WO2001081338A1 - Sulfonylaminopyrimidines substituees - Google Patents

Sulfonylaminopyrimidines substituees Download PDF

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WO2001081338A1
WO2001081338A1 PCT/EP2001/004133 EP0104133W WO0181338A1 WO 2001081338 A1 WO2001081338 A1 WO 2001081338A1 EP 0104133 W EP0104133 W EP 0104133W WO 0181338 A1 WO0181338 A1 WO 0181338A1
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lower alkyl
added
stirred
mixture
pyridine
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PCT/EP2001/004133
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Christoph Boss
Martin Bolli
Martine Clozel
Walter Fischli
Thomas Weller
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Actelion Pharmaceuticals Ltd
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Priority to AU2001265871A priority Critical patent/AU2001265871A1/en
Publication of WO2001081338A1 publication Critical patent/WO2001081338A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel substituted pyrimidines of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists.
  • Endothelins are 21 -amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).
  • ET A , ET B Two endothelin receptors have been cloned and characterized in mammals (ET A , ET B ) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732).
  • the ET A receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29:108).
  • the ET B receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248).
  • This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain.
  • ET B receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858).
  • ET A and ET B receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
  • ET-1 A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma.
  • endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
  • membranes of CHO cells expressing human recombinant ET A or ET B receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu et al, FEBS Lett 1993; 334:210).
  • the assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnCI 2 , 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates.
  • Membranes containing 0.5 ug protein were incubated for 2 h at 20°C with 8 pM [ 125 I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1 , respectively.
  • the membranes were filtered on filterplates containing GF/C filters (Glass Filters Type C, Unifilterplates from Canberra Packard S.A. Zurich, Switzerland).
  • IC 50 was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1.
  • the functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ET A receptors) and of the contraction induced by sarafotoxin S6C on rat tracheal (ET B receptors).
  • E A receptors endothelin-1 on rat aortic rings
  • E B receptors sarafotoxin S6C on rat tracheal
  • Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCI 115, KCl 4.7, MgSO 4 1.2, KH 2 P0 4 1.5, NaHCO 3 25, CaCl 2 2.5, glucose 10) kept at 37°C and gassed with 95% O 2 and 5% CO 2 .
  • the rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France).
  • the rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6C (trachea) were added after a 10 min incubation with the test compound or its vehicle.
  • the functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC 50 induced by different concentrations of test compound.
  • EC 50 is the concentration of endothelin needed to get a half-maximal contraction
  • pA 2 is the negative value of the logarithm of the antagonist concentration which induces a two-fold shift in the EC 50 value.
  • Example 83 7.51 Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension.
  • diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension.
  • Atherosclerosis prevention of restenosis after balloon or stent angioplasty, inflammation, inflammatory bowel disease, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, pain, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
  • the compounds can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol.
  • parenterally e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol.
  • examples of applications are capsules, tablets, oral administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
  • Preferred applications are intravenous, intra-muscular, eye drops or oral administrations.
  • the dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered.
  • the preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
  • the present invention relates to novel substituted pyrimidines of the general formula I,
  • R 1 represents aryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; heteroaryl- lower alkyl;
  • R 2 represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl- amino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; hydroxy-lower alkyloxy; lower alkyloxy-lower alkyl; lower alkyloxy-lower alkyloxy; hydroxy-lower alkyloxy- lower alkyl; hydroxy-lower alkyloxy-lower alkyloxy; lower alkyloxy-lower alkyloxy-lower alkyloxy; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl-amino; aryl; aryl-amino; ary
  • R 3 represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, amino, lower alkylamino, amino- lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;
  • X represents oxygen; sulfur; NH; CH 2 or a bond;
  • R 4 represents one of the following residues:
  • R and R »10 each independently represent hydrogen, or lower alkyl
  • R 6 represents hydrogen, OR 7 , or NR 8 R 9 ;
  • W represents O, or NR 5 ;
  • Y represents O, NR 9 ;
  • Z represents O, NR 9 , S, SO, or SO 2 ;
  • R 7 represents hydrogen; lower alkyl; 2-, 4- or 6-pyrimidinyl optionally mono- or disubstituted with lower alkyl, lower alkoxy, halogen; or a group -CO-NR a R b , or -CO-R b ;
  • R 8 represents hydrogen, lower alkyl
  • R 9 represents hydrogen, lower alkyl, aryl, aralkyl, or a group -CO-NR a R b , or -
  • R a represents hydrogen, lower alkyl; cycloalkyl, or aryl;
  • R b represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl or heteroaryl;
  • lower alkyl means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.
  • Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy.
  • Lower alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylene- dioxy and butylene-dioxy- groups.
  • Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl.
  • Lower alkenylen means e.g.vinylen, propenylen and butenylen.
  • Lower alkenyl and lower aikynyl means groups like ethylen, propylen, butylen, 2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc.
  • Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like.
  • Lower alkylenoxy means e.g. ethylenoxy, propylenoxy.
  • the expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be adequately substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl and lower alkenylen groups.
  • heterocyclyl referes to saturated or unsaturated (but not aromatic) four, five-, six- or seven- membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, amino, lower alkylamino, nitro, hydroxy, lower alkoxy, cyano, aminocarbonyl, alkoxycarbonyl, or carboxyl.
  • heterocyclyl substituents are piperidinyl, morpholinyl.
  • thiomorpholinyl piperazinyl, tetrahydropyranyl, dihydropyranyl, 1 ,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-(1 H)-pyrrolyl, 2,5-dihydro-(1H)-imidazolyl, pyrazolidinyl, 5-oxo- 1 ,2,4-oxadiazolyl, 5-oxo-1 ,2,4-thiadiazolyl, 5-thioxo-1 ,2,4-oxadiazolyl, 2-oxo- 1 ,2,3,5-oxathiadiazolyl, etc.
  • heteroaryl means six- membered aromatic rings containing one to three nitrogen atoms, benzo- fused six-membered aromatic rings containing one to three nitrogen atoms, purinyl, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic rings containig an oxygen and nitrogen atom and benzo-fused derivatives thereof, five Crowd aromatic rings containing a sulfur and a nitrogen atom and benzo fused derivatives thereof, five membered aromatic rings containing two nitrogen atoms and benzo-fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof, or the tetrazolyl ring.
  • Such heteroaryl rings may be substituted with lower alkyl, lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkylamino, trifluoromethoxy, trifluoromethyl, cyano, aminocarbonyl, alkoxycarbonyl, carboxyl, heterocyclyl (preferably 5-oxo-1 ,2,4-oxadiazolyl, 5- oxo-1 ,2,4-thiadiazolyl, 5-thioxo-1 ,2,4-oxadiazolyl, 2-oxo-1 ,2,3,5- oxathiadiazolyl), or heteroaryl (preferably tetrazolyl).
  • heteroaryl rings are furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl.
  • aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphtyl rings which may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-lower alkyloxy, lower alkenylen, lower alkylenoxy, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkyl-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl
  • salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- toluenesulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.
  • hydrohalogenic acids e.g. hydrochloric or hydrobromic acid
  • an inorganic base like an alkali or earth alkali base, e.
  • the compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates.
  • the present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc. Because of their ability to inhibit the endothelin binding, the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension.
  • Atherosclerosis prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, pain, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
  • compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories.
  • enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions
  • nasal form like sprays or rectically in form of suppositories.
  • These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
  • compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
  • vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
  • solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used.
  • injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc.
  • Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquid polyols etc.
  • compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.
  • the compounds of formula I may also be used in combination with one or more other therapeutically useful substances e.g. ⁇ - and ⁇ -blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol etc.; vasodilators like hydralazine, minoxidil, diazoxide, flosequinan etc.; calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil, nifedipine etc.; ACE-inhibitors like cilazapril, captopril, enalapril, lisinopril etc.; potassium activators like pinacidil etc.
