CN1812782A - Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors - Google Patents

Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors Download PDF

Info

Publication number
CN1812782A
CN1812782A CNA2004800177171A CN200480017717A CN1812782A CN 1812782 A CN1812782 A CN 1812782A CN A2004800177171 A CNA2004800177171 A CN A2004800177171A CN 200480017717 A CN200480017717 A CN 200480017717A CN 1812782 A CN1812782 A CN 1812782A
Authority
CN
China
Prior art keywords
phenyl
propoxyl group
diketone
methyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2004800177171A
Other languages
Chinese (zh)
Inventor
海因茨·弗雷兹
托马斯·格勒
克特·希尔伯特
奥利弗·豪伊勒
马库斯·雷德里尔
奥利弗·维尔丹奈尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Actelion Pharmaceuticals Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of CN1812782A publication Critical patent/CN1812782A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/542—Alkylated benzaldehydes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/548—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
    • C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

The present invention provides a pyrazolidinedione derivatives of the general formula (I), wherein R1 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkanoyl; and R2 is aryl or heteroaryl; tautomers thereof; geometric isomers thereof and tautomers of these geometric isomers, including mixtures of individual compounds of formula (I), or tautomers thereof, and their geometric isomers, or tautomers thereof, pharmaceutically acceptable acid addition salts of compounds which are basic; pharmaceutically acceptable salts of compounds containing acidic groups with bases; pharmaceutically acceptable esters of compounds containing hydroxy or carboxy groups; prodrugs of compounds in which a prodrug forming group is present; as well as hydrates or solvates thereof; are active as platelet adenosine diphosphate receptor antagonists and can be used for the prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, particularly thrombosis, and, respectively, for the manufacture of corresponding medicaments. Some, albeit not all, of the compounds of the above formula (I) are novel.

Description

Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors
The present invention relates to the alkylidene Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors, it is a kind of effective platelet ADP receptor antagonist, and can be used for the peripheral vessel relevant, heart with platelet aggregation-, liver-and the treating and/or preventing of kidney-blood vessel, cardiovascular and cerebrovascular disease and disease (comprising people and other mammiferous thrombosiss).
Hemostasis is a kind ofly to keep rapid formation that blood fluidity in the vascular system allows the solid clot simultaneously to prevent lose blood cooperation complexity, that be mutually related incident of (hemorrhage) of transition after blood vessel injury.After blood vessel injury, can cause a series of process immediately, for example the contraction of blood vessel.Thrombocyte adhesiveness and gathering, the condense activation of polyphone and the activation of fibrinolytic system subsequently.Hemostasis is carried out by the following method: platelet or blood platelet are adhered on the interior subcutaneous connective tissue of injured blood vessel exposure, the height thrombinogen and assemble, be used for hemostatic platelet plug to form one.
Hemostatic pathology obstacle can cause developing into a kind of undesirable, thrombosis in the life-threatening blood vessel in some cases.Some diseases, for example the turbulent flow blood flow in diseased vessel, basic blood vessel wall breaks, usually be attributable to the exposure of arteriosclerosis, impaired endotheliocyte and discharge amboceptor, cause the adhesion and the gathering of the activated blood platelet of artery thrombosis from circulating cells, and thereby the interruption artery blood vessel cause serious disease.Stasis in the vein or slow blood flow also can cause forming thrombosis.Thromboembolism can easily take place in thrombosis, this means their part separation and passes blood circulation, finally blocks other vascular.Venous thrombosis thrombophlebitis, arterial thrombosis, coronary artery and arteriae cerebri thrombosis, astable pharyngalgia, myocardial infarction, apoplexy, cerebral embolism, kidney and pulmonary infarction all are to cause the dead and disabled serious disease of angiopathy patient usually.
Initial impulse, for example thrombin, collagen, the von Willebrand's disease factor (vWf), thromboxane A2 (TxA2) and ADP, activated blood platelet are to realize with combining of cell surface receptor respectively by them.Many these receptors belong to seven and comprise G albumen-coupled receptor transbilayer helix family, and they have demonstrated importance at platelet activation, and (Offermans S. etc., Nature 1998,389 (11), 183-185).In when activation, hematoblastic shape has become a kind of circle that has pseudopodium from discoid, and this pseudopodium has promoted thrombocyte adhesiveness subsequently.Accumulative final common event is by Fibrinogen and its receptor, glycoprotein IIB-IIIa (GPIIb-IIIa, beta 2 integrin alpha IIbβ 3) receptor, bonded hematoblastic crosslinked in culminate.
Come in the past few years, developed a series of antiplatelet reagent (consult, Dogn é etc., Curr.Med.Chem.2002,9 (5), 577-589).In Antiplatelet therapy first and at present one of the most widely used reagent be aspirin, thereby its inhibitory enzyme cyclo-oxygenase-1 and influence the TxA2 passage irreversibly.Although be not the most effective, the treatment of using aspirin to carry out remains a kind of standard treatment, and with respect to this therapy, and new therapy is still compared and judges.After aspirin, also used phosphodiesterase inhibitor persantin and cilostazol as antiplatelet reagent.Can also use with respect to the antibody of GPIIb/IIIa receptor obtain the antiplatelet effect (TheEPIC investigators, New Engl.J.Med.1994,330,956-961).Now, but on market, can obtain GPIIb/IIIa receptor antagonist that three kinds of intravenouss are used, effectively blocking platelet cohesion (abciximab, Eptifibatide (eptifibatide) and for Nuo Feibang (tirofiban).In addition, the GPIIb/IIIa antagonist of Orally active, for example sibrafiban (sibrafiban), xemilofiban (xemilofiban) and orbofiban (orbofiban) still are among the clinical evaluation, but up to the present also do not succeed.Indirect or direct coagulation inhibitor, for example unsegregated heparin, low molecular weight heparin, hirudin have also demonstrated can be as highly effective antithrombotic reagent (Wong G.C. etc., JAMA 2003.01.05,289 (3), 331-42; Antman E.M., Circulation 1994,90,1624-1630, (GUSTO) IIa Investigators, Circulation 1994,90,1631-1637, Neuhaus K.L. etc., Circulation 1994,90,1638-1642).
Adenosine 5 '-hydrophosphate (ADP) is considered to a kind of key amboceptor (Shaver S.R., Curr.Opin.Drug Dicovery ﹠amp to the platelet ADP receptor of at least two G albumen coupling P2 receptor families at platelet activation and in assembling; Development 2001,4 (5), 665-670).P2Y 1Receptor is by activating calcium storage causing gathering and being that platelet deformation is needed.Recently the P2Y of Jian Dinging 12Receptor also is represented as P2Y ADP, P2Y AC, P2Y Cyc, P 2T, P2T AC(consult, BarnardE.A. with Simon J., Trends Pharmacol.Sci.2001,22 (8), 388-391), mediated the inhibition of adenyl cyclase and be corresponding and accumulatively stablize requisite (Gachet Ch., Thromb Hemost.2001 the gathering fully of ADP, 86,222-32; Turner N.A. etc., Blood 2001,98 (12), 3340-3345; Remijin J.A. etc., Arterioscler.Thromb.Vasc.Biol.2002,22,686-691).
The various antagonisies that demonstrate the platelet ADP receptor that suppresses platelet aggregation and anti-thrombosis activity have been reported.Up to now, the most effective known antagonist is thienopyridine ticlopidine, clopidogrel and CS-747, these medicines form reagent (Kam and Nethery at the clinical antithrombotic that still is used as, Anaesthesia 2003,58,28-35, CAPRIE Steering Committee, The Lancet 1996,348,1329-39; Doggrell S.A., Drugs of the Future 2001,26 (9) 835-840).Verified, these medicines via they reactive metabolite irreversibly block adenosine 5 '-hydrophosphate (ADP) receptor subtype P2Y 12
Some analog of endogenous antagonist ATP, for example AR-C (being called FPL or ARL before this) 67085MX and AR-C69931MX (Cangrelor) have entered II phase clinical research.These inhibitor are platelet ADP receptor antagonisies optionally, and it can suppress the platelet aggregation of ADP-dependency, and be in vivo effectively (consult, Chattaraj S.C., Curr.Opin.Invest.Drugs, 2001,2 (2), 250-255).
(PCT applies for WO99/36425 to Laibelman A.M. etc., open day: the assorted tricyclic compound that condenses that on July 22nd, 1999) discloses the effective platelet ADP receptor inhibitors of a kind of conduct.
(PCT applies for WO 01/36438 to Hardern D. etc., open day: May 25 calendar year 2001) disclose a series of triazole as active A DP receptor antagonist [4,5-d] pyrimidine.
(PCT applies for WO 01/85722, open day: November 15 calendar year 2001) disclose a kind of platelet ADP receptor (P2Y for Scarborough and Marlowe 12) three ring benzothiazole [2,3-c] thiadiazine derivatives of effective inhibitor.
(PCT applies for WO 02/16381 to Boyer etc., open day: on February 28th, 2002 and US2002/0052377, open day: on May 2nd, 2002) disclose as P2Y 12The monokaryon glycosides of receptor antagonist and double-core glycosides polyphosphate.
Bryant J. etc. (PCT applies for WO 02/098856, and open day: on December 12nd, 2002) disclose can be as the quinoline that forms reagent via the inhibition of platelet ADP receptor as antithrombotic.
(PCT applies for WO 03/011872 to Scarborough R.M. etc., open day: on February 13rd, 2003) disclose sulfonylureas and sulfamide derivative as effective platelet ADP receptor inhibitors.
A compounds of the present invention, alkylidene 3, the 5-pyrazolidinedione, also be long ago with regard to known (Michaelis A. and Burmeister R.Ber.1892,1502-1513).Yet derivant of the present invention has shown unknown up to now biology effect, and the part in them is a noval chemical compound.
(PCT applies for WO 02/102359 to Bombrun A. etc., open day: on December 27th, 2002) the alkylidene Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors is disclosed via phosphotyrosine phosphate (PTPs), the particularly inhibition of PTP1B, TC-PTP, SHP and GLEPP-1, the purposes that is used for the treatment of and/or prevents I type and/or type ii diabetes, weakening glucose tolerance, insulin resistance, hyperglycemia, obesity and polycystic ovary syndrome.
Hassan S. (Canadian Patent CA2,012,634, open day: on JIUYUE 20th, 1991) asks for protection the alkylidene Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors of blocking platelet activation factor (PAF) and leukotriene D4 (LTD4).
Krogdal T.G. (PCT applies for WO 00/54771, and open day: on JIUYUE 21st, 2000) discloses and has been used for the treatment of 3 of viral infection, the 5-Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors.
In a word, moderate oral effectiveness and limited the purposes of present known antiplatelet reagent and anticoagulant such as serious adverse effects such as bleeding problems.Still openly need to be used to prevent and/or treat angiopathy, particularly relevant angiopathy more effective, Orally active and have the form of therapy of minimal side effect with thrombosis.Especially, need effectively, optionally with the platelet ADP receptor (P2Y of Orally active 12) receptor antagonist.The invention provides chemical compound with this important pharmacological characteristics.
One aspect of the present invention relates to the purposes of the Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors of following general formula
Wherein
R 1Be hydrogen, optional alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl or the alkanoyl that replaces; With
R 2Be aryl or heteroaryl;
And tautomer;
The tautomer of its geometric isomer and these geometric isomers comprises each formula (I) chemical compound or the mixture of its tautomer and geometric isomer or its tautomer;
The pharmaceutically-acceptable acid addition of alkali compounds;
Comprise the chemical compound of acidic group and the pharmaceutically acceptable salt of alkali;
The pharmaceutically acceptable ester that comprises the chemical compound of hydroxyl or carboxyl;
The prodrug that wherein has the chemical compound of prodrug formation property group; And hydrate or solvate;
As be used to prevent and/or treat the peripheral vessel relevant, heart with platelet aggregation-, liver-and kidney-blood vessel, cardiovascular and cerebrovascular disease and disease, comprise thrombosis, and be used to make relative medicine, platelet adenosine diphosphate receptor antagonist.
The geometric isomer of above-mentioned formula (I) chemical compound has following formula (II) structure
The above-mentioned tautomer of two geometric isomers of formula (I) and formula (II) has following formula (IA) and (IIA) structure respectively:
Figure A20048001771700282
In formula (I) chemical compound, R 1Be preferably hydrogen, alkyl, aryl, heteroaryl or alkanoyl, preferred especially hydrogen, alkyl, phenyl, bromophenyl, chlorphenyl, fluorophenyl, aminomethyl phenyl, methoxyphenyl, cyano-phenyl, alkoxycarbonylphenyl, pyridine radicals or alkanoyl, more preferably hydrogen, methyl, phenyl, 2-pyridine radicals, 4-pyridine radicals, 2-aminomethyl phenyl, 4-aminomethyl phenyl, 4-methoxyphenyl, 2-chlorphenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyano-phenyl, 4-ethoxy carbonyl phenyl or acetyl group.
R 2Be preferably naphthyl, thienyl or pyridine radicals, preferred especially naphthalene-2-base, pyridin-3-yl or thiene-3-yl-.
Be preferably as follows the purposes of general formula compound especially
Figure A20048001771700291
The geometric isomer and the tautomer and composition thereof that comprise them, and their salt, ester and prodrug mentioned above, wherein
R 1Define the same;
R 3Be hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy, cycloalkyl alkoxy or alkylsulfonyloxy;
R 4Be hydrogen, halogen, hydroxyl, alkyl or alkoxyl; With
R 5Be hydrogen, halogen, hydroxyl, alkyl, alkoxyl, the alkoxyl alkoxyl, the hydroxy alkoxy base, the dihydroxy alkoxyl, the alkanoyloxy alkoxyl, the carboxyl alkoxyl, carboxyl-hydroxy alkoxy base, carboxyl-dihydroxy alkoxyl, the alkoxy carbonyl alkoxyl, alkoxy carbonyl-hydroxy alkoxy base, alkoxy carbonyl-dihydroxy alkoxyl, the carbamoyl alkoxyl, N-alkyl-carbamoyl alkoxyl, N, N-dialkyl amido alkoxyl, morpholine-4-base alkoxyl, piperidines-1-base alkoxyl, morpholine-4-base carbonylic alkoxy, 2,2-dialkyl group [1,3] dioxolanes-4-base alkoxyl or 2,2-dialkyl group-4-carboxyl [1,3] dioxolanes-5-base alkoxyl; Or
R 4And R 5Form condensed, an optional carbocyclic ring or a heterocyclic ring system that replaces with the phenyl ring that they connected.
On the one hand, the R in the formula (III) 3Can be alkyl, thiazolinyl, alkynyl, alkoxyl, cycloalkyloxy, cycloalkyl alkoxy, hydroxy alkoxy base or alkoxyl alkoxyl, and R 4And R 5All can be hydrogen, perhaps R 4Can be halogen, alkyl or alkoxyl and R 5Can be hydrogen, perhaps R 4And R 5Can be alkyl or alkoxyl independently of one another.Aspect this, R 3Be preferably methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, but-1-ene base, penta-1-thiazolinyl, fourth-1-alkynyl, penta-1-alkynyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, 3-methyl-butoxy, amoxy, cyclopentyloxy, hexyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, 2-hydroxyl-ethyoxyl, 2-methoxyl group-ethyoxyl, and preferred R 4And R 5All be hydrogen, perhaps R 4Be chlorine, bromine, methyl or methoxy, and R 5Be hydrogen, perhaps R 4With R 5Be methyl or methoxy independently of one another.
Another aspect, the R in the formula (III) 3Can be hydrogen or alkoxyl, and R 4With R 5Can form optional naphthalene, naphthane, indane, 1H-indenes, isoquinolin, dihydrobenzo [1,4] two an oxines or benzo [luxuriant residue of 1,3] Er Evil that replaces with the phenyl ring that they connected.At this on the one hand, R 3Be preferably propoxyl group, and R 4With R 5Can be preferably formed a naphthalene-1-base, indane-4-base, isoquinolin-5-base, isoquinolin-8-base, 1,2,3 with the phenyl ring that they connected, 4-tetrahydroisoquinoline-8-base, 2-alkoxy carbonyl-1,2,3,4-tetrahydroisoquinoline-8-base or 5,6,7,8-naphthane-1-base residue.
-individual preferred aspect, the R in the formula (III) 3, R 4And R 5Be respectively hydrogen; Or
R 3And R 5Hydrogen and R respectively do for oneself 4Be methoxyl group; Or
R 3And R 4Hydrogen and R respectively do for oneself 5Be methoxyl group; Or
R 4And R 5Hydrogen and R respectively do for oneself 3Be the tert-butyl group, ethyoxyl, propoxyl group or butoxy; Or
R 3Be hydrogen, R 4Be methoxyl group, and R 5Be hydroxyl; Or
R 4Be hydrogen, R 3Be methoxyl group or propoxyl group and R 5Be methoxyl group or propoxyl group; Or
R 5Be hydrogen, R 3Be methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, amoxy, hexyloxy, 3-methyl butoxy, 2-hydroxyl-oxethyl, 2-methoxy ethoxy, cyclo propyl methoxy or cyclobutyl methoxy base and R 4Be methyl, methoxyl group, chlorine or bromine; Or
R 3Be methoxyl group, propoxyl group, cyclopentyloxy, penta-1-alkynyl or ethanesulfonyloxy group;
R 4Be methyl;
R 5Be hydroxyl, methyl, amyl group, methoxyl group, propoxyl group, the 2-methoxy ethoxy, the 2-hydroxyl-oxethyl, 3-hydroxyl propoxyl group, 4-hydroxyl butoxy, 2,3-dihydroxy propoxyl group, 4-acetoxyl group butoxy, the carboxyl methoxyl group, 3-carboxyl propoxyl group, 4-carboxyl butoxy, 3-carboxyl-2-hydroxyl propoxyl group, 3-carboxyl-2,3-dihydroxy propoxyl group, ethoxycarbonyl methoxy, 3-ethoxy carbonyl propoxyl group, 4-ethoxy carbonyl butoxy, 3-ethoxy carbonyl-2-hydroxyl propoxyl group, 3-ethoxy carbonyl-2,3-dihydroxy propoxyl group, carbamyl ylmethoxy 3-N-ethylamino formoxyl propoxyl group, 4-N-ethylamino formoxyl butoxy, 2-N, the N-dimethylamino ethoxy, 3-N, the N-dimethylamino propoxy, 2-(morpholine-4-yl)-ethyoxyl, 2-(piperidines-1-yl)-ethyoxyl, 3-(morpholine-4-yl)-carbonyl propoxyl group, 4-(morpholine-4-yl)-carbonyl butoxy, 2,2-dimethyl [1,3] dioxolanes-4-ylmethoxy or 2,2-dimethyl-4-carboxyl [1,3] dioxolanes-5-ylmethoxy; Or
R 4And R 5Form a naphthalene-1-base, 5,6,7 with the phenyl ring that they connected, 8-naphthane-1-base, indane-4-base, 1,2,3,4 ,-four isoquinolin-8-base or 2-tert-butoxycarbonyl-1,2,3,4 ,-four isoquinolin-8-base residue.
Be preferably as follows the purposes of chemical compound especially:
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-methoxyl group-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-3-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,4-dimethoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-naphthalene-2-methylene-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(the 4-tert-butyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-methoxyl group benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,4-dimethoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-bromo-4-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-butoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-butoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-hexyloxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-4-amoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclobutyl methoxy base-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[3-methyl-4-(3-methyl-butoxy)-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-isobutoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[4-(2-methoxyl group-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-chloro-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[4-(2-hydroxyl-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclo propyl methoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(7-propoxyl group-indane-4-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(8-propoxyl group-isoquinolin-5-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-ethanesulfonyloxy group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2,6-dipropoxy-pyridin-3-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2-hydroxy-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2-methoxyl group-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(3-methyl-2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(ethoxy carbonyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(carboxyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-amino-2-oxo-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-carboxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethylamino-4-oxo-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethoxy carbonyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-carboxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(5-ethylamino-5-oxo-amoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
Oxygen base-phenyl in 4-[1-[3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-ethoxy carbonyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3,5-diketone and formates thereof;
4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-2,3-dihydroxy-3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-3-carboxyl-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-benzal-3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate;
4-[4-(2-hydroxyl-3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-[4-(2-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-[4-(3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-(3,5-dioxo-4-pyridin-3-yl methylene-pyrazolidine-1-yl) ethyl benzoate;
4-(3,5-dioxo-4-thiene-3-yl-methylene-pyrazolidine-1-yl) ethyl benzoate;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-(3-methyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
1-(4-bromo-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methoxyl group-phenyl)-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] phenylcyanide;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
1-(2-chloro-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(7-propoxyl group-indane-4-methylene)-pyrazolidine-3, the 5-diketone;
4-(2-methoxyl group-3-methyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(3-methyl-2,4-dipropoxy-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-methyl-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridin-4-yl-pyrazolidine-3, the 5-diketone; With
1-acetyl group-4-[1-(2,3-dimethyl-4-propoxyl group-phenyl)-methylene]-pyrazolidine-3, the 5-diketone.
Except 1-phenyl-4-(2,3,4-trimethoxy-benzal)-pyrazolidine-3, outside the 5-diketone, R wherein 3, R 4And R 5The chemical compound for the general formula of hydrogen (III) is not a noval chemical compound.Therefore a special aspect of the present invention relates to these noval chemical compounds itself and is used as active constituents of medicine; Relate to the pharmaceutical composition that comprises one or more these noval chemical compounds; Relate to these noval chemical compounds conducts as platelet adenosine diphosphate receptor antagonist, with be respectively applied for the peripheral vessel relevant, heart with platelet aggregation-, liver-and kidney-blood vessel, cardiovascular and cerebrovascular disease and disease, comprise thrombotic preventing and/or treating, and the manufacturing that is used for corresponding medicament; And relate to the manufacturing of these noval chemical compounds.
