brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neuropathy.
  • the ischemic cell death may be induced by hypoxemia.
  • the composition of the present invention can be used for the protection of organs.
  • inventive pharmaceutical composition comprising the aminothiophene derivative of formula (I) or (II) or a pharmaceutically acceptable salt thereof may be administered in oral or parentally, and may be formulated with a diluent or excipient such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant and a surfactant, in accordance with one of the known methods.
  • a diluent or excipient such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant and a surfactant, in accordance with one of the known methods.
  • the solid formulation for oral administration may be prepared by mixing at least one of the aminothiophene derivatives of formulae (I) and (II) with at least one of excipients including starch, calcium carbonate, sucrose, lactose and gelatine.
  • excipients including starch, calcium carbonate, sucrose, lactose and gelatine.
  • a lubricant such as magnesium stearate, talc and the like may be added, as well.
  • liquid formulations for oral administration may include suspensions, internal use solutions, emulsion and syrups, which may comprise a diluent such as water and liquid paraffin, and may further comprise various excipients including wetting agents, sweetening agents, aromatics and preservatives.
  • the inventive composition may be formulated into sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyopphilics and suppositories.
  • the non-aqueous solvents and suspensions may comprise injectable vegetable oil (e.g., propylene glycol, polyethylene glycol and olive oil) and esters (e.g., ethyl olate), and the base materials for suppositories may comprise witepsol, macrogol, tween 61, cacao butter, laurin better, glycerol and gelatine.
  • a proposed daily dose of the compound of the present invention for administration to a human is about from 0.1 mg/kg to 1000 mg/kg, more preferably about from 1 mg/kg to 500 mg/kg, and the inventive composition may be administered in a single dose or in divided doses per day. It should be understood that the daily dose should be determined in light of various relevant factors including the conditions to be treated, including age, body weight, sex, administration route, health state and disease severity; and, therefore, the dosage suggested above should not be construed to limit the scope of the invention in anyway.
  • the molecular structures of the compounds were determined by infrared spectroscopy, NMR spectroscopy, mass spectroscopy, liquid chromatography, X-ray crystallography, optical rotation spectroscopy, elemental analysis, or comparison studies between the calculated values and the experimentally observed values of representative compounds.
  • reaction mixture was distilled under a reduced pressure to remove the solvent, and the residue was extracted with ethyl acetate and aqueous NaCl.
  • Example 18 The procedure of Example 18 was repeated except for using 1 g (2.16 mmol) of the compound obtained in Example 17 and, and the resulting residue was dissolved in dichloromethane to obtain 0.77 g of the title compound (yield 80%).
  • Example 20 The procedure of Example 20 was repeated except for using 0.5 mg
  • Step 2 60 mg (0.14 mmol) of the compound obtained in Step 1 was dissolved in 2 mi of tetrahydrofurane, 0.031 ml (0.21 mmol) of DBU was added dropwise thereto, and the mixture was refluxed with heating under a nitrogen atmosphere for 1 hr.
  • the reaction mixture was distilled under a reduced pressure to remove the solvent, and the residue was extracted with ethyl acetate and aqueous NaCl.
  • the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure.
  • 1R NMR 300 MHz, CDCl 3 ): ⁇ 3.77(s, 2H), 4.06(t, 2H), 4.39(t, 2H),
  • 1H NMR 300 MHz, CDCl 3 ): ⁇ 3.46(m, 4H), 4.01(s, 2H), 4.73(t, OH),
  • Example 20 The procedure of Example 20 was repeated except for using 111 mg
  • 1H NMR 300 MHz, CDCl 3 ): ⁇ 2.76(t, 2H), 3.27(t, 2H), 3.89( s, 3H),
  • 1H NMR 300 MHz, CDCl 3 ): ⁇ 2.77(t, 2H), 3.28(t, 2H), 3.88(s, 3H),
  • aminothiophene derivatives of the present invention were assayed for pharmacological effects through the following experiments.
  • Test Example 1 Inhibitory effect on ischemic cell death
  • the aminothiophene derivatives of the present invention were each assayed for inhibitory activity against ischemic cell death in cells as follows.
  • Cardiomyocyte cell line H9c2 cells were cultured in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (100 x solution). I xIO 4 cells thus obtained were inoculated in 35 mm dishes and incubated at 37 ° C for 48 hrs in a CO 2 incubator. The cells for control groups were then treated only with 0.1% DMSO and the cells for test groups treated with a DMSO solution of each of the derivatives of Examples 1 to 50 (10 ⁇ M) in DMSO. After 30 min, the cells were washed once with PBS.
  • DMEM Dynamic fetal bovine serum
  • penicillin/streptomycin 100 x solution
  • control represents a group treated only with DMSO
  • cell a group which is not treated with DMSO
  • aminothiophene derivatives of the present invention showed significant inhibitory activities against ischemic cell death.
  • Test Example 2 Effect of aminothiophene derivative on a brain-disordered rat induced by temporary brain ischemia
  • aminothiophene derivatives of the present invention were each assayed for the inhibitory activity against brain ischemia in the rat as follows.
  • ECA intermal carotid artery
  • ICA intermal carotid artery
  • the image of the rat model suffering from stroke was obtained by using a superconducting MRI with a 65 cm bore, operated on 3.0 T, wherein the fast spin echo (FSE), which is a kind of technique of high speed measurement technique, is used.
  • FSE fast spin echo
  • the imaging parameters were as follows: the repetition image (TR), 4000 msec; the echo time, 96 msec; field of view (FOV), 60 mm; and the resolution,
  • control represents a group treated only with DMSO.
  • the aminothiophene derivative of the present invention (e.g., Example 1) showed remarkable inhibitory activities against ischemic cell death of the brain-disordered rat induced by a temporary brain ischemia.
  • control represents a group treated only with DMSO.
  • the aminothiophene derivative of the present invention (e.g., Example 2) showed remarkable inhibitory activities against ischemic cell death of the brain-disordered rat induced by a temporary brain ischemia.
  • An injection was prepared by mixing 100 mg of the inventive aminothiophene derivative, 180 mg of mannitol, 26 mg of Na 2 HPO 4 - 12H 2 O and 2974 mg of distilled water.