  • ⁇ - and ⁇ -blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol
  • Angiotensin II antagonists like hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone, chlortalidone etc.; sympatholitics like methyldopa, clonidine, guanabenz, reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.
  • the dosage may vary within wide limits but should be adapted to the specific situation.
  • the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 5 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg.
  • the dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
  • a preferred group of compounds are compounds of formula I wherein R 1 , R 2 , and R 4 are as defined above, and wherein R 3 represents phenyl, or mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, or halogen;
  • X represents oxygen or a single bond
  • R 2 , R 3 , R 4 , and X are defined as in formula I above, and R 1 represents lower alkyl, and hydroxy-lower alkyl,
  • Another group of preferred compounds are compounds of formula
  • R .1 , R D 3 , O R4 , and X are defined as in formula I above,
  • R >1 , D R2 , C R»3 , and X are defined as in formula I above, and pharmaceutically acceptab ⁇ e salts thereof.
  • Another group of preferred compounds are the compounds described as final products in the Examples 1 to 92 as given below, and pharmaceutically acceptable salts thereof.
  • the compounds of the general formula 1 are prepared by reacting compounds of the formula V with an excess of the alcohol or the amine VI in the presence or absence of a base (e.g. triethylamine, H ⁇ nig's base, etc.) or with an excess of the alkoxide of VI, in a polar solvent such as DMF, DMSO, THF, dimethoxyethane, etc. at temperatures between 0 and 120°C.
  • a base e.g. triethylamine, H ⁇ nig's base, etc.
  • a polar solvent such as DMF, DMSO, THF, dimethoxyethane, etc.
  • a suitable protecting group e.g.
  • the corresponding free amine resulting after the cleavage of the protecting group may then be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, or with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g.
  • the free alcohol resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, or with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R 7 -L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc.
  • a dehydrating agent e.g. a carbodiimide, BOP, or PyBOP
  • sulfonamide potassiums salts may be prepared according to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.
  • Compounds VII could be prepared by treating the corresponding compounds VIII (or tautomeric forms thereof) at elevated temperatures with a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223 - 2228; J. Med. Chem., 41 (1998), 3793 - 3803; J. Chem. Soc. 1959, 2214; Bull. Soc. Chim. Fr. 1958, 741-742).
  • a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223
  • amidines IX were prepared form the corresponding nitriles XI by treating the nitriles XI either with sodium methylate in methanol followed by the addition of ammoniumchloride, or with lithium hexamethyldisilazan followed by the addition of hydrochloric acid in isopropanol (Advanced Organic Chemistry, by J. March, 3 rd edtion, Wiley 1985, p. 803 and references cited therein).
  • the malonic ester derivatives X were either commercially available or were prepared following the procedures found in the literature starting from commercially available chloro- or bromomalonates (e.g. J. Am. Chem. Soc. 62 (1940), 1154, 1155; ibid. 74 (1952), 4466; J. Chem. Soc. Perkin 1 , 1979, 2382-2386; Collect. Czech. Chem. Comm. 55 (1990), 1278-1289; J. Med. Chem. Chim. Ther. 26 (1991), 599-604; Bull. Soc. Chim. Fr. 1973, 2065- 2071).
  • Compounds of formula I may be obtained by treating compounds XII with R 2 H or its salt (e.g. sodium salt) in the presence or absence of a base such as triethylamine, H ⁇ nig's base, etc.
  • R 2 H or its salt e.g. sodium salt
  • R 2 H functionalities of R 2 H other than the nucleophilic reaction centre evoking the desired substitution of the 2- methylsulfonyl pyrimidine may require protection during the introduction of R 2 to the scaffold XII.
  • amines may be protected as carbamates (e.g t.-BOC)
  • alcohols can be protected by ketal or acetal formation (e.g THP) (T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley & Sons, New York 1991 ; P. J. Kocienski, Protecting Groups, Thieme Verlag, Stuttgart, New York 1994).