Noval chemical compound provided by the invention is the chemical compound of following general formula
Figure A20048001771700371
The geometric isomer and the tautomer and composition thereof that comprise them, and their salt, ester and prodrug mentioned above, wherein
R 1Define the same;
R 3' be alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy, cycloalkyl alkoxy or alkylsulfonyloxy;
R 4' be halogen, hydroxyl, alkyl or alkoxyl; With
R 5' be halogen, hydroxyl, alkyl, alkoxyl, the alkoxyl alkoxyl, the hydroxy alkoxy base, the dihydroxy alkoxyl, the alkanoyloxy alkoxyl, the carboxyl alkoxyl, carboxyl-hydroxy alkoxy base, carboxyl-dihydroxy alkoxyl, the alkoxy carbonyl alkoxyl, alkoxy carbonyl-hydroxy alkoxy base, alkoxy carbonyl-dihydroxy alkoxyl, the carbamoyl alkoxyl, N-alkyl-carbamoyl alkoxyl, N, N-dialkyl amido 1 alkoxyl, morpholine-4-base alkoxyl, piperidines-1-base alkoxyl, morpholine-4-base carbonylic alkoxy, 2,2-dialkyl group [1,3] dioxolanes-4-base alkoxyl or 2,2-dialkyl group-4-carboxyl [1,3] dioxolanes-5-base alkoxyl; Or
R 4' and R 5' form condensed, an optional carbocyclic ring or a heterocyclic ring system that replaces with the phenyl ring that they connected;
Condition is, if R 1Be phenyl and R 3' be methoxyl group, R 4' and R 5' can not be methoxyl group simultaneously.
In a subgroup of these noval chemical compounds, R 3' can be alkyl, thiazolinyl, alkynyl, alkoxyl, cycloalkyloxy, cycloalkyl alkoxy, hydroxy alkoxy base or alkoxyl alkoxyl, R 4' can be halogen, alkyl or alkoxyl and R 5' can be alkyl or alkoxyl.Preferred R 3' be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, but-1-ene base, penta-1-thiazolinyl, fourth-1-alkynyl, penta-1-alkynyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, 3-methyl-butoxy, amoxy, cyclopentyloxy, hexyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, 2-hydroxyl-ethyoxyl, 2-methoxyl group-ethyoxyl, R 4' be chlorine, bromine, methyl or methoxy, and R 5' be methyl or methoxy.
In another subgroup of these noval chemical compounds, R 3' can be alkoxyl and R 4' and R 5' can form an optional naphthalene that replaces, naphthane, indane, 1H-indenes, isoquinolin, dihydrobenzo [1,4] two oxines or benzo [the luxuriant loop systems of 1,3] Er Evil with the phenyl ring that they connected.Preferred R 3' be propoxyl group and R 4' and R 5' form a naphthalene-1-base, indane-4-base, isoquinolin-5-base, isoquinolin-8-base, 1,2,3 with the phenyl ring that they connected, 4-tetrahydroisoquinoline-8-base, 2-alkoxy carbonyl-1,2,3,4-tetrahydroisoquinoline-8-base or 5,6,7,8-naphthane-1-base residue.
In a preferred subgroup of these noval chemical compounds, R 3' be methoxyl group, propoxyl group, cyclopentyloxy, penta-1-alkynyl or ethanesulfonyloxy group;
R 4' be methyl;
R 5' be hydroxyl, methyl, amyl group, methoxyl group, propoxyl group, the 2-methoxy ethoxy, the 2-hydroxyl-oxethyl, 3-hydroxyl propoxyl group, 4-hydroxyl butoxy, 2,3-dihydroxy propoxyl group, 4-acetoxyl group butoxy, the carboxyl methoxyl group, 3-carboxyl propoxyl group, 4-carboxyl butoxy, 3-carboxyl-2-hydroxyl propoxyl group, 3-carboxyl-2,3-dihydroxy propoxyl group, ethoxycarbonyl methoxy, 3-ethoxy carbonyl propoxyl group, 4-ethoxy carbonyl butoxy, 3-ethoxy carbonyl-2-hydroxyl propoxyl group, 3-ethoxy carbonyl-2,3-dihydroxy propoxyl group, carbamyl ylmethoxy 3-N-ethylamino formoxyl propoxyl group, 4-N-ethylamino formoxyl butoxy, 2-N, the N-dimethylamino ethoxy, 3-N, the N-dimethylamino propoxy, 2-(morpholine-4-yl)-ethyoxyl, 2-(piperidines-1-yl)-ethyoxyl, 3-(morpholine-4-yl)-carbonyl propoxyl group, 4-(morpholine-4-yl)-carbonyl butoxy, 2,2-dimethyl [1,3] dioxolanes-4-ylmethoxy or 2,2-dimethyl-4-carboxyl [1,3] dioxolanes-5-ylmethoxy; Or
R 4' and R 5', form a naphthalene-1-base, 5,6,7 with the phenyl ring that they connected, 8-naphthane-1-base, indane-4-base, 1,2,3,4 ,-four isoquinolin-8-base or 2-tert-butoxycarbonyl-1,2,3,4 ,-four isoquinolin-8-base residue.
Preferred noval chemical compound comprises
1-phenyl-4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-[3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-(2,4-dimethoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-ethanesulfonyloxy group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-methoxyl group benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] phenylcyanide;
4-[1-(2-hydroxy-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-pyrazolidine-3, the 5-diketone;
1-(2-chloro-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridin-4-yl-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methoxyl group-phenyl)-pyrazolidine-3, the 5-diketone;
1-(4-bromo-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-methyl-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate; With
1-acetyl group-4-[1-(2,3-dimethyl-4-propoxyl group-phenyl)-methylene]-pyrazolidine-3, the 5-diketone.
Particularly preferred chemical compound comprises
1-phenyl-4-[1-(5-propoxyl group-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-[2-(4-ethylamino-4-oxo-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethoxy carbonyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-ethoxy carbonyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-[1-(8-propoxyl group-isoquinolin-5-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-[2-(2-amino-2-oxo-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
1-phenyl-4-[1-(7-propoxyl group-indane-4-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3,5-diketone and formates thereof;
4-[1-[2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(carboxyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-2,4-dipropoxy-benzal)-pyrazolidine-3, the 5-diketone;
4-[1-(3-methyl-2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-(2-methoxyl group-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2-methoxyl group-3-methyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(7-propoxyl group-indane-4-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone; With
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone.
Most preferred noval chemical compound comprises
4-[1-[2-((2S)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-carboxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-carboxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-3-carboxyl-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(5-ethylamino-5-oxo-amoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-2,3-dihydroxy-3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(ethoxy carbonyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone; With
4-[1-[3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone.
According to the present invention, can make above-mentioned noval chemical compound by the pyrazolidinedione of condensation general formula (IV) and the aldehyde of above-mentioned general formula (IV), shown in following reaction scheme
Existing any reactive group can be by due care in formula IV and V chemical compound, and, if desired, any unwanted protecting group is sloughed from this condensation product.
Some above-mentioned general formulas (IV) and initiation material (V) are noval chemical compounds, and have also constituted a part of the present invention.These new initiation materials comprise the pyrazolidinedione of following general formula (IV):
1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(3,5-dioxo-pyrazolidine-1-yl) phenylcyanide; With
1-pyridin-4-yl-pyrazolidine-3, the 5-diketone.
And the aldehyde of following logical formula V:
4-cyclopentyloxy-2,3-dimethyl-benzaldehyde;
4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-aldehyde;
2,3-dimethyl-4-penta-1-alkynyl-benzaldehyde;
2,3-dimethyl-4-amyl group-benzaldehyde;
7-propoxyl group-indane-4-aldehyde;
5-propoxyl group-isoquinolin-8-aldehyde;
8-propoxyl group-isoquinolin-5-aldehyde;
2-tert-butoxycarbonyl-8-formoxyl-5-propoxyl group-1,2,3, the 4-tetrahydroisoquinoline;
2,3-dimethyl-4-ethanesulfonyloxy group benzaldehyde;
2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde;
2-methoxyl group-3-methyl-4-propoxyl group-benzaldehyde;
2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde;
2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde;
2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde;
2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-benzaldehyde;
(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl acetate;
(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetic acid;
2-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetamide;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate.;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid acetamide;
3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-benzaldehyde;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl valerate;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid acetamide;
3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-benzaldehyde;
2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
(3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.;
(3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid;
(3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.;
(3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid;
(4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylate methyl ester;
(4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylic acid.
Unless clearly demonstrate in addition, above and hereinafter employed general terms and title in content of the present invention, preferably have following implication:
Here the term that is used alone or in combination " alkyl " is meant a saturated fat base that comprises the straight or branched hydrocarbon chain that contains 1～8 carbon atom.The representational example of alkyl includes but not limited to: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group (or 2-methyl-propyl), cyclopropyl methyl, n-pentyl (n-pentyl), isopentyl (iso-pentyl), isopentyl (iso-amyl), n-pentyl (n-amyl), n-hexyl, n-heptyl, n-octyl etc.This alkyl can randomly be replaced by one or more substituent group; described substituent group is selected from independently of one another: thiazolinyl; alkoxyl; alkoxy carbonyl; alkyl-carbonyl; alkyl carbonyl oxy; alkylenedioxy group; the alkyl sulfinyl; the alkyl sulfide acyl group; alkylthio group; alkynyl; amino; amino carbonyl; aryl; aryl alkenyl; alkoxy aryl; aryloxy group; aryloxycarbonyl; the aryl sulfinyl; the aryl sulfonyl; arylthio; carboxyl; cyano group; formoxyl; halogen; halogenated alkoxy; heterocyclic radical; hydroxyl; sulfydryl; nitros etc., it is connected on any carbon atom of alkyl residue.
Here the term that is used alone or in combination " low alkyl group " a is meant the alkyl that has 1～4 carbon atom.The representative example of low alkyl group includes but not limited to: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group etc.
Here the term that is used alone or in combination " thiazolinyl " is meant that one contains 2～8 carbon atoms and has at least one carbon-to-carbon double bond (R aR bC=CR cR d) the straight or branched hydrocarbon.R a-R dThe expression substituent group, it is selected from hydrogen and alkyl, alkoxyl, alkoxyalkyl etc. independently of one another.The representational example of thiazolinyl includes but not limited to: vinyl, 2-acrylic, 2-methyl-2-acrylic, 3-cyclobutenyl, 4-pentenyl, 5-hexenyl etc.
Here the term that is used alone or in combination " alkylenedioxy group " is meant-O (CH 2) nThe O-group, wherein n is preferably 1 or 2, and wherein oxygen atom is connected on two adjacent carbon atoms of parent molecule residue.The representational example of alkylenedioxy group includes but not limited to: methylene dioxy base, ethylidene dioxy base etc.
Here the term that is used alone or in combination " alkynyl " refers to one to contain 2～8 carbon atoms and have is at least one carbon-to-carbon triple bond (R a-C ≡ C-R b, R aAnd R bThe expression substituent group, it is selected from hydrogen and alkyl, thiazolinyl, alkoxyl, alkoxyalkyl etc. independently of one another) the straight or branched hydrocarbon.The representational example of alkynyl includes but not limited to: acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 3-butynyl, valerylene base etc.
Here " alkoxyl is meant by oxo bridge and is connected to alkyl on the parent molecule residue term that is used alone or in combination.The representational example of alkoxyl includes but not limited to: methoxyl group, ethyoxyl, propoxyl group, 2-propoxyl group, butoxy, tert-butoxy, amoxy, hexyloxy etc.
Here the term that is used alone or in combination " alkoxyalkyl " is meant by alkyl and is connected to alkoxyl on the parent molecule residue.The representational example of alkoxyalkyl includes but not limited to: tert-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl, methoxy etc.
Here the term that is used alone or in combination " alkoxy carbonyl " is connected to alkoxyl on the parent molecule residue by carbonyl.The representational example of alkoxy carbonyl includes but not limited to: methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl etc.
Here the term that is used alone or in combination " alkoxy carbonyl alkyl " is meant by alkyl to be connected to alkoxy carbonyl on the parent molecule residue.The representational example of alkoxy carbonyl alkyl includes but not limited to: methoxycarbonyl propyl group, ethoxy carbonyl butyl, 2-tert-butoxycarbonyl ethyl etc.
Here the term that is used alone or in combination " alkyl-carbonyl " or " acyl group " are meant by carbonyl and are connected to alkyl on the parent molecule residue.The representational example of alkyl-carbonyl includes but not limited to: acetyl group, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl, 1-oxo amyl group etc.
Here the term that is used alone or in combination " alkyl-carbonyl alkyl " is meant by alkyl and is connected to alkyl-carbonyl on the parent molecule residue.The representational example of alkyl-carbonyl alkyl includes but not limited to: 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl, 3-oxo amyl group etc.
Here the term that is used alone or in combination " alkyl carbonyl oxy " is meant by an oxo bridge and is connected to alkyl-carbonyl on the parent molecule residue.The representational example of alkyl carbonyl oxy includes but not limited to: acetoxyl group, ethyl oxy carbonyl, tert-butyl group carbonyl oxygen base etc.
Here the term that is used alone or in combination " alkyl sulfinyl " is meant by sulfinyl and is connected to alkyl on the parent molecule residue.The representational example of alkyl sulfinyl includes but not limited to: methyl sulfinyl, ethylsulfinyl-1 base etc.
Here the term that is used alone or in combination " alkyl sulfinyl alkyl " is meant by alkyl and is connected to alkyl sulfinyl on the parent molecule residue.The representational example of alkyl sulfinyl alkyl includes but not limited to: methyl sulfinyl methyl, ethylsulfinyl-1 ylmethyl etc.
Here the term that is used alone or in combination " alkyl sulfide acyl group " is meant by sulfonyl and is connected to alkyl on the parent molecule residue.The representational example of alkyl sulfide acyl group includes but not limited to: methylsulfonyl group, ethyl sulfonyl etc.
Here the term that is used alone or in combination " alkyl sulfide acyl group alkyl " is meant by alkyl and is connected to alkyl sulfide acyl group on the parent molecule residue.The representational example of alkyl sulfide acyl group alkyl includes but not limited to: methylsulfonyl group methyl, ethyl sulfonyl methyl etc.
Here the term that is used alone or in combination " alkylthio group " is meant by sulfenyl and is connected to alkyl on the parent molecule residue.The representational example of alkylthio group includes but not limited to: methyl mercapto, ethylmercapto group, uncle's butylthio, own sulfenyl etc.
Here the term that is used alone or in combination " alkylthio alkyl " is meant by alkyl and is connected to alkylthio group on the parent molecule residue.The representational example of alkylthio alkyl includes but not limited to: methylthiomethyl, 2-(ethylmercapto group) ethyl etc.
Here the term that is used alone or in combination " amino " is meant-NR eR fGroup, wherein R eAnd R fBe substituent group, it is selected from hydrogen, alkyl, aryl, aryl alkyl, acyl group, alkyl-carbonyl, aryl carbonyl, carbamoyl, urea groups, formoxyl, alkyl sulfide acyl group, aryl sulfonyl etc. independently of one another.Amino representational example includes but not limited to: dimethylamino, ethylamino, benzyl-(methyl) amino etc.
Here the term that is used alone or in combination " aminoalkyl " is meant by alkyl and is connected to amino on the parent molecule residue.The representational example of aminoalkyl includes but not limited to: amino methyl, 2-(amino) ethyl, benzyl-(methyl) amino methyl, dimethylaminomethyl etc.
Here the term that is used alone or in combination " amino carbonyl " or " amide groups " are meant by carbonyl and are connected to amino on the parent molecule residue.Aminocarboxy representational example includes but not limited to: dimethylamino carbonyl, benzyl-amino carbonyl, ethylamino carbonyl etc.
Here the term that is used alone or in combination " amino carbonyl alkyl " is meant by alkyl and is connected to amino carbonyl on the parent molecule residue.The representational example of amino carbonyl alkyl includes but not limited to: 2-amino-2-oxoethyl, 2-(benzyl amino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 4-amino-4-oxo butyl, 4-(dimethylamino)-4-oxo butyl etc.
Here the term that is used alone or in combination " aryl " is meant the carbocylic radical with at least one aromatic ring, for example phenyl or xenyl, or wherein at least one ring is many condensed ring system of aromatic ring, for example 1,2,3,4-tetralyl, naphthyl, anthryl, phenanthryl, fluorenyl etc.Aryl can be replaced by one or more functional groups that are selected from following radicals: thiazolinyl; alkoxyl; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; alkyl carbonyl oxy; alkylenedioxy group; the alkyl sulfinyl; alkyl sulfinyl alkyl; the alkyl sulfide acyl group; alkyl sulfide acyl group alkyl; alkylthio group; alkylthio alkyl; alkynyl; amino; aminoalkyl; amino carbonyl; the amino carbonyl alkyl; aryl; aryl alkenyl; alkoxy aryl; aryl alkyl; aryloxy group; aryloxycarbonyl; the aryloxycarbonyl alkyl; the aryl sulfinyl; aryl sulfinyl alkyl; the aryl sulfonyl; aryl sulfonyl alkyl; arylthio; arylthio alkyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formoxyl; the formoxyl alkyl; halogen; halogenated alkoxy; haloalkyl; heteroaryl; heterocyclic radical; hydroxyl; hydroxy alkyl; sulfydryl; nitro etc.
Here the term that is used alone or in combination " aryl alkenyl " is meant by thiazolinyl and is connected to aryl on the parent molecule residue.This aryl can be unsubstituted or replace.The representational example of aryl alkenyl includes but not limited to: 2-phenyl vinyl, 3-phenyl and propylene-2-base, 2-naphthalene-2-base vinyl etc.
Here the term that is used alone or in combination " alkoxy aryl " is meant by alkoxyl and is connected to aryl on the parent molecule residue.This aryl can be unsubstituted or replace.The representational example of alkoxy aryl includes but not limited to: 2-phenyl ethoxy, 5-phenyl amoxy, 3-naphthalene-2-base propoxyl group etc.
Here the term that is used alone or in combination " aryl alkyl " is meant by alkyl and is connected to aryl on the parent molecule residue.This aryl can be unsubstituted or replace.The representational example of aryl alkyl includes but not limited to: benzyl, 2-phenylethyl, 3-phenyl propyl, 2-naphthalene-2-base ethyl etc.
Here the term that is used alone or in combination " aryloxy group " is meant by an oxo bridge and is connected to aryl on the parent molecule residue.This aryl can be unsubstituted or replace.The representational example of aryloxy group includes but not limited to: phenoxy group, naphthoxy, 3-bromine phenoxy group, 4-chlorophenoxy, 4-methylphenoxy, 3,4-dimethoxy phenoxy group etc.
Here the term that is used alone or in combination " carbamoyl " is meant-C (O) NR eR fGroup.R eAnd R fBe substituent group, it is selected from hydrogen, alkyl, aryl alkyl etc. independently of one another.
Similarly, the term that is used alone or in combination here " sulfur carbamoyl " is meant-C (S) NR eR fGroup.
Here the term that is used alone or in combination " carbonyl " is meant-C (O) group.
Here the term that is used alone or in combination " carboxyl " is meant-CO 2The H group.
Here the term that is used alone or in combination " carboxyalkyl " is meant by alkyl and is connected to carboxyl on the parent molecule residue.The representational example of carboxyalkyl includes but not limited to: carboxyl methyl, 2-carboxy ethyl, 3-carboxyl propyl group etc.
Here the term that is used alone or in combination " cyano group " is meant-C ≡ N group.
Here the term that is used alone or in combination " cyano group alkyl " is meant by alkyl and is connected to cyano group on the parent molecule residue.The representational example of cyano group alkyl includes but not limited to: cyano methyl, 2-cyano ethyl, 3-cyano group propyl group etc.
Here the term that is used alone or in combination " cycloalkyl " refers to comprise the saturated cyclic hydrocarbon radical of 3～15 carbon atoms; it is randomly replaced by one or more groups, and described group is selected from thiazolinyl independently of one another; alkoxyl; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; alkyl carbonyl oxy; alkylenedioxy group; the alkyl sulfinyl; alkyl sulfinyl alkyl; the alkyl sulfide acyl group; alkyl sulfide acyl group alkyl; alkylthio group; alkylthio alkyl; alkynyl; amino; aminoalkyl; amino carbonyl; the amino carbonyl alkyl; aryl; aryl alkenyl; alkoxy aryl; aryl alkyl; aryloxy group; aryloxycarbonyl; the aryloxycarbonyl alkyl; the aryl sulfinyl; aryl sulfinyl alkyl; the aryl sulfonyl; aryl sulfonyl alkyl; arylthio; arylthio alkyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formoxyl; the formoxyl alkyl; halogen; halogenated alkoxy; haloalkyl; heterocyclic radical; hydroxyl; hydroxy alkyl; sulfydryl; nitro etc.The representational example of cycloalkyl includes but not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.In the polycyclic naphthene base, what one of end-rings can be for armaticity, for example, 1-indanyl, 2-indanyl, naphthane etc.
Here the term that is used alone or in combination " cycloalkenyl group " and " cycloalkynyl radical " are meant the unsaturated cyclic hydrocarbon residue that comprises at least one carbon-to-carbon double bond or carbon-to-carbon triple bond respectively.The group that this residue can randomly be discussed in one or more above-mentioned cycloalkyl replaces.
Here the term that is used alone or in combination " formoxyl " is meant-C (O) H group.
Here the term that is used alone or in combination " formoxyl alkyl " refers to be connected to formoxyl on the parent molecule residue by alkyl.The representational example of formoxyl alkyl includes but not limited to: formoxyl methyl, 2-formoxyl ethyl etc.
Here the term that is used alone or in combination " halo " or " halogen " are meant fluorine, bromine, chlorine and iodine.
Here " haloalkyl " is meant the alkyl that at least one hydrogen atom is replaced by halogen atom to the term that is used alone or in combination.The representational example of haloalkyl includes but not limited to: chloromethyl, 2-fluoro ethyl, trifluoromethyl, pentafluoroethyl group, 2-chloro-3-fluorine amyl group etc.