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Abstract

La présente invention concerne l'utilisation d'un nouveau dérivé d'aminothiophène pour prévenir ou traiter une maladie ischémique, une composition servant à prévenir ou à traiter une maladie ischémique et comprenant ledit dérivé, ainsi qu'une méthode de prévention ou de traitement d'une maladie ischémique chez un mammifère, qui consiste à administrer ledit dérivé au mammifère.
PCT/KR2008/002594 2007-05-11 2008-05-08 Utilisation d'un dérivé d'aminothiophène pour prévenir ou traiter des maladies ischémiques WO2008140214A1 (fr)

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KR1020070045992A KR100860539B1 (ko) 2007-05-11 2007-05-11 아미노싸이오펜 유도체를 함유하는 허혈성 질환의 예방또는 치료용 조성물
KR10-2007-0045992 2007-05-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUB20159668A1 (it) * 2015-12-29 2017-06-29 Univ Degli Studi Di Modena E Reggio Emilia Farmaci antitumorali

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KR101197618B1 (ko) 2012-03-13 2012-11-07 한국화학연구원 결핵의 예방 또는 치료용 약제학적 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001098290A2 (fr) * 2000-06-19 2001-12-27 Pharmacia Italia S.P.A. Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant
KR20030095895A (ko) * 2002-06-15 2003-12-24 크리스탈지노믹스(주) 아미노티오펜 카르복실산 유도체를 포함하는 포스포세린포스파타아제 활성 억제용 약학 조성물
US6686382B2 (en) * 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686382B2 (en) * 1999-12-31 2004-02-03 Encysive Pharmaceuticals Inc. Sulfonamides and derivatives thereof that modulate the activity of endothelin
WO2001098290A2 (fr) * 2000-06-19 2001-12-27 Pharmacia Italia S.P.A. Derives de thiophene actifs en tant qu'inhibiteurs de kinase, leur procede de preparation, et compositions pharmaceutiques les contenant
KR20030095895A (ko) * 2002-06-15 2003-12-24 크리스탈지노믹스(주) 아미노티오펜 카르복실산 유도체를 포함하는 포스포세린포스파타아제 활성 억제용 약학 조성물

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUB20159668A1 (it) * 2015-12-29 2017-06-29 Univ Degli Studi Di Modena E Reggio Emilia Farmaci antitumorali

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