  • These protecting groups are cleaved in a final step e.g. by treatment with an acid such as TFA, HCI, etc.
  • the sulfones XII are easily obtained by oxidising the corresponding sulfides XIII with an oxidising agent such as 3-chloroperbenzoic acid, peracetic acid, hydrogenperoxide, bleach, chlorine, etc. (e.g. Heterocycles 23 (1985), 611- 616; J. Heterocycl. Chem. 18 (1981 ), 799-800; Synth. Comm. 23 (1993), 715- 723; J. Chem. Soc. 1949, 2490-2495; J. Chem. Soc. 1957, 1830-1832; J. Med. Chem.
  • Compounds XIII are prepared by reacting the monochlorides XIV with an excess of VI in the presence or absence of a base (e.g. triethylamine, H ⁇ nig's base, etc. ) or with an excess of the alkoxide of VI, in a polar solvent such as
  • Additional functionalites of VI may be protected during the introduction of VI to the monochloride XIV.
  • Amines for instance, may be protected as carbamates, amides, imides, azides etc., while alcohols may be protected as e.g. acetals or ketals, ethers, etc..
  • Such protecting groups may be cleaved by treatment with acid (e.g TFA, HCI, etc.) or by treatment with a reducing agent
  • Free amines resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R 8 -L, or R 9 -L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc.
  • a carbamoylating agent such as a carbamoyl chloride or an isocyanate
  • an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyB
  • Free alcohols resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R 7 -L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc.
  • a dehydrating agent e.g. a carbodiimide, BOP, or PyBOP
  • L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc.
  • sulfonamide potassium salts may be prepared according to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.
  • Compounds XV could be prepared by treating the corresponding compounds XVI (or tautomeric forms thereof) at elevated temperatures with a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N.N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Aust. J. Chem. 43 (1990), 47-53; J. Med. Chem. 27 (1984), 1621-1629).
  • a chlorinating agent such as POCI 3 , PCI 5 , or mixtures thereof, etc. each in the presence or absence of a base such as N.N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Aust. J. Chem. 43 (1990), 47-53; J. Med. Chem. 27 (1984), 1621-1629).
  • Compounds XVII were prepared by treating the malonic ester derivatives X and with thiourea in the presence of a base (e.g sodium alkoxides) in a polar solvent (e.g. methanol, ethanol, DMF, or mixtures thereof) at room temperature to 50°C (e.g. Eur. J. Med. Chem. Chim. Ther. 30 (1995), 769-778; Collect. Czech. Chem. Commun. 59 (1994), 957-977; ibid. 47 (1982), 2525-2529; Aust. J. Chem. 44 (1991 ), 129-134; ibid. 43 (1990), 55-62; Bull. Chim. Soc. Fr. 1988, 1005-1008; Pharmazie 38 (1983), 65-66; J. Am. Chem. Soc. 77 (1955), 745-748; J. Chem. Soc. 1954, 3263-3268).
  • a base e.g sodium alkoxides
  • compounds with one or more optically active carbon atoms are resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates in a manner known per se, and, if desired, synthesised compounds of formula I were converted into a pharmaceutically acceptable salt in a manner known per se.
  • R is given in min, molecular mass of the fraction at t. R ), by thin-layer chromatography (tic), (tlc- plates from Merck, silica gel 60 F 25 ) and occasionally by melting point.
  • the combined aqueous layers were adjusted to pH 7 by adding sat. aqueous K 2 CO 3 and extracted three times with DCM. The organic layer was collected, dried over MgSO 4 and evaporated. The crude product was purified by chromatography on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate:methanol:sat. aq. ammonia 8:2:1) and recrystallisation from 2-propanol.
  • the organic layer was washed with 10% aqueous citric acid.
  • the aqueous phase was extracted two more times with ethyl acetate.
  • the combined organic layers were washed with water and brine, dried over MgSO 4 and evaporated.
  • the crude product was treated several times with hexane.
  • the hexane was decanted.