Here the term that is used alone or in combination " halogenated alkoxy " is meant the alkoxyl that at least one hydrogen atom is replaced by halogen atom.The representational example of halogenated alkoxy includes but not limited to: chlorine methoxyl group, 2-fluorine ethyoxyl, trifluoromethoxy, five fluorine ethyoxyls etc.
Here the term that is used alone or in combination " heterocyclic radical " is meant and comprises 15 annular atomses at the most, and at least one heteroatom is independently selected from monocycle, bicyclo-or the multi-loop system of nitrogen, oxygen or sulfur.This ring can be saturated, fractional saturation, undersaturated or armaticity.The representational example of heterocyclic radical includes but not limited to: furyl, imidazole radicals, imidazolinyl, the imidazoles thiazolinyl, isothiazolyl isoxazolyl, morpholinyl oxadiazole base oxazolyl oxazolinyl oxazolidinyl, piperazinyl, piperidyl, pyranose, pyrazinyl, pyrazolyl, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrrole radicals, pyrrolinyl, pyrrolidinyl, tetrahydrofuran base, tetrahydrofuran base, tetrahydro-thienyl, thiadiazolyl group, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thio-morpholinyl, 1,1-dioxo thio-morpholinyl, benzimidazolyl, benzothiazolyl, benzothienyl benzoxazolyl, benzofuranyl, indyl, indolinyl, isobenzofuran-base, isobenzo-thienyl, isoindolyl, iso-dihydro-indole-group, isoquinolyl, quinolyl etc.Defined heterocycle residue can randomly be replaced by one or more group, and described group is selected from thiazolinyl independently of one another; alkoxyl; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; alkyl carbonyl oxy; alkylenedioxy group; the alkyl sulfinyl; alkyl sulfinyl alkyl; the alkyl sulfide acyl group; alkyl sulfide acyl group alkyl; alkylthio group; alkylthio alkyl; alkynyl; amino; aminoalkyl; amino carbonyl; the amino carbonyl alkyl; aryl; aryl alkenyl; alkoxy aryl; aryl alkyl; aryloxy group; aryloxycarbonyl; the aryloxycarbonyl alkyl; the aryl sulfinyl; aryl sulfinyl alkyl; the aryl sulfonyl; aryl sulfonyl alkyl; arylthio; arylthio alkyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; cycloalkyl; formoxyl; the formoxyl alkyl; halogen; halogenated alkoxy; haloalkyl; heterocyclic radical; heteroaryl; hydroxyl; hydroxy alkyl; sulfydryl; nitro etc.
Here the term that is used alone or in combination " heteroaryl " is a special case of heterocyclic radical, and be meant at least one heterocycle wherein be armaticity monocycle-, bicyclo--or multi-ring aromatic ring system.
Here the term that is used alone or in combination " heterocyclic radical thiazolinyl " is meant by thiazolinyl and is connected to heterocyclic radical on the parent molecule residue.The representational example of heterocyclic radical thiazolinyl includes but not limited to: 2-pyridin-3-yl vinyl, 3-quinoline-3-base propylene-2-base, 5-pyridin-4-yl amylene-4-base etc.
Here the term that is used alone or in combination " heterocyclic radical alkoxyl " is meant by alkoxyl and is connected to heterocyclic radical on the parent molecule residue.The representational example of heterocyclic radical alkoxyl includes but not limited to: 2-pyridin-3-yl ethyoxyl, 3-quinoline-3-base propoxyl group, 5-pyridin-4-yl amoxy etc.
Here the term that is used alone or in combination " heterocyclic radical alkyl " is meant by alkyl and is connected to heterocyclic radical on the parent molecule residue.The representational example of heterocyclic radical alkyl includes but not limited to: 2-pyridin-3-yl methyl, 2-pyrimidine-2-base propyl group etc.
Here the term that is used alone or in combination " heterocyclic oxy group " is meant that logical peroxy is connected to the heterocyclic radical on the parent molecule residue.The representational example of heterocyclic oxy group includes but not limited to: pyridine-3-oxygen base, quinoline-3-oxygen base etc.
Here the term that is used alone or in combination " hydroxyl (hydroxy) " or " hydroxyl (hydroxyl) " are meant-the OH group.
Here the term that is used alone or in combination " hydroxy alkyl " is meant the alkyl that at least one hydrogen atom is replaced by hydroxyl.The representational example of hydroxy alkyl includes but not limited to: hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyl heptyl etc.
Here the term that is used alone or in combination " nitro " is meant-NO 2Group.
Here the term that is used alone or in combination " oxo " is meant=the O group.
Here the term that is used alone or in combination " oxygen base " is meant-the O-group.
Here the term that is used alone or in combination " sulfydryl " and " mercaptan " are meant-the SH group.
Here the term that is used alone or in combination " sulfo-", " sulfinyl " and " sulfonyl " be meant n be respectively 0,1 and 2-S (O) nGroup.
Within the scope of the invention, unless otherwise indicated, formula (I) and chemical compound (III), the latter comprise that formula (III ') or its pharmaceutically acceptable salt comprise with isomeric forms and exist or isolating.Comprise cis or transisomer or and composition thereof and tautomer.Other chemical compound of the present invention can comprise one or more solids or asymmetric center, for example one or more asymmetric carbon atoms, and thereby obtain the mixture, epimer of diastereomer, the diastereomer of mixture, racemoid, the enantiomer-pure of optically pure enantiomer, enantiomer and other can be defined by according to the absolute stereo chemistry (R)-, (S)-or (R, S)-and configuration, the stereoisomer form of preferred (R)-or (S)-configuration.Can in the scope of the knowledge that is no more than those skilled in the art, obtain this isomer, for example synthetic by what use chirality spatial chemistry synthetic or chiral reagent to control; Stratographic or by classical separating technology, for example chromatography or crystallization process; Or, for example, for example form salt by chiral acid with an enantiomer-pure by forming diastereomeric salt by additive method known in the art; Perhaps by chromatography, for example by using the chromatographic material of chiral ligand modification.In addition, the present invention relates to comprise any geometric asymmetry, for example the chemical compound of the two keys (comprising E or Z geometric isomer and composition thereof) of the thiazolinyl of asymmetric replacement.Usually, for isomer mixture, the more preferably pure isomer of formula (I) and chemical compound (III).
In the present invention, the form that formula (I) and chemical compound (III) can " pharmaceutically acceptable salts " is used.Term " pharmaceutically acceptable salt " is meant nontoxic relatively, inorganic or organic acid and base addition salts, wherein keeps the biological effectiveness and the characteristic of parent compound, and not to be that biology or other aspects are undesirable (for example consult, Berge etc., J.Pharm.Sci.1977,66,1-19).
Some chemical compound of the present invention can comprise one or more basic functionalities, for example amino, alkyl amino or arylamino, and thereby can form pharmaceutically-acceptable acid addition.These acid-addition salts can be in appropriate solvent, method by standard, (for example include but not limited to hydrochloric acid from the mineral acid of formula (I) or parent compound (III) and suitable amount, hydrobromic acid, sulphuric acid, or phosphoric acid) or organic acid (include but not limited to acetic acid, propanoic acid, sad, capric acid, hydroxyacetic acid, acetone acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, aminoacid (for example glutamic acid or aspartic acid), benzoic acid, cinnamic acid, salicylic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid or other acid organic compound) obtain.
On the other hand, some chemical compound of the present invention can comprise one or more acid functional group, and thereby can form pharmaceutically acceptable base addition salts.These salt can be by adding suitable amount in the free acid in being dissolved in appropriate solvent, usually stoichiometric proportion comprises suitable cationic alkaline reagent, and for example hydroxide, carbonate or alkoxide prepare.Preferred inorganic salt includes but not limited to: ammonium salt, sodium salt, potassium salt, calcium salt or magnesium salt or zinc salt etc.The salt that preferably derives from organic base includes but not limited to: the primary, the amine of the second month in a season, tertiary amine, replacement, cyclammonium and basic ion exchanger resin, for example salt of isopropylamine, Trimethylamine, diethylamide, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidines, polyamino resin etc.
The chemical compound of the present invention that comprises acid and basic group simultaneously can also form inner salt (amphion).
In order to separate and purification, can also use unacceptable salt on the medicine, for example perchlorate, picoline salt, picrate etc.In order in treatment, to use, tightly can use pharmaceutically acceptable salt or free cpds, form that wherein can pharmaceutical preparation is used, and thereby preferably they.
Some formula (I) and chemical compound (III) comprise their salt, can solvation or not the form of solvation (for example hydrate forms) exist, perhaps their crystal can comprise and is used for crystalline solvent.Can there be different crystal formations.That the present invention comprises all these solvations or the form of solvation not.
The invention still further relates to the prodrug derivant of formula (I) and parent compound (III).Term " prodrug " is meant can be in vivo, under physiological condition, for example when carrying out solvolysis or enzymatically degrading in blood or in the cell, can be converted into treatment and go up pharmaceutically inactive precursor (the Bundgard H. of the medicine of active form, " Design of Prodrugs ", p7-9,21-24, Elsevier, Amsterdam (1985); Silverman R.B., " The Organic Chemistry of Drug Design and DrugAction ", p352-401, Academic Press, San Diego, CA (1992); Higuchi T. etc., " Pro-drug as Novel Delivery Systems ", A.C.S.Symposium Series, Vol.14).Term " prodrug " also comprises any covalently bound carrier, and when to the mammal administration, this carrier discharges this parent compound in vivo.A kind of prodrug of chemical compound is provided by the advantage that usually provides dissolubility, bioavailability, absorption, tissue compatibility, tissue distribution or the delay in the mammal organism to discharge.Prodrug is under metabolism conditions, has the formula (I) of the group that can cut off and the variation or the derivant of chemical compound (III), for example pharmaceutically acceptable ester or amide.These groups can pass through enzymolysis ground or non-enzymolysis ground or hydrolysis ground to cut off, and obtains free hydroxyl, carboxyl or the amino of reactive precursor chemical compound.In another instantiation, prodrug is a kind of reduction form that is oxidized to the treatment chemical compound in vivo, for example is oxidized to sulphonic acid ester or sulfuric ester mercaptan, is oxidized to the alcohol of carboxylic acid.
Other comprise within the scope of the invention be the pharmaceutically acceptable ester of formula (I) and chemical compound (III).Term " pharmaceutically acceptable ester " is meant the product of avirulent relatively, the esterification of parent compound.In the end prepare these esters in position during the isolated or purified of chemical compound, perhaps make the purified compound of free acid or OH-form and the independent reaction of suitable esterifying agent prepare these esters.Can use alcohol, in the presence of catalyst, carboxylic acid is converted into ester.Can the hydroxyl derivant be changed into ester through using esterifying agent (for example alkane etheride) to handle.This term further comprises can be by the lower hydrocarbon group of solvation under physiological condition, alkane ester for example, and preferred methyl ester, ethyl ester and propyl ester, methoxyl group methyl ester, methyl mercapto methyl ester, pivaloyl group oxygen base methyl ester etc. (are for example consulted; Berge etc.; J.Pharm.Sci.1977,66,1-19).
Chemical compound of the present invention has useful, and particularly the pharmacology goes up useful characteristic.They can be at its platelet ADP receptor, P2Y 12On the receptor, the effect of antagonism endogenous ADP specifically.Platelet ADP receptor P2Y 12When using the ADP activation, cause platelet aggregation.Therefore formula (I) and chemical compound (III) can be used in and P2Y 12The treatment or the prevention of the angiopathy that the blocking-up of receptor is relevant.
Chemical compound of the present invention or pharmaceutical composition can be used as and be used for preventing and/or treating peripheral vessel, cardiovascular and cerebrovascular disease relevant with platelet aggregation, that particularly be correlated with the thrombosis of human and other mammals or the medicine that prevents and/or treats (medicine) of disease.This chemical compound can be used as platelet activation, the inhibitor of gathering and degranulation, as antithrombotic agents, perhaps be used for for example any thrombosis, the thrombotic disease of platelet dependency particularly, include but not limited to, acute myocardial infarction, astable pharyngalgia, coronary angioplasty (PTCA), periphery thrombolytic (perithrombolysis), atherosclerotic constitutional artery thrombosis complication (for example thrombosis or bolt apoplexy), chronic stable angina pectoris, transient ischemic attack (TIA), apoplexy, peripheral vascular disease, have or do not have thromboclastic myocardial infarction, preeclampsia/convulsions, venous thrombosis (for example depths venous thrombosis), venous occlusion disease, thromboembolism, disseminated inravascular coagulation, thrombotic thrombocytopenic purpura, bringing out property of heparin thrombocytopenia, hemolytic uremic syndrome, septicemic cemia thrombotic complications, adult respiratory distress syndrome, anti-phospholipid syndrome, hematologic disease, for example growing property of myelosis disease comprises thrombocytosis; In invasive surgical (for example the expansion of angioplasty, carotid endarterectomy, post coronary bypass grafting operation, vascular grafts operation, endovascular device and prosthese place and the insert) thrombosis afterwards and the thrombotic complications of restenosis complication, surgery or mechanical damage (for example the reconstructive operation of skin and muscle flap is remedied, comprised to the tissue after the formula outside unexpected or operation), treatment and prevention.
Chemical compound of the present invention can also be used to prevent mechanically cause platelet activation in the body, for example be used for preventing the cardiopulmonary branch road the microcosmic thromboembolism; Perhaps be used for the external preservation of blood products (for example platelet concentrate); For example perhaps prevent in kidney dialysis and plasmapheresis arteriovenous fistula obturation, to blood vessel injury damage/inflammation (for example vasculitis, arteritis, glomerulonephritis, inflammatory bowel and organ-graft refection's) secondary thrombus disease, for example migraine Raynaud's phenomenon, atheromatous plaque formation/development, angiostenosis/restenosis and asthma, the wherein platelet-derived factor has been played the part of important effect in lysis.
On the other hand, formula (I) and chemical compound (III) can be used as and relate to platelet ADP receptor P2Y 12The test of inhibition or the standard substance or the reference compound of evaluation.This chemical compound can be to market supply to be used for for example relating to P2Y when developing 12When activity rating or rules, in pharmaceutical products research, be used as with reference to product, quality standard product or reference substance.
As mentioned above, formula (I) and chemical compound (III) or its salt or prodrug are to platelet ADP receptor P2Y 12ADP dependency activation produce antagonism.The biological effect of this chemical compound can not comprise interior evaluating by various external, measures.
Formula (I) and chemical compound (III) and P2Y 12The ability of receptors bind can be by being similar to GachetC. etc., Br.J.Hematol.1995,91,434-444 and hereinafter embodiment 16 described methods measure.
By this evaluation, the IC of discoverable type (I) and test compounds (III) 50Value (that is, finding the maximum concentration that suppresses of interactional half) is 0.001～10 μ M, preferably is lower than 1 μ M, especially preferably is lower than 0.05 μ M.Exemplary IC in this test 50Value is shown in following embodiment 17.
Chemical compound of the present invention suppresses hematoblastic accumulative ability that ADP-brings out can be by being similar to Born G.V.R. and Cross M.J., J.Physiol.1963,168,178-195 and hereinafter embodiment 18 described methods measure.
By this evaluation, the ED of discoverable type (I) and test compounds (III) 50Value (that is, finding the maximum effective dose that suppresses of accumulative half) is 0.005～5 μ M, preferably is lower than 1 μ M, especially preferably is lower than 0.1 μ M.
Can pass through the human P2Y of a kind of use 12The functional evaluation of the cell of expression of receptor detects the variation of the level of the cellular calcium concentration after compounds for treating.After adding this chemical compound, use ADP to bring out this cell.At a fluorescence imaging plate reader (FLIPR TM, molecular device, Sunnyvale, California) in, being recorded in the fluorescent emission during twice adding, the emission peak on the datum-plane after ADP is added is derived, and its normalize to low contrast (no ADP) and height contrasted (non-active compound).Use the relative value of residual activity and the sigmoid curve by their curve fittings being become four-parameter ratio to measure IC 50Value.
Calculating formula
Figure A20048001771700561
This chemical compound is via P2Y 12The ability of the cellular calcium level that inhibition ADP causes can be measured by method known to those skilled in the art or by the method for following embodiment 19.
By this evaluation, obtain the IC of formula (I) and test compounds (III) 50Value (that is, the compound concentrations during residue 50% activity) is 0.001～10 μ M, preferably is lower than 0.5 μ M.
The result of these evaluations clearly proves, the invention provides the P2Y that suppresses platelet aggregation 12The functional antagonist of receptor, and thereby can be used for the treatment of angiopathy, particularly thrombosis.
Based on above-mentioned biological study, formula of the present invention (I) or chemical compound (III) can demonstrate the angiopathy that this paper is mentioned, particularly to the therapeutic effect of thrombotic disease.
Formula (I) or chemical compound (III), its pharmaceutically acceptable salt or its prodrug can be pure form administration, perhaps with one or more other the blended form administration of therapeutic agent, adopt the possible therapeutic alliance of fixing blended form, perhaps take other therapeutic agent of chemical compound of the present invention and one or more respectively or alternately, perhaps mix administration with one or more other therapeutic agent fixing blended.Can also be in addition or take formula (I) or chemical compound (III) extraly to be used for and other the antithrombotic treatment of angiopathy.As mentioned above, the long-term treatment of auxiliary treatment of therapeutic strategy as other also is possible.Other possible treatment is a prophylactic treatment, for example is used for susceptible patient's treatment.
The invention still further relates to the pharmaceutical composition that comprises formula (III) chemical compound, their purposes in treatment, of the present invention one wideer aspect, also relate to the prophylactic treatment or the Therapeutic Method of above-mentioned disease, relate to the chemical compound that is used for described purposes, and relate to the preparation of pharmaceutical preparation (medicine).
Pharmaceutically acceptable chemical compound of the present invention can be used for for example comprising effective amount of actives and or mix that one or more of significant quantity are inorganic, organic, the preparation of drug combination of solid or the pharmaceutically acceptable carrier of liquid.
The invention still further relates to and be fit to homoiothermic animal, particularly the people (particularly derives from homoiothermic animal, particularly people's cell or cell strain, platelet for example) pharmaceutical composition of administration, it is used for the treatment of, perhaps of the present invention one wideer aspect, be used for prevention (being preventative preventing) by replying the interactional blocking-up disease of platelet adenosine diphosphate ester (ADP) receptor and ADP, it comprise a certain amount of formula (I) or (III) chemical compound or pharmaceutically acceptable salt or its can be effective to the prodrug of described inhibition, and contain at least a pharmaceutically acceptable carrier.
Pharmaceutical composition of the present invention is for being used for to homoiothermic animal, people particularly, the pharmaceutical composition of enteral administration, for example nose administration, buccal administration, rectally, corium administration or, particularly oral administration and intestinal external administration, for example (intravitreal) administration in administration in intramuscular administration, intravenous administration or subcutaneous administration, the breastbone, the vitreous body, injection or dipping administration.This compositions comprises this active constituents of medicine of a kind of effective dose separately, perhaps mixes with the pharmaceutically acceptable carrier of significant quantity.The dosage of active component depends on kind, body weight, age and the individual condition of homoiothermic animal, individual metabolite data, disease of being treated and mode of administration.
The invention still further relates to a kind of above described pathological condition that is used for the treatment of, particularly reply the process or the method for the interaction disease, particularly thrombosis of blocking platelet adenosine diphosphate ester (ADP) receptor and ADP.Formula (I) and compound or its salt (III) or prodrug can directly be taken or take with the form of pharmaceutical composition especially.
Give homoiothermic animal, for example the dosage taken of the mankind of 70kg body weight is preferably about 3 milligrams～about 30g, more preferably approximately the 1000mg of 10mg～approximately for each person every day, and to be divided into can be 1～3 dosage of identical size.The amount of the actual chemical compound of taking will be decided according to the situation of reality by the doctor usually, this comprises the reaction of the disease of being treated, selected route of administration, the pragmatize compound of being taken, age weight and individual patient, the order of severity of patient's symptom, and for example the child uses the dosage that reduces by half of adult's dosage usually.
That this pharmaceutical composition comprises is about 1%～about 95%, and 20%～about 90% active component preferably approximately.Pharmaceutical composition of the present invention can be a unit dosage forms for example, for example sugar-coat or do not have tablet, pill, ampoule, bottle, suppository, dragee or the capsule of sugar-coat.Other dosage form is the plaster of for example unguentum, emulsifiable paste, paste, Emulsion, foam, chewing gum, tincture, lip pomade, drop, spray or aerosol, syrup or elixir, dispersion liquid, transdermal effect or tablet or via an intravitreal device that continues to discharge chemical compound.Example is the capsule that comprises about 0.05g～about 1.0g active component.
Pharmaceutical composition of the present invention is by a kind of known mode itself, and for example mixing, granulation, coating, dissolving, lyophilizing or the forming processes by routine prepares.
The preferred solution that uses active component, and suspension, particularly isotonic aqueous solution or suspension, for example, comprising active component separately or containing simultaneously in other the situation of freeze-dried composition of carrier (for example mannitol), can before using, make this solution or suspension.Can and/or can comprise excipient with this pharmaceutical composition sterilization, for example antiseptic, stabilizing agent, wetting agent and/or emulsifying agent, solubilizing agent, be used to regulate the salt and/or the buffer agent of osmotic pressure, and be by known mode itself, for example handle and prepare by traditional dissolving or lyophilizing.Described solution or suspension can comprise tackify material, for example sodium carboxy methyl cellulose, carboxy methyl cellulose, glucosan, polyvinylpyrrolidone or gelatin.