  • the remaining solid was recrystalised from 2-propanol. The crystals were collected, washed with 2-propanol and diethyl ether, and dried.
  • Example 1f (Example 1f) was added and the mixture was stirred for 24 h at r.t.
  • the organic layer was washed with 10% aqueous citric acid.
  • the aqueous phase was extracted two more times with ethyl acetate, was then adjusted to pH 7 by adding sat. aqueous K 2 CO 3 and extracted three times with ethyl acetate.
  • the combined organic layers were dried over MgSO 4 and evaporated.
  • the crude product was purified by chromatography on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate:methanol:sat. aq. ammonia 8:2:1 ) and recrystallised from 2-propanol.
  • the mixture was stirred at 80°C for 17 h before it was diluted with 100 ml of 10% aq. citric acid.
  • the mixture was extracted four times with 50 ml of ethyl acetate, the combined organic layer was washed with twice with 50 ml of 10% citric acid and four times with 50 ml of water, dried over MgSO 4 and evaporated.
  • the mixture was stirred at 80°C for 18 h before it was diluted with 50 ml of 10% aq. citric acid.
  • the mixture was extracted four times with 50 ml of ethyl acetate, the combined organic layer was washed with twice with 50 ml of water, dried over MgSO 4 and evaporated.
  • the residue was suspended in 15 ml of diethyl ether, stirred for 1 h at r.t..
  • Example 1f (Example 1f) was added. The suspension was stirred at 60°C for 28 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water.
  • Example 1f (Example 1f) was added. The suspension was stirred at 60°C for 48 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x50 ml of water.
  • Example 1f (Example 1f) was added. The mixture was stirred at 65°C for 144 h. After 120 h further 200 mg of (R)-5-hydroxymethyl-pyrrolidinone has been added. EventuaUy, the mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water.
  • the mixture was stirred for 72 h at r.t. and 24 h at 50°C. Further 175 mg of 1 ,4-anhydro-2-deoxy-D-erythro-pentitol and 32 mg of NaH was added and stirring was continued for 96 h at 50°C.
  • the mixture was diluted with 75 ml of ethyl acetate and washed with 2x50 ml of 10% aq. citric acid and 50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with ethyl acetate: methanol :sat. aq.
  • Example 24a was added and the mixture was stirred at r.t. for 18 h. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 by adding acetic acid. The precipitate that formed was collected and dried. The material was recrystallised from methanol/diethyl ether. This gave 70 mg of 5- isopropyl-N-[6-(cyclopropylmethoxy)-5-(2-methoxyphenoxy)-2- ⁇ 2-(1 H-tetrazol- 5-yl)-pyridin-4-yl ⁇ -pyrimidin-4-yl]-2-pyridine sulfonamide as a beige solid.
  • the aqueous layer was extracted with 400 ml of DCM.
  • the combined DCM layers were dried over Na 2 SO 4 and the solvent was removed to a volume of about 100 ml.
  • the remaining solution was filtered over 50 g of silica gel eluting with DCM.
  • the filtrate was evaporated.
  • the resulting residue was suspended in 50 ml of diethyl ether.
  • the solid was filtered off and dried to give 13.85 g of 4,6- dichloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-pyrimidine as a white crystalline powder.
  • Racemic 1 ,4-anhydro-2,3-isopropylidene-ribitol (rac-(3aR, 4R, 6aS)- (2,2- dimethyl-tetrahydro-furo[3,4-d][1 ,3]dioxol-4-yl)-methanol) was prepared starting from ribitol (adonitol) in analogy to the procedures given by S. Shuto, Y. Ueno, A. Matsuda in J. Org. Chem. 63 (1998), 8815-8824 and by T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd Edition, Wiley 1991.
  • the solution was poured into 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and twice with 50 ml of water.
  • the organic layer was separated, dried over MgSO , and evaporated.
  • the crude product was purified by crystallisation from ethyl acetate. The crystals were collected, washed with ethyl acetate and diethyl ether, and dried.