Be suspended in suspension in the oil and comprise the oily vegetable oil that is generally used for injecting purpose, synthetic or semi-synthetic oil as oil ingredient.The liquid fatty acid as acid constituents that can also be mentioned is to contain 8～22 carbon atoms, the particularly long-chain fatty acid of 12～22 carbon atoms, for example lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, Palmic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired, can also add antioxidant, for example vitamin E, beta-carotene or 3,5-two-tertiary butyl-4-hydroxy toluene.The alkoxide component of those fatty acid esters has maximum 6 carbon atoms, and is monohydroxy or polyhydroxy, for example monohydroxy, dihydroxy or trihydroxy alcohol, and for example methanol, ethanol, propanol, butanols or amylalcohol and isomer thereof is in particular ethylene glycol and glycerol.Therefore the following example of fatty acid ester is mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, " Labrafil M2375 " (polyoxyethylene trioleate, Gattefoss é, Paris), " Miglyol 812 " (triglyceride of satisfied fatty acid that contain the long-chain of C8～C12, H ü ls AG, Germany), but be in particular vegetable oil, for example Oleum Gossypii semen, almond oil, olive oil, Oleum Ricini, Oleum sesami, Oleum Glycines or the like, particularly Oleum Arachidis hypogaeae semen.
Injection or dip composition prepare under aseptic condition in a conventional manner; For the situation that compositions is placed in ampoule or the bottle and seal this container also is the same.
Can pass through active component is mixed with solid carrier, if desired, the resulting mixture of granulation; and if desired or necessary; after in tablet, dragee or capsule, adding appropriate excipients, handle this mixture, obtain being used for oral pharmaceutical composition.Can also comprise plastic carrier, to allow this active component diffusion or to discharge with measurable amount.
Suitable carrier is in particular filler, for example sugar, for example lactose, sucrose, mannitol or Sorbitol; Cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate; And binding agent, for example use for example paste of corn, Semen Tritici aestivi, rice or potato starch, gelatin, Tragacanth, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium carboxy methyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrating agent, for example above-mentioned starch and/or carboxyl methyl starch, crospolyvinylpyrrolidone, agar, alginic acid or its salt, for example sodium alginate.Excipient is in particular flowing regulator and lubricant, for example silicic acid, Pulvis Talci, stearic acid or its salt, for example magnesium stearate calcium calcium stearate and/or Polyethylene Glycol.Dragee nuclear has suitable, optional casing, sugar-coat, and especially use the spissated sugar juice that can comprise Radix Acaciae senegalis, Pulvis Talci, polyvinylpyrrolidone, Polyethylene Glycol and/or titanium dioxide, perhaps be dissolved in the sugar-coat solution of suitable organic solvent, perhaps, the solution of the preparation of enteric coating, suitable cellulose preparation, for example ethyl cellulose phthalate or HYDROXY PROPYL METHYLCELLULOSE phthalate.Capsule is the dry-packing capsule made of gelatin or the soft seal capsule of being made by gelatin and plasticizer (for example glycerol or Sorbitol).This dry-packing capsule can comprise the active component of particle form, for example contains filler (for example lactose), binding agent (for example starch) and/or fluidizer (for example Pulvis Talci or magnesium stearate), and if desired, contains stabilizing agent.In soft capsule, preferably active component is dissolved or suspended in suitable oily excipient, for example in fatty oils, paraffin oil or the liquid macrogol, can also add stabilizing agent and/or antibacterial.For example be in the purpose of identification or, can in tablet or dragee sugar-coat or capsulation, add dyestuff or pigment for the various dose of active component.
For the intestinal external administration, the aqueous solution of the active component of water-soluble form (for example water soluble salt) or the water injection suspension liquid that comprises viscosity enhancing substance or stabilizing agent are specially suitable.This active component randomly with excipient, can also be lyophilized form and made solution by adding solvent before the intestinal external administration.
Can be by using or revise known method, employed compromise method in the document up to now for example, for example Larock R.C. is at " Comprehensive organic transformations:a guide tofunctional group preparations ", VCH publishers, method described in the version in 1999 prepares chemical compound of the present invention.
In the described hereinafter reaction, needing these reactive functional groups in final products, when hydroxyl, amino, imino group, sulfenyl or carboxyl, may be necessary to these reactive functional groups protections for example, participates in undesirable reaction to avoid them.Can use the common protecting group in the conventional way, for example consult Greene T.W. and Wuts P.G.M., " Protective groups in organicsynthesis ", Wiley-Interscience, 1999.
Usually, can make the alkylidene pyrazolidinedione of formula (I) by the following method: optional in the presence of suitable alkali (for example pyridine, piperidines, diisopropyl ethyl amine, triethylamine), in appropriate solvent (for example ethanol, methanol, 1-butanols or acetic acid), the al of formula V pyrazolidinedione and formula V is closed, shown in following route 1.Preferred condition is for to be heated to 60～80 ℃ with the pyrazolidinedione of formula V and the aldehyde of formula V in ethanol.
Some R in formula (I) structure that in step a, obtains 2Residue for example comprises shielded reactive substituent residue, and (step b), deprotection steps for example obtain the chemical compound of a formula (I ') can to allow further synthetic modification.
Route 1
Therefore, can remove by for example HCl and be present in 4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the tert-butoxycarbonyl in the 5-diketone obtains 1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone; Perhaps can remove and be present in 4-[1-[2-(2 by HCl, 2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, ketal in the 5-diketone, obtain 4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone.
Can be by being similar to Conrad M.and Zart A., Ber.1906, the described method of 2282-2288, and, shown in hereinafter route 2, in appropriate solvent (for example methanol or ethanol), at alkali for example under the existence or non-existent condition of Feldalat NM or Sodium ethylate, the cyclic condensation of the malonate derivative of the hydrazine of formula 1 and formula 2, wherein LG 1And LG 2Represent suitable leaving group separately, for example halogen, preferably chlorine; Or alkoxyl, preferred methoxy or ethoxy; Or aryloxy group, the pyrazolidinedione of preparation formula (VI).
Route 2
Figure A20048001771700611
In another preferable methods, can be shown in hereinafter route 3, by a kind of Michaelis A. and Burmeister R. of being similar to, Ber.1892, the described method of 1502-1513, by in the presence of suitable alkali (for example sodium hydroxide, potassium hydroxide, Feldalat NM, Sodium ethylate, potassium carbonate or sodium hydride), at appropriate solvent (for example alcohol, for example ethanol or methanol; Oxolane; Or N, dinethylformamide) in, cyclisation formula 3 chemical compounds, the chemical compound of preparation formula (IV).
Under preferred condition, by with this compound dissolution in solvent (for example ethanol), and in the presence of sodium hydroxide, at room temperature stir this solution, cyclisation formula 3 chemical compounds.
Preferably, formula 3 chemical compounds are for example at coupling reagent, for example 1,3-dicyclohexylcarbodiimide, O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, or halogen, preferred chlorine, under the existence of alkali (triethylamine, N, N-diisopropyl ethyl amine or pyridine), at appropriate solvent (for example oxolane, dioxane or N, dinethylformamide) in, under lower temperature, (preferably be lower than room temperature), the condensation prepared of the malonate derivative of the hydrazine of through type 1 and formula 2
LG wherein 1Be leaving group, for example OH; And LG 2The expression alkoxyl, preferred methoxy or ethoxy; Or aryloxy group.
Route 3
The method of other of the pyrazolidinedione of preparation formula (IV) is:
-in appropriate solvent (for example THF), by a kind of hydrazine and malonyl dichloro that is similar to the described method shrinking type 1 of WO02/102359.
-in the presence of phosphoryl chloride phosphorus oxychloride, by a kind of Michaelis A. and Schenk K. of being similar to, Ber.1907, the described method of 3568-3569, condensation N '-acethydrazide and malonic acid (that is, formula 2 chemical compounds, wherein LG 1And LG 2All represent hydroxyl).
-by a kind of van Alphen J. that is similar to, Recl.Trav.Chim.Pays-Bas 1924, the described method of 823-866, the hydrazine and 1 of condensation and formula 1,2-allene-1,3-diketone.
-by a kind of Weissberger A. and Porter H.D. of being similar to, J.Am.Chem.Soc.1943, the described method of 52-54, the hydrazine and the cyan-acetic ester of condensation and formula 1, acidolysis subsequently.
The aldehyde of formula V perhaps can prepare according to the procedure known to those skilled in the art with commercially available, and perhaps the method by hereinafter described prepares.
A preferred instantiation of the present invention provides the trisubstituted benzaldehyde (R wherein of formula V 3The expression alkoxyl, preferred propoxyl group; And R 4And R 5Define the same) preparation method, shown in route 4 hereinafter.Can be by obtaining this trisubstituted benzaldehyde as route 4 described methods, by a kind of Carreno M.C. etc. that is similar to, J. Org.Chem.1995, the described method of 5328-5331, trisubstituted benzene from corresponding formula 4b, by in acetonitrile, at room temperature using N-bromine succinamide to carry out bromination, obtain the bromobenzene derivant (step a) of formula 5.Second step (in the step b), at first by using a kind of alkyl lithium reagents (preferred butyl lithium), in solvent as the oxolane, be lower than under 0 ℃ the temperature, preferably-78 ℃, the bromobenzene derivant of formula 5 is changed into corresponding aryl-lithium intermediate, use dialkylformamide (N for example then, dinethylformamide) or formic acid alkane ester (for example methyl formate) condensation reaction, obtain the aldehyde of formula V.
Route 4
Figure A20048001771700631
Another instantiation of the present invention provides the trisubstituted benzene derivative (R wherein of formula 4b 3Be alkoxyl, preferred propoxyl group; And R 4And R 5Form a phenyl ring with the phenyl ring that they connected, preferred optional carbocyclic ring or the heteroaryl ring system that replaces) preparation method: at solvent (N for example, dinethylformamide) in, in the presence of alkali (for example potassium carbonate or sodium hydride), under 30 ℃～100 ℃ high temperature, use alkyl halide (preferred 1-N-Propyl Bromide), with the phenol of corresponding formula 4a (R wherein 3The expression hydroxyl) alkylation.
The particularly preferred example of the bicyclic compound of formula 4b is as mentioned below:
Can be by in solvent (for example alcohol, particular methanol), use Reducing agent (for example sodium borohydride) ketone of reduction-type 7a to obtain the benzyl alcohol (R wherein of formula 7b 6Expression hydrogen).
Benzyl alcohol that can be by reduction-type 7b (R wherein 6Expression hydrogen), for example by hydrogenation in the presence of metallic catalyst (for example charcoal supported palladium), obtain the chemical compound of formula 7d, this chemical compound is the representative compounds of the trisubstituted benzene of above-mentioned formula 4b.
Can be by in the presence of alkali, use alkyl halide to the benzyl alcohol of formula 7b (R wherein 6Expression hydrogen) further modify, to obtain formula 7c chemical compound (R wherein 6The expression alkyl), this chemical compound has also been represented an example of the trisubstituted benzene of above-mentioned formula 4b.
The reduction of the pyridine ring in the isoquinilone derivatives of formula 8a and 9a, for example, obtain corresponding 5-alkoxyl-1,2 respectively by in the presence of metallic catalyst (for example platinum oxide), carrying out hydrogenation, 3,4-tetrahydrochysene-isoquinolin and 8-alkoxyl-1,2,3,4-tetrahydrochysene-isoquinolin, subsequently in the existence of coupling reagent or formyl chloride, in the presence of alkali, use-CO-R 7Transfering reagent (for example carboxylic acid halide or anhydride or carboxylic acid) post processing obtains tetrahydrochysene-isoquinilone derivatives of formula 8b and 9b respectively, wherein R 7Preferred expression alkoxy carbonyl or alkyl-carbonyl.
Use alkyl halide or use the alkyl sulfide acyl halide to handle above-mentioned 5-alkoxyl-1; 2; 3; 4-tetrahydrochysene-isoquinolin or 8-alkoxyl-1; 2; 3,4-tetrahydrochysene-isoquinolin obtains the chemical compound corresponding to formula 8b and 9b respectively, but wherein nitrogen-atoms connect an alkyl or alkyl sulfide acyl group rather than-CO-R 7Group.
The isoquinilone derivatives of formula 9a (this chemical compound be above-mentioned formula 4b trisubstituted benzene representative example) can be by being similar to Hendrickson J.B. etc., J.Org.Chem.1983,3346-3347 is described to be prepared from 2-alkoxyl-benzaldehyde respectively.
The representative example of the subgroup of the benzaldehyde of formula V is formula (VI) and (VI '), shown in following route 6, and R wherein 8And R 9Represent alkyl separately, and R 4The expression methyl.The method of this chemical compound shown in can pass course 6 prepares.
According to Nielsen S.F. etc., J.Med.Chem.1998,4819-4832 is described, at a known formylation reaction, in the Vilsmeier formylated, can be the benzaldehyde (step a) of formula 11 with the phenol conversion of formula 10.Subsequently can be by aldehyde and R with formula 11 8-transfering reagent (for example alkyl halide, methanesulfonic acid alkane ester or toluenesulfonic acid alkane ester; preferred 1-N-Propyl Bromide); in solvent (for example acetonitrile); in the presence of alkali (for example potassium carbonate); in room temperature to the temperature range of reflux temperature; preferred 50 ℃, the hydroxy alkyl that will be positioned at para-position changes into formoxyl (step b).Can be by using a R 9-transfering reagent (for example alkyl halide, methanesulfonic acid alkane ester or toluenesulfonic acid alkane ester); in the presence of weak base (for example cesium carbonate or potassium carbonate); randomly in the presence of sodium iodide or potassium iodide; in the temperature range of room temperature to 140 ℃; handle the aldehyde of described formula 12; to be arranged in the adjacent hydroxy alkylated of formoxyl of the aldehyde of formula 12, obtain the trisubstituted benzaldehyde of a formula (VI), subsequently at R 9Go up further chemical modification, (step d) obtains the benzaldehyde of formula (VI ') for example to remove any protective agent.
Route 6
In following formula embodiment, special instantiation of the present invention has been described, these embodiment are used to be described more specifically the present invention, rather than to the restriction of any way of scope of the present invention.
Embodiment
Temperature with degree centigrade (℃) expression.Unless otherwise indicated, reaction at room temperature takes place.
In mixture, unless otherwise indicated, the relation of solvent in the liquid or eluant or the blended umber of reaction reagent is represented with volume relationship (v/v).
Employed abbreviation and abbreviation:
AcOH: acetic acid, br: broad peak (wave spectrum), BSA: bovine serum albumin, n-BuLi: n-BuLi, CH 2Cl 2: dichloromethane, d: doublet (wave spectrum), DIPEA:N, N-diisopropyl ethyl amine, DMF:N, dinethylformamide, DMSO: dimethyl sulfoxine, EDTA: ethylenediaminetetraacetic acid, ESI: electro-spray ionization, Et 3N: triethylamine, EtOAc: ethyl acetate, EtOH: ethanol, g: gram, h: hour, HATU:O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, H 2O: water, HCl: hydrochloric acid, HPLC: high performance liquid chromatography, k: thousand, K 2CO 3: potassium carbonate, l: rise LiOH: Lithium hydrate, μ: little, m: in the least, and mol: mole, M: mole, MeOH: methanol, Me: methyl, min: minute, MS: mass spectrum, N: the normal state of solution, NMR: nuclear magnetic resonance, NMR, NaCl: sodium chloride, NaHCO 3: sodium bicarbonate, Na 2CO 3: sodium carbonate, NaOH: sodium hydroxide, Na 2SO 4: sodium sulfate, 10%Pd/C: load on the palladium of 10 weight % on the active carbon, Pd (PPh 3) 2Cl 2: two (triphenylphosphine) palladiums (II) of dichloro, ppm: per hundred sub very much parts, q: quartet (wave spectrum), s: unimodal (wave spectrum), SDS: dodecyl sodium sulfate, t: triplet (wave spectrum), THF: oxolane, TBAF: tetrabutyl ammonium fluoride, t R: retention time.
Instrument and analysis
It is at WatersAlliance HPLC that is equipped with Waters 996 photodiode array detectors and Micromass ZQ that-HPLC/MS analyzes TMFinish on the Waters mass spectrograph (ESI).
-analytical HPLC condition:
LC-A
Analytical HPLC is at Xterra TMMS C 18(2.1 * 50mm, 5 μ m carry out on Waters) post.
Linear gradient is that water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) reached 95% from 5% in 6 minutes, keeps final condition then 1 minute, flow velocity 0.25ml/min.
LC-B
Analytical HPLC is at Xterra TMMS C 18(2.1 * 50mm, 5 μ m carry out on Waters) post.
Linear gradient is that water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) reached 95% from 5% in 2 minutes, keeps final condition then 0.5 minute, flow velocity 0.75ml/min.
LC-C
Analytical HPLC is that (4.6 * 50mm, 5 μ m carry out on Agilent) at Zorbax SB-Aq.
Linear gradient is that water/0.06% formic acid (A) and acetonitrile/0.06% formic acid (B) reached 95% from 5% in 1 minute, keeps final condition then 0.25 minute, flow velocity 3ml/min.
-preparation HPLC condition:
Xterra TMPrep MS C 18Post (19 * 50mm, 5 μ m, Waters).
- 1H NMR wave spectrum writes down on Varian Mercury 300VX FT-NMR spectrometer.Chemical shift (δ) is to be reference with the proton resonance absworption peak of the NMR solvent in incomplete deuterium generation (for example dimethyl sulfoxine δ (H) 2.49ppm, chloroform δ (H) 7.24ppm), is that unit represents with 1,000,000/(ppm).
Embodiment 1 (R 1Be phenyl)
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone
In absolute ethanol (4ml), in inert atmosphere, with 1-phenyl-pyrazole alkane-3,5-diketone (53mg, 0.30mmol, according to Conrad M. and Zart A., Ber., 1906, the method preparation of 2282-2288) and 2, (mixture heated 0.45mmol) refluxed 16 hours 3-dimethyl-4-propoxyl group benzaldehyde for embodiment 2b1b, 87mg.After being cooled to room temperature, by filtering collecting precipitation.(3 * 2ml) wash this solid and dry in a vacuum, and the title compound (80mg, 76%) that obtains the kermesinus solid, shaped is as initiation material: t to use absolute ethanol R=7.45min (LC-A); MS (cation mode): m/z 351.3[M+H] +MS (anion mode): m/z 349.5[M-H] -
Embodiment 2 (R 1Be phenyl)
2a) following product 2a1-2a65 still uses aldehyde to replace 2,3-dimethyl-4-propoxyl group benzaldehyde respectively by being similar to embodiment 1 described method preparation:
2a1) 4-(4-methoxyl group-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-methoxyl group-3-tolyl aldehyde (Fluka) as initiation material: t R=6.48min (LC-A); MS (cation): m/z 309.3[M+H] +MS (anion): m/z 307.5[M-H] -
2a2) 4-(4-ethyoxyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-ethoxy-benzaldehyde (Aldrich) as initiation material: t R=6.47min (LC-A); MS (cation): m/z 309.3[M+H] +MS (anion): m/z 307.5[M-H] -
2a3) 4-(4-ethyoxyl-3-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-ethyoxyl-3-methoxybenzaldehyde (Aldrich) as initiation material: t R=6.16min (LC-A); MS (cation): [M+H] +339.3; MS (anion): [M-H] -337.5.
2a4) 4-(2,4-dimethoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 4-dimethoxy benzaldehyde (Aldrich) is as initiation material: t R=6.21min (LC-A); MS (cation): m/z 325.3[M+H] +MS (anion): m/z 323.5[M-H] -
2a5) 4-naphthalene-2-methylene-1-phenyl-pyrazole alkane-3, the 5-diketone uses naphthalene-2-aldehyde (Aldrich) to prepare as initiation material: t R=6.91min (LC-A); MS (cation): m/z 315.1[M+H] +MS (anion): m/z 313.3[M-H] -
2a6) 4-(the 4-tert-butyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses the 4-tert-butyl group-benzaldehyde (Fluka) as initiation material: t R=7.35min (LC-A); MS (cation): m/z 321.4[M+H] +MS (anion): m/z 319.6[M-H] -
2a7) 4-(2,3-dimethyl-4-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 3-dimethyl-4-methoxybenzaldehyde (Aldrich) is as initiation material: t R=6.78min (LC-A); MS (cation): m/z 323.1[M+H] +MS (anion): m/z 321.3[M-H] -
2a8) 4-(2,4-dimethoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 4-dimethoxy-3-tolyl aldehyde (Aldrich) is as initiation material: t R=6.67min (LC-A); MS (cation): m/z 339.1[M+H] +MS (anion): m/z 337.3[M-H] -
2a9) 4-(3-bromo-4-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-bromo-4-methoxybenzaldehyde (Acros) as initiation material: t R=6.48min (LC-A); MS (cation): m/z 373.3,375.2[M+H] +MS (anion): m/z 371.3,373.4[M-H] -
2a10) 1-phenyl-4-(4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone uses 4-propoxyl group benzaldehyde (Aldrich) as initiation material: t R=6.86min (LC-A); MS (cation): m/z 323.3[M+H] +MS (anion): m/z 321.5[M-H] -
2a11) 4-(4-butoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-butyl phenyl ether formaldehyde (Acros) as initiation material: t R=7.21min (LC-A); MS (cation): m/z 337.4[M+H] +MS (anion): m/z 335.6[M-H] -
2a12) 4-(4-ethyoxyl-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-ethyoxyl-3-tolyl aldehyde (embodiment 2b2) as initiation material: t R=6.86min (LC-A); MS (cation): m/z 323.4[M+H] +MS (anion): m/z 321.5[M-H] -
2a13) 4-(3-methyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-4-propoxyl group benzaldehyde (embodiment 2b3) as initiation material: t R=7.35min (LC-A); MS (cation): m/z 337.4[M+H] +MS (anion): m/z 335.6[M-H] -
2a14) 4-(4-butoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-butoxy-3-tolyl aldehyde (embodiment 2b4) as initiation material: t R=7.82min (LC-A); MS (cation): m/z 351.2[M+H] +MS (anion): m/z 349.3[M-H] -
2a15) 4-(4-hexyloxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-hexyloxy-3-tolyl aldehyde (embodiment 2b5) as initiation material: t R=8.53min (LC-A); MS (cation): m/z 379.2[M+H] +MS (anion): m/z 377.3[M-H] -
2a16) 4-(3-methyl-4-amoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-4-amyl phenyl ether formaldehyde (embodiment 2b6) as initiation material: t R=7.98min (LC-A); MS (cation): m/z 365.4[M+H] +MS (anion): m/z 363.6[M-H] -
2a17) 4-(4-cyclobutyl methoxy base-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-cyclobutyl methoxy base-3-tolyl aldehyde (embodiment 2b7) as initiation material: t R=8.02min (LC-A); MS (cation): m/z 363.1[M+H] +MS (anion): m/z 361.3[M-H] -
2a18) 4-[3-methyl-4-(3-methyl-butoxy)-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-4-(3-methyl butoxy) benzaldehyde (embodiment 2b8) as initiation material: t R=8.14min (LC-A); MS (cation): m/z 365.1[M+H] +MS (anion): m/z 363.3[M-H] -
2a19) 4-(4-isobutoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone, use 4-isobutoxy-3-tolyl aldehyde (embodiment 2b9): MS (cation) is as initiation material: t R=7.86min (LC-A); M/z 351.1[M+H] +MS (anion): m/z 349.3[M-H] -
2a20) 4-[4-(2-methoxyl group-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-(2-methoxy ethoxy)-3-tolyl aldehyde (embodiment 2b10) as initiation material: t R=6.31min (LC-A); MS (cation): m/z 353.4[M+H] +MS (anion): m/z 351.5[M-H] -
2a21) 4-(3-chloro-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-chloro-4-propoxyl group benzaldehyde (embodiment 2b11) as initiation material: t R=7.18min (LC-A); MS (cation): m/z 357.3[M+H] +MS (anion): m/z 355.5[M-H] -
2a22) 4-[4-(2-hydroxyl-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-(2-hydroxyl-oxethyl)-3-tolyl aldehyde (embodiment 2b12b) as initiation material: t R=5.57min (LC-A); MS (cation): m/z 339.4[M+H] +MS (anion): m/z 337.5[M-H] -
2a23) 4-(4-cyclo propyl methoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-cyclo propyl methoxy-3-methyl-benzaldehyde (embodiment 2b13) as initiation material: t R=7.39min (LC-A); MS (cation): m/z 349.1[M+H] +MS (anion): m/z 347.3[M-H] -
2a24) 4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-cyclopentyloxy-2, and 3-dimethyl-benzaldehyde (embodiment 2b14) is as initiation material: t R=7.79min (LC-A); MS (cation): m/z 377.4[M+H] +MS (anion): m/z 375.6[M-H] -
2a25) 1-phenyl-4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone uses 4-propoxyl group-5,6,7, and 8-tetrahydrochysene-naphthalene-1-aldehyde (embodiment 2b15c) is as initiation material: t R=7.97min (LC-A); MS (cation): m/z 377.2[M+H] +MS (anion): m/z 375.4[M-H] -
2a26) 4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 3-dimethyl-4-penta-1-alkynyl-benzaldehyde (embodiment 2b16b) is as initiation material: t R=7.77min (LC-A); MS (cation): m/z 359.2[M+H] +MS (anion): m/z 357.3[M-H] -
2a27) 4-(2,3-dimethyl-4-amyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 3-dimethyl-4-amyl group-benzaldehyde (embodiment 2b16c) is as initiation material: t R=8.10min (LC-A); MS (cation): m/z 363.3[M+H] +MS (anion): m/z 361.4[M-H] -
2a28) 1-phenyl-4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone uses 4-propoxyl group-1-naphthaldehyde (embodiment 2b17) as initiation material: t R=7.63min (LC-A); MS (cation): m/z 373.1[M+H] +MS (anion): m/z 371.3[M-H] -
2a29) 1-phenyl-4-[1-(7-propoxyl group-indane-4-yl)-methylene]-pyrazolidine-3, the 5-diketone uses 7-propoxyl group-indane-4-aldehyde (embodiment 2b18e) as initiation material: t R=7.64min (LC-A); MS (cation): m/z 363.3[M+H] +MS (anion): m/z 361.4[M-H] -
2a30) 1-phenyl-4-[1-(5-propoxyl group-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone uses 5-propoxyl group-isoquinolin-8-aldehyde (embodiment 2b19c) as initiation material: t R=6.03min (LC-A); MS (cation): m/z 374.3[M+H] +MS (anion): m/z 372.4[M-H] -
2a31) 1-phenyl-4-[1-(8-propoxyl group-isoquinolin-5-yl)-methylene]-pyrazolidine-3, the 5-diketone uses 8-propoxyl group-isoquinolin-5-aldehyde (embodiment 2b20d) as initiation material: t R=5.61min (LC-A); MS (cation): m/z 374.2[M+H] +MS (anion): m/z 372.2[M-H] -
2a32) 4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3; 4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-tert-butoxycarbonyl-8-formoxyl-5-propoxyl group-1; 2,3,4-tetrahydroisoquinoline (embodiment 2b21d) is as initiation material: t R=2.69min (LC-B); MS (anion): m/z 476.5[M-H] -
2a33) 4-(2,3-dimethyl-4-ethanesulfonyloxy group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 3-dimethyl-4-ethanesulfonyloxy group benzaldehyde (embodiment 2b22) is as initiation material: t R=6.47min (LC-A); MS (cation): m/z 401.3[M+H] +MS (anion): m/z 399.2[M-H] -
2a34) 4-[1-(2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 4-dipropoxy-benzaldehyde (embodiment 2b23) is as initiation material: t R=1.18min (LC-C); MS (cation): m/z 381.1[M+H] +MS (anion): m/z 379.3[M-H] -
2a35) 4-[1-(2,6-dipropoxy-pyridin-3-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2, and 6-dipropoxy-pyridine-3-aldehyde (embodiment 2b24b) is as initiation material: t R=1.21min (LC-C); MS (cation): m/z 382.0[M+H] +MS (anion): m/z 380.3[M-H] -
2a36) 4-[1-(2-hydroxy-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) as initiation material: t R=7.09min (LC-A); , MS (cation): m/z 353.3[M+H] +MS (anion): m/z 351.2[M-H] -
2a37) 4-[1-(2-methoxyl group-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-methoxyl group-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b26) as initiation material: t R=7.39min (LC-A); MS (cation): m/z 367.3[M+H] +MS (anion): m/z 365.4[M-H] -
2a38) 4-[1-(3-methyl-2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-2, and 4-dipropoxy-benzaldehyde (embodiment 2b27) is as initiation material: t R=8.07min (LC-A); MS (cation): m/z 395.4[M+H] +MS (anion): m/z 393.5[M-H] -
2a39) 4-[1-[2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b28) as initiation material: t R=7.32min (LC-A); MS (cation): m/z 411.3[M+H] +MS (anion): m/z 409.3[M-H] -
2a40) 4-[1-[2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b29b) as initiation material: t R=6.67min (LC-A); MS (cation): m/z 397.4[M+H] +MS (anion): m/z 395.3[M-H] -
2a41) 4-[1-[2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b30b) as initiation material: t R=6.96min (LC-A); MS (cation): m/z 411.2[M+H] +MS (anion): m/z 409.2[M-H] -
2a42) 4-[1-[2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b31) as initiation material: t R=7.72min (LC-A); MS (cation): m/z 467.2[M+H] +MS (anion): m/z 465.3[M-H] -
2a43) 4-[1-[2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b32) as initiation material: t R=6.85min, 6.98min (LC-A); MS (cation): m/z 425.2[M+H] +MS (anion): m/z 423.3[M-H] -
2a44) 4-[1-[2-(ethoxy carbonyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl acetate (embodiment 2b33) as initiation material: t R=7.44min (LC-A); MS (cation): m/z 439.3[M+H] +MS (anion): m/z 437.3[M-H] -
2a45) 4-[1-[2-(carboxyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetic acid (embodiment 2b34) as initiation material: t R=6.58min (LC-A); MS (cation): m/z 411.4[M+H] +MS (anion): m/z 409.3[M-H] -
2a46) 4-[1-[2-(2-amino-2-oxo-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses 2-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetamide (embodiment 2b35) as initiation material: t R=6.34min (LC-A); MS (cation): m/z 410.2[M+H] +MS (anion): m/z 408.3[M-H] -
2a47) 4-[1-[2-(3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate. (embodiment 2b36) as initiation material: t R=7.86min (LC-A); MS (cation): m/z 467.4[M+H] +MS (anion): m/z 465.3[M-H] -
2a48) 4-[1-[2-(3-carboxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid (embodiment 2b37) as initiation material: t R=6.95min (LC-A); MS (cation): m/z 439.4[M+H] +MS (anion): m/z 437.3[M-H] -
2a49) 4-[1-[2-(4-ethylamino-4-oxo-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid acetamide (embodiment 2b38) as initiation material: t R=7.16min (LC-A); MS (cation): m/z 466.2[M+H] +MS (anion): m/z 464.3[M-H] -
2a50) 4-[1-[3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-benzaldehyde (embodiment 2b39) as initiation material: t R=7.16min (LC-A); MS (cation): m/z 508.2[M+H] +MS (anion): m/z 506.4[M-H] -
2a51) 4-[1-[2-(4-ethoxy carbonyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl valerate (embodiment 2b40) as initiation material: t R=8.37min (LC-A); MS (cation): m/z 481.2[M+H] +MS (anion): m/z 479.4[M-H] -
2a52) 4-[1-[2-(4-carboxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid (embodiment 2b41) as initiation material: t R=7.34min (LC-A); MS (cation): m/z 453.2[M+H] +MS (anion): m/z 451.3[M-H] -
2a53) 4-[1-[2-(5-ethylamino-5-oxo-amoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid acetamide (embodiment 2b42) as initiation material: t R=7.42min (LC-A); MS (cation): m/z 480.2[M+H] +MS (anion): m/z 478.4[M-H] -
2a54) 4-[1-[3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone uses 3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-benzaldehyde (embodiment 2b43) as initiation material: t R=7.29min (LC-A); MS (cation): m/z 522.3[M+H] +MS (anion): m/z 520.4[M-H] -
2a55) 4-[1-[2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-dione hydrochloride uses 2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde hydrochlorate (embodiment 2b44) as initiation material: t R=4.93min (LC-A); MS (cation): m/z 424.3[M+H] +MS (anion): m/z 422.3[M-H] -
2a56) 4-[1-[3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-dione hydrochloride uses 3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-benzaldehyde hydrochlorate (embodiment 2b45) as initiation material: t R=5.05min (LC-A); MS (cation): m/z 466.3[M+H] +MS (anion): m/z 464.3[M-H] -
2a57) 4-[1-[3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-dione hydrochloride uses 3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-benzaldehyde hydrochlorate (embodiment 2b46) as initiation material: t R=5.20min (LC-A); MS (cation): m/z 464.4[M+H] +MS (anion): m/z 462.3[M-H] -
2a58) 4-[1-[2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-dione hydrochloride uses 2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde hydrochlorate (embodiment 2b47) as initiation material: t R=5.09min, 5.27min (LC-A); MS (cation): m/z 438.4[M+H] +MS (anion): m/z 436.3[M-H] -
2a59) 4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone, use 2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b48) is as initiation material: t R=7.68min (LC-A); MS (cation): m/z 467.2[M+H] +MS (anion): m/z 465.3[M-H] -
2a60) 4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone, use 2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b49) is as initiation material: t R=7.65min (LC-A); MS (cation): m/z 467.3[M+H] +MS (anion): m/z 465.3[M-H] -
2a61) 4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone, use 2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b50) is as initiation material: t R=7.66min (LC-A); MS (cation): m/z 467.3[M+H] +MS (anion): m/z 465.3[M-H] -
2a62) 4-[1-[2-((2R)-3-ethoxy carbonyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate. (embodiment 2b51b) as initiation material: t R=6.97min, 7.11min (LC-A); MS (cation): m/z 483.3[M+H] +MS (anion): m/z 481.3[M-H] -
2a63) 4-[1-[2-((2R)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid (embodiment 2b52) as initiation material: t R=6.18min, 6.41min (LC-A); MS (cation): m/z 455.2[M+H] +MS (anion): m/z 453.3[M-H] -
2a64) 4-[1-[2-((2S)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone uses (3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid (embodiment 2b54) as initiation material: t R=6.15min, 6.39min (LC-A); MS (cation): m/z 455.1[M+H] +MS (anion): m/z 453.2[M-H] -
2a65) 4-[1-[2-((4R; 5S)-4-carboxyl-2; 2-dimethyl-[1; 3] dihydro penta ring-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3; the 5-diketone, use (4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2; 2-dimethyl-[1,3] dioxolanes-4-carboxylic acid (embodiment 2b56) is as initiation material: t R=6.92min, 7.09min (LC-A); MS (cation): m/z 511.3[M+H] +MS (anion): m/z 509.3[M-H] -
2a66) 1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3,5-diketone formic acid esters
To 4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3,5-diketone (embodiment 2a32,30mg, 0.063mmol) THF (5ml) mixture in add ether (628 μ l, 1.25mmol) solution of 2N HCl.At room temperature preserved 1 hour, and evaporated volatile matter then in a vacuum, and, obtain the title compound (2mg, 8%) of Off-white solid shape: t by the refining resulting residue of preparation HPLC R=1.68min (LC-B); MS (cation): m/z 378.3[M+H] +MS (anion): m/z 376.3[M-H] -
2a67) 4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
HCl aqueous solution to 25% (280 μ l, 2.25mmol) and the mixture of EtOH (6ml) in add 4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone (embodiment 2a59,210mg, 0.45mmol).With reactant mixture be heated to 80 ℃ 1 hour.After being cooled to room temperature, by filtering collecting precipitation.(2 * 3ml) wash solids, and dry in a vacuum, obtain the title compound (98mg, 51%) of orange solids shape: t to use EtOH R=6.04min, 6.26min (LC-A); MS (cation): m/z 427.2[M+H] +MS (anion): m/z 425.2[M-H] -
2a68) 4-[1-[2-((2S)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
Similar fashion according to the described method of embodiment 2a67, but use 4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone (embodiment 2a60) replaces 4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone obtains title compound: t R=6.05min, 6.27min (LC-A); MS (cation): m/z 427.2[M+H] +MS (anion): m/z 425.2[M-H] -
2a69) 4-[1-[2-((2R)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
Similar fashion according to the described method of embodiment 2a67, but use 4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone (embodiment 2a61) replaces 4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone obtains title compound: t R=6.02min, 6.24min (LC-A), MS (cation): m/z 427.3[M+H] +MS (anion): m/z 425.2[M-H] -
2a70) 4-[1-[2-((2S, 3R)-2,3-dihydroxy-3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
Similar fashion according to the described method of embodiment 2a67, but use 4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone (embodiment 2a65) replaces 4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone obtains title compound: t R=6.72min, 6.85min (LC-A); MS (cation): m/z499.3[M+H] +MS (anion): m/z 497.3[M-H] -
2a71) 4-[1-[2-((2S, 3R)-3-carboxyl-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone
To 1NHCl aqueous solution (160 μ l, 0.16mmol) with the mixture of THF (1ml) in add 4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone (embodiment 2a65,20mg, 0.04mmol).With reactant mixture be heated to 70 ℃ 16 hours.Be cooled to room temperature, evaporate volatile matter then in a vacuum, and use diisopropyl ether (4ml) to pulverize resulting residue.Collect the precipitation that suspends by filtering, and (2 * 4ml) wash this solid, dry in a vacuum then, obtain the title compound (12.5mg, 80%) of red solid shape: t to use diisopropyl ether R=6.04min, 6.31min (LC-A), MS (cation): m/z 471.2[M+H] +MS (anion): m/z 469.3[M-H] -
2b) employed aldehyde prepares by the following method among embodiment 1 and the 2a12-2a65:
2b1) 2, the preparation of 3-dimethyl-4-propoxyl group benzaldehyde
2b1a) 2,3-dimethyl-4-hydroxy benzaldehyde
Under-78 ℃, (7.56ml 80mmol), handles 2,3-dimethyl-4-methoxybenzaldehyde (6.40g, anhydrous CH 40mmol) dropwise to add pure Boron tribromide via syringe 2Cl 2(160ml) solution.Down stirred these solution 10 minutes at-78 ℃, be warmed to room temperature and stirred 48 hours.This reactant mixture is to be cooled to 0 ℃ and the condensation water (100ml) by this addition.Use CH 2Cl 2(the isolating water of 3 * 100ml) extractions.Use the blended organic facies of saline (100ml) washing, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, make with extra care resulting residue, obtain the title compound (2.43g, 40%) of light yellow solid shape: t R=5.15min (LC-A); MS (cation): m/z 151.2[M+H] +MS (anion): m/z 149.3[M-H] -
2b1b) 2,3-dimethyl-4-propoxyl group benzaldehyde
Phase 2, (embodiment 2b1a, 2.43g add K in dry DMF 16.2mmol) (33ml) solution to 3-dimethyl-4-hydroxyl-benzaldehyde 2CO 3(2.24g, 24.3mmol).At room temperature stirred this mixture 10 minutes, and adding 1-N-Propyl Bromide (1.47ml, 17.8mmol).This mixture of heating under 50 ℃-whole night.After being cooled to room temperature, use H 2O (150ml) dilutes this mixture, and uses EtOAc (3 * 100ml) extractions.Use H 2O (100ml), the blended organic facies of saline (100ml) washing are at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, make with extra care resulting residue, obtain the title compound (2.74g, 88%) of milky color solid, shaped: t R=7.24min (LC-A); MS (cation): m/z 193.3[M+H] +
2b2) 4-ethyoxyl-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde (Aldrich) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde and bromoethane replaces the 1-N-Propyl Bromide, obtains title compound: t R=6.36min (LC-A); MS (cation): m/z165.2[M+H] +
2b3) 3-methyl-4-propoxyl group benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=6.89min (LC-A); MS (cation): m/z 179.3[M+H] +
2b4) 4-butoxy-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use the 1-n-butyl bromide to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.42min (LC-A); MS (cation): m/z 193.2[M+H] +
2b5) 4-hexyloxy-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use hexyl bromide 1 bromohexane to replace the 1-N-Propyl Bromide, obtain title compound: t R=8.25min (LC-A); MS (cation): m/z 221.3[M+H] +
2b6) 4-amoxy-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use the 1-bromo pentane silane to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.85min (LC-A); MS (cation): m/z 207.3[M+H] +
2b7) 4-cyclobutyl methoxy base-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use the bromomethyl Tetramethylene. to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.57min (LC-A); MS (cation): m/z 205.2[M+H] +
2b8) 3-methyl-4-(3-methyl-butoxy) benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use 1-bromo-3-methybutane to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.73min (LC-A); MS (cation): m/z 207.3[M+H] +
2b9) 4-isobutoxy-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use 1-bromo-2-methylpropane to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.38min (LC-A); MS (cation): m/z 193.2[M+H] +
2b10) 4-(2-methoxyl group-ethyoxyl)-3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use 1-bromo-2-methoxyl group-ethane to replace the 1-N-Propyl Bromide, obtain title compound: t R=5.71min (LC-A); MS (cation): m/z 195.2[M+H] +
2b11) 3-chloro-4-propoxyl group benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxyl-3-chlorobenzaldehyde (ABCR) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=6.80min (LC-A); MS (cation): m/z 199.2[M+H] +
2b12) the preparation of 4-(2-hydroxyl-oxethyl)-3-tolyl aldehyde
2b12a) 4-[2-(tert-butyl group-dimethyl-silicon alcoxyl base)-ethyoxyl]-the 3-tolyl aldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use (2-bromine methoxyl group)-tert-butyl group-dimethylsilane to replace the 1-N-Propyl Bromide, obtain title compound: t R=8.39min (LC-A); MS (cation): m/z 295.3[M+H] +
2b12b) 4-(2-hydroxyl-oxethyl)-3-tolyl aldehyde
To 4-[2-(tert-butyl group-dimethyl-silicon alcoxyl base)-ethyoxyl]-the 3-tolyl aldehyde (embodiment 2b12a, 500mg, 1.70mmol), and AcOH (60 μ l dropwise add 1NTBAF (2ml, THF solution 2mmol) in THF 1.0mmol) (5ml) solution.At room temperature stir this reactant mixture a whole night.Use H then 2O (20ml) dilutes this mixture and uses EtOAc (3 * 20ml) extractions.Use H 2O (20ml), the blended organic facies of saline (20ml) washing are at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, make with extra care resulting residue, obtain the title compound (259mg, 85%) of colorless oil: t R=4.68min (LC-A); MS (cation): m/z 181.2[M+H] +
2b13) 4-cyclo propyl methoxy-3-methyl-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxy-3-methyl benzaldehyde to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use (bromomethyl) cyclopropane to replace the 1-N-Propyl Bromide, obtain title compound: t R=6.89min (LC-A); MS (cation): m/z 191.2[M+H] +
2b14) 4-cyclopentyloxy-2,3-dimethyl-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use bromocyclopentane to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.68min (LC-A); MS (cation): m/z219.6[M+H] +
2b15) 4-propoxyl group-5,6,7, the preparation of 8-tetrahydrochysene-naphthalene-1-aldehyde
2b15a) 5-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene
According to the mode that is similar to the described method of embodiment 2b1b, but use 5,6,7,8-naphthane-1-phenol (Acros) replaces 2, and 3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=8.40min (LC-A); MS (cation): m/z 191.4[M+H] +
2b15b) 5-bromo-8-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene
To the 5-propoxyl group-1,2,3 that stirs, and 4-tetrahydrochysene-naphthalene (embodiment 2b15a, 1.14g, adding N-bromine succinamide in acetonitrile 6mmol) (30ml) solution (1.17g, 6.6mmol).At room temperature reactant mixture was stirred 2 hours.Under reduced pressure, boil off solvent then, and in resulting residue, add entry (20ml).(3 * 25ml) extract this aqueous solution to use EtOAc then.Use H 2O (20ml), the blended organic facies of saline (20ml) washing are at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, make with extra care resulting residue, obtain the title compound (1.60g, 99%) of colorless oil: t R=9.02min (LC-A).