  • Example 1 b To a solution of 24.5 g of sodium methylate in 400 ml of methanol was added 42.2 g of dimethyl-(2-methoxyphenoxy)malonate (Example 1 b). The mixture was stirred for 30 min. At 10°C 15.2 g of thiourea was added and stirring was continued at r.t. for 24 h. Eventually, the solvent was removed under reduced pressure. The residue was taken up in 800 ml of water and to the resulting solution 14 ml of methyliodide was added. The mixture was stirred at r.t. for 3 h. Then, 60 ml of 25% aqueous hydrochloric acid was slowly added.
  • Example 48 74 mg of NaN 3 , and 61 mg of NH CI in 5 ml of DMF was stirred at 80°C for 16 h. The mixture was diluted with 75 ml of ethyl acetate and washed twice with 50 ml 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated and evaporated. The crude product was purified on prep, tic plates (silica gel, thickness 0.5 mm, DCM: methanol .water.acetic acid 100:20:2:1).
  • Example 47 was added. The clear solution was stirred at 80°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water.
  • Example 47 was added. The brown solution was stirred at 85°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water.
  • the solution was poured into 100 ml of ethyl acetate and washed once with 100 ml of 10% aqueous citric acid and twice with 100 ml of water. The organic layer was separated, dried over MgSO 4 and evaporated.
  • the crude product was purified by column chromatography on silica gel eluting hexane:ethyl acetate 1 :1. The product was further purified by crystallisation from ethyl acetate/diethyl ether/heptane at 4°C.
  • the aqueous layer was extracted five times with 200 ml DCM. The organic layers were combined, dried over MgSO 4 , and evaporated. The resulting oil was dissolved in 125 ml of THF and cooled to - 20°C. 25 ml of saturated aqueous ammonium hydroxide solution was slowly added. The mixture was stirred overnight at r.t.. Excess of ammonia was neutralised by adding hydrochloric acid and the THF was removed in vacuo. The remaining aqueous solution was extracted three times with 150 ml of ethyl acetate. The combined organic layers were dried over MgSO 4 and the solvent was evaporated.
  • Example 1d Under argon, 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine (Example 1d) was dissolved in 40 ml of dry DMF and 3.62 g of 5- methylpyridine-2-sulfonamide potassium salt followed by 2.95 ml of H ⁇ nig's base was added. The dark solution was stirred at r.t. for 22 h. A further portion of 0.75 g of 5-methylpyridine-2-sulfonamide potassium salt was added and stirring was continued for 18 h. The reaction mixture was poured onto 150 ml of 10% citric acid in water and extracted four times with 150 ml of ethyl acetate.
  • the mixture was diluted with 150 ml of ethyl acetate and washed once with 200 ml of 10% aqueous citric acid, 150 ml of brine and twice with 150 ml of water.
  • the organic layer was evaporated and the crude product was purified by column chromatography on silica gel eluting with DCM containing 2% of methanol.

Abstract

L'invention concerne de nouvelles pyrimidines substituées représentées par la formule générale (I) et leur utilisation comme principes actifs dans la préparation de compositions pharmaceutiques. Cette invention concerne également des aspects connexes, notamment des procédés de préparation de ces composés, des compositions pharmaceutiques contenant au moins un composé représenté par la formule générale (I), et particulièrement l'utilisation de ces derniers comme antagonistes des récepteurs d'endothéline.