2b15c) 4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-aldehyde
Under-78 ℃, to 5-bromo-8-propoxyl group-1,2,3, (embodiment 2b15b, 1.60g dropwise added hexane (4.4ml, 7.1mmol) solution of 1.6N n-BuLi to 4-tetrahydrochysene-naphthalene in 5 minutes in THF .9mmol) (12.9ml) solution.Down stirred these reactant mixtures 5 minutes at-78 ℃, add then DMF (2.5ml, 32.2mmol).In 30 minutes, be warmed to room temperature, and under this temperature, stirred 30 minutes, make water (20ml) diluted reaction mixture and use EtOAc (3 * 50ml) extractions.Use the blended organic facies of saline (50ml) washing, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, refining resulting residue obtains light yellow oily (800mg, 57%) title compound: t R=7.81min (LC-A); MS (cation): m/z 219.1[M+H] +
2b16) 2, the preparation of 3-diethyl-4-amyl group-benzaldehyde
2b16a) 2,3-dimethyl-4-trifluoro-methanesulfonyl oxy benzaldehyde
At room temperature with 2,3-dimethyl-4-hydroxy benzaldehyde (embodiment 2b1a, 1.0g, 6.7mmol), N-phenyl two (fluoroform sulfimide) (2.38g, 6.7mmol) and DIPEA (1.14ml, CH 6.7mmol) 2Cl 2(10ml) mixture stirs a whole night.Use CH2Cl2 (50ml) to dilute this reactant mixture.Use NaHCO then 3Saturated aqueous solution (2 * 30ml) and saline (30ml) wash resulting organic facies continuously, at MgSO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, make with extra care resulting residue, obtain the title compound (1.50g, 80%) of colorless oil: t R=7.09min (LC-A); MS (cation): m/z 283.0[M+H] +
2b16b) 2,3-dimethyl-4-penta-1-alkynyl-benzaldehyde
Comprise Pd (PPh to being dissolved in DMF (5ml's) 3) 2Cl 2(362mg, 0.52mmol), Copper diiodide (98mg, 0.52mmol), 2,3-dimethyl-4-trifluoro-methanesulfonyl oxy benzaldehyde (embodiment 2b16a, 1.47g, 5.2mmol) and DIPEA (2.83ml, and adding 1-pentyne in de gassed solution 16.5mmol) (1.02ml, 10.3mmol).After at room temperature preserving 24 hours, pour in the water reactant mixture into (50ml) and use EtOAc (2 * 50ml) extractions.Use the blended organic facies of saline (50ml) washing, at MgSO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain pale yellow oily title compound (971mg, 94%): t R=7.78min (LC-A); MS (cation): m/z 201.4[M+H] +
2b16c) 2,3-dimethyl-4-amyl group-benzaldehyde
At room temperature, in hydrogen, will be dissolved in 2 of EtOAc (4ml), 3-dimethyl-4-penta-1-alkynyl-benzaldehyde (embodiment 2b16b, 300mg, 1.50mmol) and 10%Pd/C (45mg) mixture stirred 1 hour 30 minutes.Filter on Celite pad, and use the EtOAc washing, vacuum concentrated filtrate obtains colorless oil title compound (285mg, 93%): t R=8.12min (LC-A); MS (cation): m/z 205.4[M+H] +
2b17) 4-propoxyl group-1-naphthaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxyl-1-naphthaldehyde (Aldrich) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=7.38min (LC-A); MS (cation): m/z 215.3[M+H] +
2b18) the preparation of 7-propoxyl group-indane-4-aldehyde
2b18a) 4-propoxyl group-indan-1-one
According to the mode that is similar to the described method of embodiment 2b1b, but use 4-hydroxyl-indan-1-one (TCI) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=6.50min (LC-A); MS (cation): m/z 191.4[M+H] +
2b18b) 4-propoxyl group-indane-1-alcohol
Under 0 ℃ to 4-propoxyl group-indan-1-one (embodiment 2b18a, 2.77g, add in MeOH 14.6mmol) (10ml) solution small part sodium borohydride (275mg, 7.3mmol).Stir this solution down at 0 ℃, and be warmed to room temperature.After at room temperature keeping 48 hours, destroy excessive sodium borohydride by adding acetic acid (2.5ml).Make water (100ml) diluted reaction mixture then and use t-butyl methyl ether (2 * 50ml) extractions.Use H 2O (50ml), the blended organic facies of saline (50ml) washing are at Na 2SO 4Last dry, filter and concentrate, obtain light yellow solid shape title compound (1.80g, 64%): t R=6.00min (LC-A).
2b18c) 4-propoxyl group-indane
At room temperature, under hydrogen, will be dissolved in the alcoholic solution (50ml) of 0.5N HCl 4-propoxyl group-indane-1-alcohol (embodiment 2b18b, 2.35g, 12.2mmol) and the mixture of 10%Pd/C (235mg) stirred 1 hour.Filter on Celite pad, and use the EtOAc washing, vacuum concentrated filtrate obtains light brown oily title compound (1.81g, 84%): t R=8.01min (LC-A); MS (cation): m/z 177.3[M+H] +
2b18d) 4-bromo-7-propoxyl group-indane
According to the mode that is similar to the described method of embodiment 2b15b, but use 4-propoxyl group-indane (embodiment 2b18c) to replace 5-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene obtains title compound: t R=8.59min (LC-A).
2b18e) 7-propoxyl group-indane-4-aldehyde
According to the mode that is similar to the described method of embodiment 2b15c, but use 4-bromo-7-propoxyl group-indane (embodiment 2b18d) to replace 5-bromo-8-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene obtains title compound: t R=7.40min (LC-A); MS (cation): m/z 205.3[M+H] +
2b19) 5-propoxyl group-isoquinolin-8-aldehyde
2b19a) 5-propoxyl group-isoquinolin
Under 0 ℃, to the 5-hydroxyl-isoquinolin that is dissolved in dry DMF (45ml) (3.0g, 20.6mmol, Aldrich) add in the solution small part sodium hydride (779mg, 32.432.4mmol).Stirred this mixture 5 minutes down at 0 ℃, and adding 1-N-Propyl Bromide (2.10ml, 20.6mmol).Then this mixture is warmed to room temperature.After at room temperature preserving 14 hours, use H 2O (50ml) dilutes this mixture and uses EtOAc (2 * 50ml) extractions.Use 1N NaOH aqueous solution (2 * 50ml), the blended organic facies of saline (50ml) washing, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain the buttery title compound of purple (3.23g, 83%): t R=1.63min (LC-B); MS (cation): m/z 188.3[M+H] +
2b19b) 8-bromo-5-propoxyl group-isoquinolin
According to the mode that is similar to the described method of embodiment 2b15b, but use 5-propoxyl group-isoquinolin (embodiment 2b19a) to replace 5-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene obtains title compound: t R=2.37min (LC-B); MS (cation): m/z 266.2,268.2[M+H] +
2b19c) 5-propoxyl group-isoquinolin-8-aldehyde
Under-78 ℃, in 5 minutes, (embodiment 2b19b, 174mg 0.65mmol) dropwise add in the solution and are dissolved in hexane (262 μ l, the n-butyllithium solution of 2.5N 0.65mmol) to the 8-bromo-5-propoxyl group-isoquinolin that is dissolved in THF (5ml).Down stirred these reactant mixtures 5 minutes at-78 ℃, add then the anhydrous formic acid methyl ester (65 μ l, 1.05mmol).Stirred 20 minutes down at-78 ℃, add NH then 4The Cl saturated aqueous solution, and reactant mixture is warmed to room temperature.Make water (50ml) diluted reaction mixture then and use EtOAc (2 * 50ml) extractions.Make water (50ml), saline (50ml washs blended organic facies), at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain brown solid shape oily title compound (50mg, 36%): t R=1.67min (LC-B); MS (cation): m/z 216.3[M+H] +
2b20) the preparation of 8-propoxyl group-isoquinolin-5-aldehyde
2b20a) 2-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy benzaldehyde (Acros) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde obtains title compound: t R=6.59min (LC-A); MS (cation): m/z 165.3[M+H] +
2b20b) 8-propoxyl group-isoquinolin
According to being similar to Hendrickson J.B. and Rodriguez C., J.Org.Chem.1983, the mode of the described method of 3346-3347, but use 2-propoxyl group-benzaldehyde (embodiment 2b20a), to obtain title compound as initiation material: t R=1.44min (LC-B); MS (cation): m/z 188.4[M+H] +
2b20c) 5-bromo-8-propoxyl group-isoquinolin
According to the mode that is similar to the described method of embodiment 2b15b, but use 8-propoxyl group-isoquinolin (embodiment 2b20b) to replace 5-propoxyl group-1,2,3,4-tetrahydrochysene-naphthalene obtains title compound: t R=2.11min (LC-B); MS (cation): m/z 266.2,268.2[M+H] +
2b20d) 8-propoxyl group-isoquinolin-5-aldehyde
According to the mode of the method that is similar to embodiment 2b19c, but use 5-bromo-8-propoxyl group-isoquinolin (embodiment 2b20c) to replace 8-bromo-5-propoxyl group-isoquinolin, obtain title compound: t R=1.67min (LC-B); MS (cation): m/z 216.6[M+H] +
2b21) 2-tert-butoxycarbonyl-8-formoxyl-5-propoxyl group-1,2,3, the preparation of 4-tetrahydroisoquinoline
2b21a) 5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinoline hydrochloride
At room temperature, will be dissolved in alcoholic acid 5-propoxyl group-isoquinolin (embodiment 2b19a, 2.0g, 10.7mmol), mixture hydrogenation a whole night of dense HCl aqueous solution (1.5ml) and platinum oxide.Filter on Celite pad, and use washing with alcohol, vacuum concentrated filtrate obtains Off-white solid shape title compound (2.32g, 95%): t R=0.37min, 1.46min (LC-B); MS (cation): m/z 192.3[M+H] +
2b21b) 2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin
At room temperature will be dissolved in 1,4-dioxane-H 2The 5-propoxyl group-1,2,3 of O (12.5ml-12.5ml), and 4-tetrahydrochysene-isoquinoline hydrochloride (embodiment 2b21a, 1.16g, 5.1mmol), Et 3N (0.71ml, 5.1mmol), (1.12g 5.40mmol) stirs 18 hours to the bicarbonate di tert butyl carbonate, concentrates in a vacuum then.Residue is dissolved in EtOAc (100ml), and uses H 2O (50ml) and saline (50ml) flushing.At Na 2SO 4Go up dry organic facies, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain white solid title compound (1.05g, 75%): t R=2.75min (LC-B); MS (cation): m/z 292.4[M+H] +
2b21c) 8-bromo-2-tert-butoxycarbonyl-5-propoxyl group-1,2,3, the 4-tetrahydroisoquinoline
According to the mode that is similar to the described method of embodiment 2b15b, but use 2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin (embodiment 2b21b) replaces 5-propoxyl group-1,2,3, and 4-tetrahydrochysene-naphthalene obtains title compound: t R=2.97min (LC-B).
2b21d) 2-tert-butoxycarbonyl-8-formoxyl-5-propoxyl group-1,2,3, the 4-tetrahydroisoquinoline
According to the mode of the method that is similar to embodiment 2b19c, but use 8-bromo-2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydroisoquinoline (embodiment 2b21c) replaces 8-bromo-5-propoxyl group-isoquinolin, obtains title compound: t R=2.63min (LC-B); MS (cation): m/z 320.3[M+H] +
2b22) 2,3-dimethyl-4-ethanesulfonyloxy group benzaldehyde
Under 0 ℃, to being dissolved in CH 2Cl 2(30ml) 2,3-dimethyl-4-hydroxy benzaldehyde (embodiment 2b1b, 1g, 6.7mmol) and Et 3(4.5ml dropwise adds the second chlorosulfuric acid to N in solution 32.6mmol).Reactant mixture is warmed to room temperature.After 2 hours, use CH 2Cl 2(50ml) washing reaction mixture.(2 * 30ml) wash resulting organic facies continuously, at MgSO to use 1N NaOH aqueous solution (30ml), water then 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain colorless oil title compound (1.50g, 80%): t R=6.04min (LC-A); MS (cation): m/z 243.3[M+H] +
2b23) 2,4-dipropoxy-benzaldehyde
To being dissolved in 2 of dry DMF (2ml), (300mg, 2.2mmol add K in solution Acros) to 4-dihydroxy-benzaldehyde 2CO 3(913mg, 6.6mmol).At room temperature stirred this mixture 10 minutes, and adding 1-N-Propyl Bromide (454 μ l, 5mmol).Under 60 ℃ with this mixture heated a whole night.After being cooled to room temperature, use H 2This mixture of O (10ml) eluting, and use EtOAc (3 * 10ml) extractions.Use H 2O (2 * 20ml), the blended organic facies of saline (20ml) washing, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow solid shape title compound (412mg, 84%): t R=1.13min (LC-C); MS (cation): m/z 223.1[M+H] +
2b24) 2, the preparation of 6-dipropoxy-pyridine-3-aldehyde
2b24a) 2,6-dipropoxy-pyridine
Under 0 ℃ with sodium hydride (1.08g, 27.0mmol) dropwise join the normal propyl alcohol that is dissolved in dry DMF (8ml) (2.03ml, 27.0mmol) in.Then this reactant mixture is warmed to room temperature.After keeping 30 minutes under this temperature, add and be dissolved in 2 of DMF (5ml), the 6-dichloropyridine (1g, 6.8mmol) and with reactant mixture be heated to 100 ℃ 1 hour 30 minutes.After the cooling, use H 2O (50ml) dilution, (3 * 50ml) extract this reactant mixture to use EtOAc.Use H 2O (2 * 50ml), saline (2 * 20ml) washing blended organic facies, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light brown oily title compound: t R=1.15min (LC-C); MS (cation): m/z 196.6[M+H] +, this chemical compound is directly used in next step, and need not to be further purified.
2b24b) 2,6-dipropoxy-pyridine-3-aldehyde
Under 0 ℃, to dry DMF (1.03ml, 13.3mmol) dropwise add phosphoryl chloride phosphorus oxychloride (1.22ml, 13.3mmol).Then reactant mixture is warmed to room temperature.After 30 minutes, dropwise adding is dissolved in 2 of DMF (3ml), 6-dipropoxy-pyridine (embodiment 2b24a) solution.Then reactant mixture is heated to 70 ℃ 1 hour 30 minutes, and at room temperature stir a whole night, pour into then in the 2N NaOH aqueous solution (25ml).So EtOAc (50ml) extraction water solution.Use H 2O (2 * 25ml), (2 * 25ml) wash resulting water to saline, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain yellow oily title compound (230mg, 15%): t R=1.17min (LC-C); MS (cation): m/z 224.0[M+H] +
2b25) 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde
To be dissolved in anhydrous acetonitrile (300ml) according to Nielsen S.F. etc., J.Med.Chem.1998, the 3-methyl-2 of the described method preparation of 4819-4832, (9.2g 60.4mmol) adds K to the 4-4-dihydroxy benzaldehyde in the solution 2CO 3(8.76g, 63.5mmol).At room temperature stirred this mixture 10 minutes, and adding 1-N-Propyl Bromide (11.0ml, 121mmol).Heated this reactant mixture 60 hours down at 50 ℃.After being cooled to room temperature, will evaporate volatile matter in a vacuum.Use H 2O (200ml) dilutes resulting residue, and by 1N HCl aqueous solution pH value of aqueous solution is adjusted to 1.(2 * 200ml) use this mixture of extraction to EtOAc then.Use H 2O (2 * 50ml), saline (2 * 50ml) washing blended organic facies, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow solid shape title compound (8.34g, 85%): t R=7.26min (LC-A); MS (cation): m/z 195.3[M+H] +MS (anion): m/z 193.2[M-H] -
2b26) 2-methoxyl group-3-methyl-4-propoxyl group-benzaldehyde
(embodiment 2b25,400mg 2.06mmol) add K in the solution to the 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde that is dissolved in dry DMF (6ml) 2CO 3(427mg, 3.09mmol).At room temperature stirred this mixture then 10 hours, add then iodomethane (193 μ l, 3.09mmol).At room temperature stir this mixture 3 hours, and use H 2CH is used in O (40ml) dilution then 2Cl 2(3 * 20ml) extractions.Use H 2O (2 * 20ml), the blended organic facies of saline (20ml) washing, at MgSO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow oily title compound (332mg, 77%): t R=6.92min (LC-A); MS (cation): m/z 209.4[M+H] +
2b27) 3-methyl-2,4-dipropoxy-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b23, but use according to Nielsen S.F. etc., J.Med.Chem.1998, the 3-methyl-2 of the described method preparation of 4819-4832, the 4-4-dihydroxy benzaldehyde replaces 2, and 4-dihydroxy-benzaldehyde obtains title compound: t R=7.76min (LC-A); MS (cation): m/z 237.4[M+H] +
2b28) 2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use 1-bromo-2-methoxyl group-ethane to replace the 1-N-Propyl Bromide, obtain title compound: t R=6.90min (LC-A); MS (cation): m/z 253.3[M+H] +
2b29) the preparation of 2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde
2b29a) 2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use (2-bromine methoxyl group)-tert-butyl group-dimethylsilane to replace the 1-N-Propyl Bromide, obtain title compound: t R=9.15min (LC-A); MS (cation): m/z 353.6[M+H] +
2b29b) 2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b12b, but use 2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b29a) replacement 4-[2-(tert-butyl group-dimethyl-silicon alcoxyl base)-ethyoxyl]-the 3-tolyl aldehyde, obtain title compound: t R=6.06min (LC-A); MS (cation): m/z 239.3[M+H] +
2b30) the preparation 2b30a of 2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde) 2-[3-(tert-butyl group-dimethyl-silicon alkoxyl)-propoxyl group]-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use (3-bromine propoxyl group)-tert-butyl group-dimethylsilane to replace the 1-N-Propyl Bromide, obtain title compound: t R=3.24min (LC-B); MS (cation): m/z 367.2[M+H] +
2b30b) 2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b12b, but use 2-[3-(tert-butyl group-dimethyl-silicon alkoxyl)-propoxyl group]-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b30a) replacement 4-[2-(tert-butyl group-dimethyl-silicon alcoxyl base)-ethyoxyl]-the 3-tolyl aldehyde, obtain title compound: t R=6.14min (LC-A); MS (cation): m/z 253.2[M+H] +
2b31) 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use 4-brombutyl acetas to replace the 1-N-Propyl Bromide, obtain title compound: t R=2.46min (LC-B); MS (cation): m/z 331.3[M+Na] +
2b32) 2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-benzaldehyde
To the 2-that is dissolved in THF (2ml) (4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b31,200mg, add in being dissolved in 0.65mmol) 2N LiOH aqueous solution (648 μ l, 1.3mmol).At room temperature stirred reaction mixture is 12 hours, heats 3 hours down at 60 ℃, is cooled to room temperature then.Use after the 1N HCl acidified aqueous solution, use H 2O (1Oml) washing reaction mixture, and use EtOAc (10ml) extraction.Use H 2O (1 * 10ml), (2 * 10ml) wash this organic facies to saline, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow oily title compound (124mg, 72%): t R=2.15min (LC-B); MS (cation): m/z 289.1[M+Na] +
2b33) (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl acetate
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use bromoacetate to replace the 1-N-Propyl Bromide, obtain title compound: t R=7.00min (LC-A); MS (cation): m/z 281.3[M+H] +
2b34) (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetic acid
According to the mode that is similar to the described method of embodiment 2b32; but use (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl acetate (embodiment 2b33) to replace 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtain title compound: t R=6.00min (LC-A); MS (cation): m/z 253.3[M+H] +MS (anion): m/z 251.3[M-H] -
2b35) 2-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetamide
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use the 2-acetbromamide to replace the 1-N-Propyl Bromide, obtain title compound: t R=1.95min (LC-B); MS (cation): m/z 274.3[M+Na] +
2b36) 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate.
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use ethyl 4-bromobutanoate to replace the 1-N-Propyl Bromide, obtain title compound: t R=2.56min (LC-A); MS (cation): m/z 331.2[M+Na] +
2b37) 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid
According to the mode that is similar to the described method of embodiment 2b32; but use 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate. (embodiment 2b36) to replace 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtain title compound: t R=2.16min (LC-B); MS (cation): m/z 303.2[M+Na] +MS (anion): m/z 279.3[M-H] -
2b38) 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid acetamide
To the 4-that is dissolved in dry DMF (0.5ml) (6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid (embodiment 2b37,50mg, add continuously in solution 0.18mmol) DIPEA (122 μ l, 0.71mmol) and HATU (71mg, 0.19mmol).After 10 minutes, (18mg 0.22mmol), and stirs a whole night with reactant mixture to add ethylamine hydrochloride.Use H then 2O (10ml) diluted reaction mixture, and use EtOAc (10ml) extraction.Use H 2O (1 * 10ml), (2 * 5ml) wash this organic facies to saline, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow oily title compound (124mg, 72%): t R=2.18min (LC-B); MS (cation): m/z 308.2[M+H] +
2b39) 3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b38, but use morpholino, obtain title compound: t for ethylamine hydrochloride R=2.22min (LC-B); MS (cation): m/z 372.2[M+Na] +
2b40) 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl valerate
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use ethyl 5-bromine valerate to replace the 1-N-Propyl Bromide, obtain title compound: t R=2.62min (LC-B); MS (cation): m/z 345.2[M+Na] +
2b41) 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid
According to the mode that is similar to the described method of embodiment 2b32; but use 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl valerate (embodiment 2b40) to replace 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtain title compound: t R=2.27min (LC-B); MS (cation): m/z 317.1[M+Na] +
2b42) 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid acetamide
According to the mode that is similar to the described method of embodiment 2b38; but use 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid (embodiment 2b41) to replace 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid, obtain title compound: t R=2.24min (LC-B); MS (cation): m/z 322.2[M+H] +
2b43) 3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b38; but use 5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid (embodiment 2b41) to replace 4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid; and use morpholino for ethylamine hydrochloride, obtain title compound: t R=2.24min (LC-B); MS (cation): m/z 386.2[M+Na] +
2b44) 2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde hydrochlorate
(embodiment 2b25,200mg 1.0mmol) add K continuously in the solution to the 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde that is dissolved in dry DMF (3ml) 2CO 3(356mg, 2.58mmol), potassium iodide (17mg, 0.1mmol) and (2-chloro-ethyl)-dimethyl-amine hydrochlorate (163mg, 1.10mmol).60 ℃ of following heating with this mixture-whole night.After being cooled to room temperature, use H 2This mixture of O (10ml) eluting, and use EtOAc (2 * 100ml) extractions.Use H 2O (2 * 5ml), saline (2 * 5ml) washing blended organic facies, at Na 2SO 4Last dry, filter and concentrate.Use thin layer chromatography, on silica gel.Use CH 2Cl 2/ MeOH/Et 3N 100/10/1 obtains light yellow oily 2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde (139mg, 50%) as eluent.
To being dissolved in 1, (139mg, adding is dissolved in 1,4-dioxane (0.20ml, 4N HCl solution 0.8mmol) to the 2-of 4-dioxane (2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde in solution 0.52mmol).Evaporate volatile matter then in a vacuum, obtain brown solid shape title compound (159mg, 100%): t R=0.99min, 4.44min (LC-A); MS (cation): m/z 266.2[M+H] +
2b45) 3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-benzaldehyde hydrochlorate
According to the mode that is similar to the described method of embodiment 2b44, but use 4-(2-chloro-ethyl)-morpholine hydrochloride to replace (2-chloro-ethyl)-dimethyl-amine hydrochlorate, obtain title compound: t R=0.37min, 1.52min (LC-B); MS (cation): m/z 308.2[M+H] +MS (anion): m/z 306.3[M-H] -
2b46) 3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-benzaldehyde hydrochlorate
According to the mode that is similar to the described method of embodiment 2b44, but use 1-(2-chloro-ethyl)-piperidine hydrochlorate to replace (2-chloro-ethyl)-dimethyl-amine hydrochlorate, obtain title compound: Method B t R=0.36min, 1.56min (LC-B); MS (cation): m/z 306.3[M+H] +
2b47) 2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde hydrochlorate
According to the mode that is similar to the described method of embodiment 2b44, but use (3-chloro-propyl group)-dimethyl-amine hydrochlorate to replace (2-chloro-ethyl)-dimethyl-amine hydrochlorate, obtain title compound: method B t R=0.37min, 1.58min (LC-B); MS (cation): m/z 280.3[M+H] +
2b48) 2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde
(embodiment 2b25,400mg 2.1mmol) add K continuously in the solution to the 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde that is dissolved in dry DMF (4ml) 2CO 3(427mg, 3.09mmol), potassium iodide (35mg, 0.21mmol) and 2,2-dimethyl-1,3-dioxolanes-4-ylmethyl p-toluenesulfonic esters (650mg, 2.27mmol).Under 90 ℃, this reactant mixture is heated a whole night.After being cooled to room temperature, use this mixture of eluting H 2O (20ml), and use extraction EtOAc (2 * 30ml).Use the blended organic facies H of washing 2O (2 * 10ml), saline (2 * 10ml), at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow oily title compound (340mg, 54%): t R=2.51min (LC-B); MS (cation): m/z 331.2[M+Na] +
2b49) 2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b48, but use (4S)-2,2-dimethyl-1,3-dioxolanes-4-ylmethyl p-toluenesulfonic esters replaces 2,2-dimethyl-1,3-dioxolanes-4-ylmethyl p-toluenesulfonic esters obtains title compound: t R=2.45 (LC-B); MS (cation): m/z 331.2[M+Na] +
2b50) 2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde
According to the mode that is similar to the described method of embodiment 2b48, but use (4R)-2,2-dimethyl-1,3-dioxolanes-4-ylmethyl p-toluenesulfonic esters replaces 2,2-dimethyl-1,3-dioxolanes-4-ylmethyl p-toluenesulfonic esters obtains title compound: t R=2.46 (LC-B); MS (cation): m/z 331.2[M+Na] +
2b51) the preparation of (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.
2b51a) (3R)-3-(tert-butyl group-dimethyl-silicon alcoxyl base)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate.
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use according to Hareau G.P-J. etc., J.Am.Chem.Soc.1999, ethyl (3R)-3-(tert-butyl group-dimethyl-silicon the alkoxyl)-4-iodo-butyrate of the described method preparation of 3640-3650 replaces the 1-N-Propyl Bromide, obtains title compound: t R=3.15min (LC-B); MS (cation): m/z 461.4[M+Na] +
2b51b) (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.
At room temperature; to (the 3R)-3-that is dissolved in THF (0.8ml) (tert-butyl group dimethyl siloxy)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate. (embodiment 2b51a; 200mg; 0.46mmol) add in the solution and be dissolved in THF (684 μ l, 1M TBAF solution 0.68mmol).Then reactant mixture is stirred a whole night, and use H 2O (15ml) dilution.Use after EtOAc (25ml) extraction, use H 2O (2 * 5ml), saline (2 * 5ml) flushing organic faciess, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain light yellow oily title compound (78mg, 53%): t R=2.24min (LC-B); MS (cation): m/z 347.3[M+Na] +
2b52) (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid
According to the mode that is similar to the described method of embodiment 2b32; but use (3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate. (embodiment 2b51b) to replace 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtain title compound: t R=1.96min (LC-B); MS (cation): m/z 319.2[M+Na] +MS (anion): m/z 295.2[M-H] -
2b53) the preparation of (3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.
2b53a) (3S)-3-(tert-butyl group-dimethyl-silicon alcoxyl base)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate.
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde) (embodiment 2b25) replacement 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use (3S)-3-(tert-butyl group-dimethyl-silicon alcoxyl base)-4-bromo-butyric acid ethyl ester to replace the 1-N-Propyl Bromide, obtain title compound: t R=3.19min (LC-B); MS (cation): m/z 461.4[M+Na] +
2b53b) (3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.
According to the mode that is similar to the described method of embodiment 2b51b; but use ethyl (3S)-3-(tert-butyl group-dimethyl-silicon alcoxyl base)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butyrate (embodiment 2b53a) to replace ethyl (3R)-3-(tert-butyl group-dimethyl-silicon alcoxyl base)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butyrate, obtain title compound: t R=2.24min (LC-B); MS (cation): m/z 347.3[M+Na] +
2b54) (3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid
According to the mode that is similar to the described method of embodiment 2b32; but use (3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate. (embodiment 2b53b) to replace 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtain title compound: t R=2.33min (LC-B); MS (cation): m/z 319.2[M+Na] +MS (anion): m/z 295.2[M-H] -
2h55) (4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylate methyl ester
According to the mode that is similar to the described method of embodiment 2b1b, but use 2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b25) to replace 2,3-dimethyl-4-hydroxyl-benzaldehyde, and use methyl (4R, 5S)-5-mesyloxy methyl-2,2-dimethyl-1, the 3-dioxolanes-the 4-carboxylate (wherein, this chemical compound is according to Batsanov A.S. etc., J.Chem.Soc., PerkinTrans.1,1995,1281-1294 and Ortuno R.M. etc., Tetrahedron 1997, the described method of 2191-2198, with 2,3-O-isopropylidene-L-dimethyl tartrate is raw material in fact, in two steps prepared in reaction) replacement 1-N-Propyl Bromide, obtain title compound: t R=2.48min (LC-B); MS (cation): m/z 389.2[M+Na] +
2b56) (4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylic acid
According to the mode that is similar to the described method of embodiment 2b32; but use (4R; 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2; 2-dimethyl-[1; 3] dioxolanes-4-carboxylate methyl ester (embodiment 2b55) replaces 2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde, obtains title compound: t R=2.48min (LC-B); MS (anion): m/z 351.3[M-H] -
Embodiment 3 (R 1Be 4-ethoxy carbonyl phenyl)
3a) following product 3a1-3a7 prepares according to the mode that is similar to embodiment 1 described method, but use 4-(3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate (embodiment 3b2) replaces 1-phenyl-pyrazole alkane-3, the 5-diketone, and use different aldehyde respectively:
3a1) 4-(4-benzal-3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate uses benzaldehyde (Fluka) as initiation material: t R=6.73min (LC-A); MS (cation): m/z 337.3[M+H] +MS (anion): m/z 335.5[M-H] -
3a2) 4-[4-(2-hydroxyl-3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate, use 2-hydroxy 3-methoxybenzene formaldehyde (Acros) as initiation material: t R=6.34min (LC-A); MS (cation): m/z 383.3[M+H] +MS (anion): m/z 381.5[M-H] -
3a3) 4-[4-(2-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl]-ethyl benzoate, use 2-methoxybenzaldehyde (Acros) as initiation material: t R=6.77min (LC-A); MS (cation): m/z 367.3[M+H] +MS (anion): m/z 365.5[M-H] -
3a4) 4-[4-(3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl]-ethyl benzoate, use 3-methoxybenzaldehyde (Acros): MS (cation) as initiation material: t R=6.84min (LC-A); M/z 367.3[M+H] +MS (anion): m/z 365.5[M-H] -
3a5) 4-(3,5-dioxo-4-pyridin-3-yl methylene-pyrazolidine-1-yl)-ethyl benzoate uses 3-pyridine carboxaldehyde (Acros) as initiation material: t R=5.64min (LC-A); MS (cation): m/z 338.5[M+H] +MS (anion): m/z 336.5[M-H] -
3a6) 4-(3,5-dioxo-4-thiene-3-yl-methylene-pyrazolidine-1-yl)-ethyl benzoate uses 3-thio phenyl formaldehyde (Aldrich) as initiation material: t R=6.59min (LC-A); MS (cation): m/z 343.3[M+H] +MS (anion): m/z 341.5[M-H] -
3a7) 4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl]-ethyl benzoate, use 2,3-dimethyl-4-propoxyl group benzaldehyde (embodiment 2b1b) is as initiation material: t R=7.89min (LC-A); MS (cation): m/z 423.4[M+H] +MS (anion): m/z 421.6[M-H] -
3b) the preparation 3b1 of 4-(3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate) 4-[N '-(2-ethoxy carbonyl-acetyl group)-diazanyl] ethyl benzoate
At room temperature, at 10% Na 2CO 3Aqueous solution (100ml) and CH 2Cl 2In the mixture (200ml), with (4-diazanyl) ethyl benzoate ester hydrochloride (according to Coquet G. etc., Tetrahedron 2000 for 12g, 551.4mmol,, 56, the described method preparation of 2975-2984) stirring 15 minutes.Use CH 2Cl 2(the isolating aqueous solution of 3 * 200ml) extractions.At Na 2SO 4Last dry blended organic facies is filtered and is concentrated.Residue is dissolved in anhydrous THF (100ml) and adds Et 3N (8.11ml, 58.3mmol).Reactant mixture is cooled to-10 ℃ and dropwise add the ethyl malonyl chloride be dissolved in anhydrous THF (50ml) (7.12ml, 56.6mmol).Then reactant mixture is warmed to room temperature and stirs and spend the night.Use H 2O (100ml) washing reaction mixture, and use EtOAc (3 * 100ml) extractions.Use H 2O (100ml), the blended organic facies of saline (100ml) washing are at Na 2SO 4Last dry, filter and concentrate, obtain the brown residue (16.3g) of crude product title compound: t R=5.34min (LC-A); MS (cation): m/z 295.1[M+H] +MS (anion): m/z 293.3[M-H] -
3b2) 4-(3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate
With crude product 4-[N '-(2-ethoxy carbonyl-acetyl group)-diazanyl] and ethyl benzoate (embodiment 3b1 16.3g) is dissolved in EtOH (100ml), and the alcoholic solution of adding 1N NaOH (110ml, 110mmol).Stirred reaction mixture 30 minutes at room temperature then.Then by adding this reactant mixture of 1N HCl acidified aqueous solution.Collect formed precipitation by filtering, use H 2(3 * 20ml) washings on sintered glass, carry out drying in a vacuum, obtain Off-white solid shape title compound (8.27g, 60%): t to O R=4.50min (LC-A); MS (cation): m/z 249.2[M+H] +MS (anion): m/z 247.3[M-H] -
Embodiment 4 (R 1Be the 2-pyridine radicals)
4a) following product 4a1 and 4a2 prepare according to being similar to the following mode of embodiment 1 described side, but use 1-pyridine-2-base-pyrazolidine-3, and 5-diketone (embodiment 4b2) replaces 1-phenyl-pyrazole alkane-3, the 5-diketone, and use different aldehyde respectively:
4a1) 4-(3-methyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone uses 3-methyl-4-propoxyl group benzaldehyde (embodiment 2b3) as initiation material: t R=7.30min (LC-A); MS (cation): m/z 338.3[M+H] +MS (anion): m/z 336.3[M-H] -
4a2) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone uses 2, and 3-dimethyl-4-propoxyl group benzaldehyde (embodiment 2b1b) is as initiation material: t R=7.44min (LC-A); MS (cation): m/z 352.2[M+H] +MS (anion): m/z 350.3[M-H] -
4b) 1-pyridine-2-base-pyrazolidine-3, the preparation of 5-diketone
4b1) (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate
To be cooled to-10 ℃ the 2-hydrazino pyridine that is dissolved in anhydrous THF (30ml) (2.0g, 18.3mmol) and Et 3N (2.68ml, dropwise add in solution 19.2mmol) the ethyl malonyl chloride (2.35ml, 18.7mmol).Then reactant mixture is warmed to room temperature and stirs and spend the night.Use H 2O (20ml) washing reaction mixture, and use EtOAc (2 * 20ml) extractions.Use the blended organic facies of saline (20ml) washing, at Na 2SO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain brown solid shape title compound (2.11g, 52%): t R=0.98min (LC-A); MS (cation): m/z 224.5[M+H] +MS (anion): m/z 222.5[M-H] -
4b2) 1-pyridine-2-base-pyrazolidine-3, the 5-diketone
Will (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate (embodiment 4b1,1.0g, 4.48mmol) be dissolved in 1N NaOH alcoholic solution (9ml, 9mmol) in.At room temperature stir this reactant mixture 30 minutes, and used the AcOH acidify, use H then 2O (20ml) dilution, and use CH 2Cl 2(2 * 30ml) extractions.Use H 2O (30ml) washs blended organic facies, at Na 2SO 4Last dry, filter and concentrate, obtain yellow solid shape title compound (500mg, 63%): t R=2.26min (LC-A); MS (cation): m/z 178.2[M+H] +MS (anion): m/z 176.3[M-H] -
Embodiment 5 (R 1Be the 4-bromophenyl)
5a) 1-(4-bromo-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to embodiment 1 described method, but use 1-(4-bromo-phenyl)-pyrazolidine-3,5-diketone (embodiment 5b2) replaces 1-phenyl-pyrazole alkane-3, and the 5-diketone obtains title compound: t R=7.95min (LC-A); MS (cation): m/z 429.3,431.2[M+H] +MS (anion): m/z 427.5,429.4[M-H] -
5b) 1-(4-bromo-phenyl)-pyrazolidine-3, the preparation of 5-diketone
5b1) ethyl [N '-(4-bromo-phenyl)-diazanyl carbonyl]-acetas
According to the mode that is similar to the described method of embodiment 4b1, but use 4-bromophenyl hydrazonium salt hydrochlorate to replace the 2-hydrazino pyridine, obtain title compound: t R=5.53min (LC-A); MS (cation): m/z 301.0,303.1[M+H] +MS (anion): m/z 299.1,301.2[M-H] -
5b2) 1-(4-bromo-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 3b2, but the use ethyl [N '-(4-bromo-phenyl)-diazanyl carbonyl]-acetas (embodiment 5b1) replacement 4-[N '-(2-ethoxy carbonyl-acetyl group)-diazanyl] ethyl benzoate, obtain title compound: t R=4.96min (LC-A); MS (cation): m/z 255.3,257.3[M+H] +MS (anion): m/z 253.4,255.4[M-H] -
Embodiment 6 (R 1Be the 4-methoxyphenyl)
6a) 1-(4-methoxyl group-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to embodiment 1 described method, but use 1-(4-methoxyl group-phenyl)-pyrazolidine-3,5-diketone (embodiment 6b2) replaces 1-phenyl-pyrazole alkane-3, and the 5-diketone obtains title compound: t R=7.22min (LC-A); MS (cation): m/z 381.4[M+H] +MS (anion): m/z 379.6[M-H] -
6b) 1-(4-methoxyl group-phenyl)-pyrazolidine-3, the preparation of 5-diketone
6b1) [N '-(4-methoxyl group-phenyl)-diazanyl carbonyl]-ethyl acetate
According to the mode that is similar to the described method of embodiment 4b1, but use 4-methoxyphenyl hydrazonium salt hydrochlorate to replace the 2-hydrazino pyridine, obtain title compound: MS (cation): m/z 253.1[M+H] +
6b2) 1-(4-methoxyl group-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 4b2, but use [N '-(4-methoxyl group-phenyl)-diazanyl carbonyl]-ethyl acetate (embodiment 6b1) replacement (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate, obtain title compound: t R=3.85min (LC-A); MS (cation): m/z 206.9[M+H] +
Embodiment 7 (R 1Be the 4-cyano-phenyl)
7a) 4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] phenylcyanide
According to the mode that is similar to embodiment 1 described method, but use 4-(3,5-dioxo-pyrazolidine-1-yl) phenylcyanide (embodiment 7b2) to replace 1-phenyl-pyrazole alkane-3, the 5-diketone obtains title compound: t R=7.58min (LC-A); MS (cation): m/z 376.4[M+H] +MS (anion): m/z 374.6[M-H] -
7b) the preparation of 4-(3,5-dioxo-pyrazolidine-1-yl) phenylcyanide
7b1) [N '-(4-cyano group-phenyl)-diazanyl carbonyl]-ethyl acetate
According to the mode that is similar to the described method of embodiment 4b1, but use 4-cyano-phenyl hydrazonium salt hydrochlorate to replace the 2-hydrazino pyridine, obtain title compound: t R=4.67min (LC-A); MS (cation): m/z 247.8[M+H] +MS (anion): m/z 245.9[M-H] -
7b2) 4-(3,5-dioxo-pyrazolidine-1-yl) phenylcyanide