PCT/EP2001/004133 2000-04-25 2001-04-11 Sulfonylaminopyrimidines substituees WO2001081338A1 (fr)

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Cited By (14)

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WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
JP2005533803A (ja) * 2002-06-24 2005-11-10 アストラゼネカ・アクチエボラーグ システインプロテアーゼ活性と関連する疾患の処置のためのピリミジン−またはトリアジン−２−カルボニトリルの新規使用および新規ピリミジン−２−カルボニトリル誘導体
US7531547B2 (en) 2005-09-01 2009-05-12 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7776872B2 (en) 2005-09-01 2010-08-17 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7799796B2 (en) 2005-09-01 2010-09-21 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
US8329337B2 (en) 2004-12-14 2012-12-11 Nissan Motor Co., Ltd. Electrode for use in a battery
CN103923094A (zh) * 2014-04-14 2014-07-16 石河子大学 一种采用离子液体支撑液膜分离纯化光甘草定的方法
AU2010338011B2 (en) * 2009-12-28 2015-04-02 Development Center For Biotechnology Novel pyrimidine compounds as mTOR and P13K inhibitors
US9315491B2 (en) 2009-12-28 2016-04-19 Development Center For Biotechnology Pyrimidine compounds as mTOR and PI3K inhibitors
US20160146809A1 (en) * 2013-07-02 2016-05-26 Institut De Recherche Pour Le Developpment Peptides and methods for the detection of leishmaniasis
CN111867590A (zh) * 2017-07-13 2020-10-30 德州大学系统董事会 Atr激酶的杂环抑制剂

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EP0633259A1 (fr) * 1993-06-28 1995-01-11 F. Hoffmann-La Roche Ag Sulfonylaminopyrimidines, leur préparation et leur usage comme médicament
EP0658548A1 (fr) * 1993-12-17 1995-06-21 Tanabe Seiyaku Co., Ltd. Dérivés de la benzènesulfonamide et procédé de préparation
EP0713875A1 (fr) * 1994-11-25 1996-05-29 F. Hoffmann-La Roche AG Sulfonamides
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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
US7094781B2 (en) 2000-12-18 2006-08-22 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
EP1693372A1 (fr) * 2000-12-18 2006-08-23 Actelion Pharmaceuticals Ltd. Nouveaux sulfamides et leur utilisation comme antagoniste du récepteur d'endotheline
US7285549B2 (en) 2000-12-18 2007-10-23 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
JP2005533803A (ja) * 2002-06-24 2005-11-10 アストラゼネカ・アクチエボラーグ システインプロテアーゼ活性と関連する疾患の処置のためのピリミジン−またはトリアジン−２−カルボニトリルの新規使用および新規ピリミジン−２−カルボニトリル誘導体
US9556127B2 (en) 2004-03-05 2017-01-31 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8846705B2 (en) 2004-03-05 2014-09-30 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8329337B2 (en) 2004-12-14 2012-12-11 Nissan Motor Co., Ltd. Electrode for use in a battery
US7776872B2 (en) 2005-09-01 2010-08-17 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7799796B2 (en) 2005-09-01 2010-09-21 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US7531547B2 (en) 2005-09-01 2009-05-12 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 modulators
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
AU2010338011B2 (en) * 2009-12-28 2015-04-02 Development Center For Biotechnology Novel pyrimidine compounds as mTOR and P13K inhibitors
US9315491B2 (en) 2009-12-28 2016-04-19 Development Center For Biotechnology Pyrimidine compounds as mTOR and PI3K inhibitors
EP2519102B1 (fr) * 2009-12-28 2016-10-19 Development Center For Biotechnology NOUVEAUX COMPOSÉS DE PYRIMIDINE EN TANT QU'INHIBITEURS DE mTOR ET P13K
US9801888B2 (en) 2009-12-28 2017-10-31 Development Center For Biotechnology Pyrimidine compounds as mTOR and PI3K inhibitors
US20160146809A1 (en) * 2013-07-02 2016-05-26 Institut De Recherche Pour Le Developpment Peptides and methods for the detection of leishmaniasis
US9804158B2 (en) * 2013-07-02 2017-10-31 Institut De Recherche Pour Le Développement Peptides and methods for the detection of Leishmaniasis
CN103923094A (zh) * 2014-04-14 2014-07-16 石河子大学 一种采用离子液体支撑液膜分离纯化光甘草定的方法
CN111867590A (zh) * 2017-07-13 2020-10-30 德州大学系统董事会 Atr激酶的杂环抑制剂
CN111867590B (zh) * 2017-07-13 2023-11-17 德州大学系统董事会 Atr激酶的杂环抑制剂

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