According to the mode that is similar to the described method of embodiment 4b2, but use [N '-(4-cyano group-phenyl)-diazanyl carbonyl]-ethyl acetate (embodiment 7b1) replacement (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate, obtain title compound: t R=4.17min (LC-A); MS (cation): m/z 201.9[M+H] +MS (anion): m/z 199.9[M-H] -
Embodiment 8 (R 1Be the 4-fluorophenyl)
8a) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to embodiment 1 described method, but use 1-(4-fluoro-phenyl)-pyrazolidine-3,5-diketone (embodiment 8b2) replaces 1-phenyl-pyrazole alkane-3, and the 5-diketone obtains title compound: t R=7.51min (LC-A); MS (cation): m/z 369.4[M+H] +MS (anion): m/z 367.6[M-H] -
8b) 1-(4-fluoro-phenyl)-pyrazolidine-3, the preparation of 5-diketone
8b1) [N '-(4-fluoro-phenyl)-diazanyl carbonyl]-ethyl acetate
According to the mode that is similar to the described method of embodiment 4b1, but use 4-fluorophenyl hydrazonium salt hydrochlorate to replace the 2-hydrazino pyridine, obtain title compound: t R=4.55min (LC-A); MS (anion): m/z 238.9[M-H] -
8b2) 1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 4b2, but use [N '-(4-fluoro-phenyl)-diazanyl carbonyl]-ethyl acetate (embodiment 8b1) replacement (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate, obtain title compound: t R=3.93min (LC-A); MS (cation): m/z 195.0[M+H] +MS (anion): m/z 193.0[M-H] -
Embodiment 9 (R 1Be the 4-aminomethyl phenyl)
9a) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to embodiment 1 described method, but use 1-(4-methyl-phenyl)-pyrazolidine-3,5-diketone (embodiment 9b2) replaces 1-phenyl-pyrazole alkane-3, and the 5-diketone obtains title compound: t R=7.65min (LC-A); MS (cation): m/z 365.4[M+H] +MS (anion): m/z 363.6[M-H] -
9b) 1-(4-methyl-phenyl)-pyrazolidine-3, the preparation of 5-diketone
9b1) ethyl [N '-(4-methyl-phenyl)-diazanyl carbonyl]-acetas
According to the mode that is similar to the described method of embodiment 4b1, but use 4-methylphenylhydrazine hydrochlorate to replace the 2-hydrazino pyridine, obtain title compound: t R=5.18min (LC-A); MS (anion): m/z 235.0[M-H] -
9b2) 1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 4b2, but the use ethyl [N '-(4-methyl-phenyl)-diazanyl carbonyl]-acetas (embodiment 9b1) replacement (N '-pyridine-2-base-diazanyl carbonyl)-ethyl acetate, obtain title compound: t R=4.34min (LC-A); MS (cation): m/z 190.8[M+H] +MS (anion): m/z 188.9[M-H] -
Embodiment 10 (R 1Be the 2-chlorphenyl)
10a) 1-(2-chloro-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone
Under inert atmosphere, under refluxing, will be dissolved in 1-(2-chloro-phenyl)-pyrazolidine-3 of absolute ethanol (4ml), the 5-diketone (embodiment 10b, 64mg is 0.3mmol) with 2,3-dimethyl-4-propoxyl group benzaldehyde (embodiment 2b1,87mg, mixture heated 0.45mmol) 16 hours.After being cooled to room temperature, under vacuum, boil off solvent.By flash chromatography, on silica gel, use EtOAc/ heptane gradient elution, resulting residue is made with extra care, obtain orange red solid, shaped title compound (62mg, 54%): t R=7.16min (LC-A); MS (cation): m/z 385.4[M+H] +MS (anion): m/z 383.5[M-H] -
10b) 1-(2-chloro-phenyl)-pyrazolidine-3, the 5-diketone
In the Sodium ethylate that is dissolved in absolute ethanol (22ml) (42mmol) solution, add diethyl malonate (2.12ml, 14.0mmol) and 2-chlorphenyl hydrazonium salt hydrochlorate (2.5g, 14.0mmol).Volatile matter distillation thing immediately under atmospheric pressure, and 140 ℃ down further the resulting residues of heating to dry.After being cooled to room temperature, with residue water-soluble (50ml).(2 * 100ml) extractions are removed neutrals from aqueous solution by using ether.Is 1 by adding 1N HCl aqueous solution with aqueous phase as acidified to pH value.And (3 * 100ml) extract to use EtOAc.Use H 2O (50ml), the blended organic facies of saline (50ml) washing are at MgSO 4Last dry, filter and concentrate.By flash chromatography, on silica gel, use MeOH/CH 2Cl 2Gradient elution is made with extra care resulting residue, obtains light brown solid, shaped title compound (500mg, 17%): t R=3.48min (LC-A); MS (cation): m/z 211.1[M+H] +MS (anion): m/z 208.8[M-H] -
Embodiment 11 (R 1Be the 2-aminomethyl phenyl)
11a) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 10a, but use 1-(2-methyl-phenyl)-pyrazolidine-3,5-diketone (embodiment 11b) replaces 1-(2-chloro-phenyl)-pyrazolidine-3, and the 5-diketone obtains title compound: t R=7.16min (LC-A); MS (cation): m/z 365.5[M+H] +MS (anion): m/z 363.6[M-H] -
11b) 1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 10b, but use 2-methylphenylhydrazine hydrochlorate to replace 2-chlorphenyl hydrazonium salt hydrochlorate, obtain title compound: t R=3.45min (LC-A); MS (cation): m/z 191.3[M+H] +
Embodiment 12 (R 1Be H)
Following product 12a1-12a9 prepares according to the mode that is similar to embodiment 1 described method, but use pyrazolidine-3, (this chemical compound is according to Fritsch G. etc. to the 5-diketone, Arch.Pharm., Weinheim Ger.1986, the described method preparation of 70-78) replacement 1-phenyl-pyrazole alkane-3, the 5-diketone, and use different aldehyde respectively:
12a1) 4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone uses 2, and 3-dimethyl-4-propoxyl group benzaldehyde (embodiment 2b1b) is as initiation material: t R=5.91min (LC-A); MS (cation): m/z 275.4[M+H] +MS (anion): m/z 273.5[M-H] -
12a2) 4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-pyrazolidine-3, the 5-diketone uses 4-cyclopentyloxy-2, and 3-dimethyl-benzaldehyde (embodiment 2b14) is as initiation material: t R=6.29min (LC-A); MS (cation): m/z 301.5[M+H] +MS (anion): m/z 299.6[M-H] -
12a3) 4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone uses 4-propoxyl group-5,6,7, and 8-tetrahydrochysene-naphthalene-1-aldehyde (embodiment 2b15c) is as initiation material: t R=6.36min (LC-A); MS (cation): m/z 301.2[M+H] +MS (anion): m/z 299.3[M-H] -
12a4) 4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-pyrazolidine-3, the 5-diketone uses 2, and 3-dimethyl-4-penta-1-alkynyl-benzaldehyde (embodiment 2b16b) is as initiation material: t R=6.32min (LC-A); MS (cation): m/z 283.2[M+H] +MS (anion): m/z 281.3[M-H] -
12a5) 4-(2,3-dimethyl-4-amyl group-benzal)-pyrazolidine-3, the 5-diketone uses 2, and 3-dimethyl-4-amyl group-benzaldehyde (embodiment 2b16c) is as initiation material: t R=6.64min (LC-A); MS (cation): m/z 287.2[M+H] +MS (anion): m/z 285.3[M-H] -
12a6) 4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone uses 4-propoxyl group-1-naphthaldehyde (embodiment 2b17) as initiation material: t R=6.13min (LC-A); MS (cation): m/z 297.2[M+H] +MS (anion): m/z 295.3[M-H] -
12a7) 4-(7-propoxyl group-indane-4-methylene)-pyrazolidine-3, the 5-diketone uses 7-propoxyl group-indane-4-aldehyde (embodiment 2b18e) as initiation material: t R=6.11min (LC-A); MS (cation): m/z 287.3[M+H] +MS (anion): m/z 285.3[M-H] -
12a8) 4-(2-methoxyl group-3-methyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone uses 2-methoxyl group-3-methyl-4-propoxyl group-benzaldehyde (embodiment 2b26) as initiation material: t R=6.02min (LC-A); MS (cation): m/z 291.3[M+H] +MS (anion): m/z 289.4[M-H] -
12a9) 4-(3-methyl-2,4-dipropoxy-benzal)-pyrazolidine-3, the 5-diketone uses 3-methyl-2, and 4-dipropoxy-benzaldehyde (embodiment 2b27) is as initiation material: t R=6.59min (LC-A); MS (cation): m/z 319.3[M+H] +MS (anion): m/z 317.4[M-H] -
Embodiment 13 (R 1Be methyl)
13a) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-methyl-pyrazolidine-3, the 5-diketone
According to the mode that is similar to embodiment 1 described method, but use 1-methyl-pyrazolidine-3,5-diketone (embodiment 13b) replaces 1-phenyl-pyrazole alkane-3, and the 5-diketone obtains title compound: t R=6.15min (LC-A); MS (cation): m/z 289.5[M+H] +MS (anion): m/z 287.5[M-H] -
13b) 1-methyl-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 10b, but use methyl hydrazine to replace 2-chlorphenyl hydrazonium salt hydrochlorate, obtain title compound: t R=0.93min (LC-A); MS (cation): m/z 115.2[M+H] +MS (anion): m/z 113.3[M-H] -
Embodiment 14 (R 1Be the 4-pyridine radicals)
14a) 4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridin-4-yl-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 10a, but use 1-pyridin-4-yl-pyrazolidine-3,5-diketone (embodiment 14b) replaces 1-(2-chloro-phenyl)-pyrazolidine-3, and the 5-diketone obtains title compound: t R=5.56min (LC-A); MS (cation): m/z 352.5[M+H] +MS (anion): m/z 350.6[M-H] -
14b) 1-pyridin-4-yl-pyrazolidine-3, the 5-diketone
According to the mode that is similar to the described method of embodiment 10b, but (this chemical compound is according to Mann F.G. etc. to use 4-pyridine radicals hydrazonium salt hydrochlorate, J.Chem.Soc.1959, the described method preparation of 3830-3834) replacement 2-chlorphenyl hydrazonium salt hydrochlorate, title compound obtained: t R=0.93min (LC-A); MS (anion): m/z 176.4[M-H] -
15) 1-acetyl group-4-[1-(2,3-dimethyl-4-propoxyl group-phenyl)-methylene]-pyrazolidine-3, the 5-diketone
At room temperature, to be dissolved in the pyrazolidine-3 of acetic acid (1.5ml) and acetic anhydride (200 μ l), the 5-diketone (50mg, 0.5mmol is according to Fritsch G. etc., Arch.Pharm., Weinheim Ger.1986, the described method preparation of 70-78) and 2,3-dimethyl-4-propoxyl group benzaldehyde (embodiment 2b1b, 96mg, mixture 0.5mmol) stirred 3 days.Collect formed precipitation by filtering.Use H 2(2 * 4ml) wash this solid to O, and (2 * 4ml) wash, and dry in a vacuum, obtain yellow solid shape title compound (26mg, 16%): t to re-use ethanol R=6.87min (LC-A); MS (cation): m/z 317.3[M+H] +MS (anion): m/z 315.4[M-H] -
The NMR data of method selected are as follows.
Embodiment Chemical shift (δ), unit (ppm) Solvent
1 1.00 (t, 3H), 1.77 (m, 2H), 2.15 (s, 3H), 2.37 (s, 1.5H), 2.38 (s, 1.5H), 3.30 (br s, 1H is tradable), 4.04 (t, 2H), 6.92 (m, 1H), 7.15 (t, 1H), 7.38 (m, 2H), 7.69 (d, 2H), 8.08 (s, 0.5H), 8.15 (s, 0.5H), 8.73 (br s, 0.5H), 8.85 (d, 0.5H) DMSO-d 6
2a25 1.00(t，3H)，1.73(m，6H)，2.58(m，2H)，2.88(m，2H)， 4.04(t，2H)，6.85(m，1H)，7.15(t，1H)，7.40(m，2H)， 7.70(d，2H)，8.08(s，0.5H)，8.10(s，0.5H)，8.85(br s，0.5H)， 8.96(d，0.5H)，11.10(br s，1H) DMSO-d 6
2a34 1.00 (t, 3H), 1.04 (t, 3H), 1.80 (m, 4H), (3.30 br s, 1H is tradable), 4.08 (m, 4H), 6.60 (s, 1H), 6.70 (m, 1H), 7.15 (t, 1H), 7.40 (t, 2H), 7.70 (m, 2H), 8.20 (s, 0.4H), 8.25 (s, 0.6H), 9.25 (br s, 0.6H), 9.30 (d, 0.4H) DMSO-d 6
2a39 1.00 (t, 3H), 1.78 (m, 2H), 2.14 (s, 3H), 3.27 (s, 3H), (3.30 br s, 1H is tradable), 3.65 (m, 2H), 3.98 (m, 2H), 4.08 (t, 2H), 6.94 (m, 1H), 7.16 (t, 1H), 7.40 (t, 2H), 7.71 (m, 2H), 8.20 (s, 0.5H), 8.25 (s, 0.5H), 9.16 (br s, 0.5H), 9.24 (d, 0.5H) DMSO-d 6
2a40 1.04 (t, 3H), 1.80 (m, 2H), 2.13 (s, 3H), 3.30 (br s, 1H is tradable), 3.73 (m, 2H), 3.85 (m, 2H), 4.10 (t, 2H), 4.96 (t, 1H), 6.92 (m, 1H), 7.15 (t, 1H), 7.40 (t, 2H), 7.69 (m, 2H), 8.15 (s, 0.5H), 8.20 (s, 0.5H), 9.15 (br s, 0.5H), 9.23 (d, 0.5H) DMSO-d 6
2a41 1.00 (t, 3H), 1.79 (m, 2H), 1.96 (m, 2H), 2.10 (s, 3H), (3.30 br s, 1H is tradable), 3.65 (m, 2H), 3.88 (t, 2H), 4.12 (t, 2H), 4.54 (t, 1H), 7.00 (m, 1H), 7.15 (t, 1H), 7.42 (t, 2H), 7.69 (m, 2H), 8.08 (br s, 0.4H), 8.13 (br s, 0.6H), 9.20 (br s, 0.6H), 9.25 (d, 0.4H) DMSO-d 6
2a42 1.00(t，3H)，1.80(m，6H)，2.00(s，3H)，2.10(s，3H)， 3.85(m，2H)，4.10(m，4H)，6.95(m，1H)，7.20(t，1H)， 7.40(t，2H)，7.70(m，2H)，8.06(s，0.5H)，8.15(s，0.5H)， 9.12(br s，0.5H)，9.25(d，0.5H)，11.15(br s，1H) DMSO-d 6
2a43 1.00 (t, 3H), 1.65 (m, 2H), 1.80 (m, 4H), 2.12 (s, 3H), (3.30 br s, 1H is tradable), 3.44 (m, 2H), 3.80 (t, 2H), 4.08 (t, 2H), 4.42 (t, 1H), 6.96 (m, 1H), 7.20 (t, 1H), 7.40 (t, 2H), 7.69 (m, 2H), 8.08 (s, 0.5H), 8.13 (s, 0.5H), 9.20 (br s, 0.5H), 9.23 (d, 0.5H) DMSO-d 6
2a44 1.00 (t, 3H), 1.23 (t, 3H), 1.80 (m, 2H), 2.12 (s, 3H), (3.30 br s, 1H is tradable), 4.10 (t, 2H), 4.20 (q, 2H), 4.60 (s, 2H), 7.00 (m, 1H), 7.20 (t, 1H), 7.40 (t, 2H), 7.70 (m, 2H), 8.20 (s, 0.5H), 8.27 (s, 0.5H), 9.12 (br s, 0.5H), 9.23 (d, 0.5H) DMSO-d 6
2a46 1.00 (t, 3H), 1.80 (m, 2H), 2.13 (s, 3H), (3.30 br s, 1H is tradable), 4.10 (t, 2H), 4.20 (s, 2H), 7.00 (m, 1H), 7.17 (t, 1H), 7.40 (t, 2H), 7.50 (br s, 1H), 7.70 (m, 3H), 8.04 (br s, 0.5H), 8.08 (s, 0.5H), 9.09 (br s, 0.5H), 9.11 (d, 0.5H) DMSO-d 6
2a47 1.00(t，3H)，1.18(m，3H)，1.78(m，2H)，2.02(m，2H)， 2.10(s，3H)，2.55(t，2H)，3.30(br s，1H)，3.82(t，2H)， 4.04(m，4H)，6.98(m，1H)，7.17(t，1H)，7.40(t，2H)， 7.70(m，2H)，8.12(br s，1H)，9.18(br s，0.5H)，9.22(d， 0.5H) DMSO-d 6
2a48 1.00 (t, 3H), 1.73 (m, 2H), 2.00 (t, 2H), 2.10 (s, 3H), 2.50 (m, 2H), 3.30 (br s, 2H is tradable), 3.81 (t, 2H), 4.08 (t, 2H), 6.96 (m, 1H), 7.15 (t, 1H), 7.40 (t, 2H), 7.65 (m, 2H), 8.08 (s, 0.4H), 8.12 (s, 0.6H), 9.15 (br s, 0.6H), 9.27 (d, 0.4H) DMSO-d 6
2a51 1.00 (t, 3H), 1.16 (t, 3H), 1.78 (m, 6H), 2.08 (s, 3H), 2.35 (m, 2H), 3.30 (br s, 1H is tradable), 3.80 (m, 2H), 4,00 (q, 2H), 4.06 (t, 2H), 6.94 (m, 1H), 7.14 (t, 1H), 7.40 (t, 2H), 7.67 (m, 2H), 8.12 (br s, 1H), 9.18 (br s, 0.5H), 9.20 (d, 0.5H) DMSO-d 6
2a52 1.00 (t, 3H), 1.73 (m, 6H), 2.08 (s, 3H), 2.31 (t, 2H), 3.30 (br s, 2H is tradable), 3.80 (t, 2H), 4.08 (t, 2H), 6.92 (m, 1H), 7.12 (t, 1H), 7.40 (t, 2H), 7.65 (m, 2H), 8.04 (s, 0.4H), 8.12 (s, 0.6H), 9.12 (br s, 0.6H), 9.21 (d, 0.4H) DMSO-d 6
2a53 1.00(m，6H)，1.79(m，6H)，2.15(s，3H)，2.16(m，2H)， 3.05(m，2H)，3.80(t，2H)，4.10(t，2H)，7.00(m，1H)， 7.20(t，1H)，7.43(t，2H)，7.73(m，3H)，8.15(br s，1H)， 9.15(m，1H)，11.15(br s，1H) DMSO-d 6
2a54 1.00(t，3H)，1.78(m，6H)，2.08(s，3H)，2.40(t，2H)， 3.40(m，4H)，3.50(m，4H)，3.80(t，2H)，4.08(t，2H)， 6.94(m，1H)，7.14(t，1H)，7.40(t，2H)，7.70(m，2H)， 8.05(s，0.5H)，8.12(s，0.5H)，9.17(br s，0.5H)，9.20(d， 0.5H)，11.20(br s，1H) DMSO-d 6
2a64 1.00 (t, 3H), 1.80 (m, 2H), 2.12 (s, 3H), 2.60 (m, 1H), 2.80 (m, 1H), 3.30 (br s, 2H is tradable), 3.73 (d, 2H), 4.08 (t, 2H), 6.23 (m, 1H), 5.23 (br s, 1H), 7.00 (d, 1H), 7.20 (t, 1H), 7.40 (t, 2H), 7.70 (d, 2H), 8.20 (s, 1H), 9.20 (br s, 1H) DMSO-d 6
2a65 1.00 (t, 3H), 1.35 (s, 3H), 1.42 (s, 3H), 1.80 (m, 2H), 2.13 (s, 3H), 3.30 (br s, 2H is tradable), 4.00 (m, 2H), 4.12 (t, 2H), 4.42 (s, 2H), 7.00 (m, 1H), 7.16 (t, 1H), 7.40 (m, 2H), 7.70 (m, 2H), 8.20 (s, 0.5H), 8.23 (s, 0.5H), 8.12 (br s, 0.5H), 9.20 (d, 0.5H) DMSO-d 6
2a67 1.00(t，3H)，1.73(m，2H)，2.12(s，3H)，3.46(m，2H)， 3.73(m，1H)，3.81(m，2H)，4.08(t，2H)，4.62(t，1H)， 5.00(d，1H)，6.92(m，1H)，7.15(t，1H)，7.40(1，2H)， 7.65(d，2H)，8.15(s，0.5H)，8.23(s，0.5H)，9.12(br s，0.5H)， 9.21(d，0.5H)，11.10(br s，1H) DMSO-d 6
2a68 1.00(t，3H)，1.73(m，2H)，2.12(s，3H)，3.46(m，2H)， 3.73(m，1H)，3.81(m，2H)，4.08(t，2H)，4.62(t，1H)， 5.00(d，1H)，6.92(m，1H)，7.15(t，1H)，7.40(t，2H)， 7.65(d，2H)，8.15(s，0.5H)，8.23(s，0.5H)，9.12(br s，0.5H)， 9.21(d，0.5H)，11.10(br s，1H) DMSO-d 6
2a69 1.00(t，3H)，1.73(m，2H)，2.12(s，3H)，3.46(m，2H)， 3.73(m，1H)，3.81(m，2H)，4.08(t，2H)，4.62(t，1H)， 5.00(d，1H)，6.92(m，1H)，7.15(t，1H)，7.40(t，2H)， 7.65(d，2H)，8.15(s，0.5H)，8.23(s，0.5H)，9.12(br s，0.5H)， 9.21(d，0.5H)，11.10(br s，1H) DMSO-d 6
2a70 1.00(t，3H)，1.10(m，3H)，1.80(m，2H)，2.10(s，3H)， 3.70(m，1H)，3.95(m，1H)，4.10(m，4H)，4.20(m，1H)， 4.25(m，1H)，5.25(m，2H)，7.00(m，1H)，7.20(t，1H)， 7.40(t，2H)，7.70(m，2H)，8.20(br s，1H)，9.20(m，1H)， 11.10(br s，1H) DMSO-d 6
2a71 1.00 (t, 3H), 1.80 (m, 2H), 2.16 (s, 3H), (3.30 br s, 2H is tradable), 3.73 (m, 1H), 3.96 (m, 1H), 4.12 (t, 2H), 4.23 (s, 2H), 4.95 (br s, 1H), 5.20 (br s, 1H), 7.00 (m, 1H), 7.20 (t, 1H), 7.40 (t, 2H), 7.70 (m, 2H), 8.15 (s, 0.5H), 8.20 (s, 0.5H), 9.20 (br s, 0.5H), 9.21 (d, 0.5H) DMSO-d 6
2b1a 2.08(s，3H)，2.50(s，3H)，6.80(d，1H)，7.50(d，1H)， 10.0(s，1H)，10.35(br s，1H) DMSO-d 6
2b1b 1.08(t，3H)，1.85(m，2H)，2.20(s，3H)，2.60(s，3H)， 4.00(t，2H)，6.80(d，1H)，7.62(d，1H)，10.12(s，1H) CDCl 3
2b15c 1.08(t，3H)，1.77(m，6H)，2.65(m，2H)，3.15(m，2H)， 4.OO(t，2H)，6.73(d，1H)，7.58(d，1H)，10.08(s，1H) CDCl 3
2b16b 1.04(t，3H)，1.60(m，2H)，2.40(s，3H)，2.50(m，2H)， 2.54(s，3H)，7.37(d，1H)，7.60(d，1H)，10.25(s，1H) DMSO-d 6
2b16c 0.85(t，3H)，1.30(m，4H)，1.50(m，2H)，2.20(s，3H)， 2.54(s，3H)，2.65(m，2H)，7.20(d，1H)，7.54(d，1H) 10.20(s，1H) DMSO-d 6
2b17 1.20(t，3H)，2.00(m，2H)，4.20(t，2H)，6.90(d，1H)， 7.56(dd，1H)，7.70(dd，1H)，7.87(d，1H)，8.35(d，1H)， 9.27(d，1H)，10.20(s，1H) CDCl 3
2b18c 1.08(t，3H)，1.85(m，2H)，2.08(m，2H)，2.85(t，2H)， 2.96(t，2H)，4.00(t，2H)，6.65(d，1H)，6.85(d，1H)， 7.10(dd，1H) CDCl 3
2b18e 1.05(t，3H)，1.81(m，2H)，2.15(m，2H)，2.85(t，2H)， 3.27(t，2H)，4.00(t，2H)，6.77(d，1H)，7.60(d，1H)， 10.00(s，1H) CDCl 3
2b19a 1.10(t，3H)，1.95(m，2H)，4.05(t，2H)，6.95(d，1H)， 7.45(m，2H)，8.00(d，1H)，8.46(d，1H)，9.15(s，1H) CDCl 3
2b19c 1.20(t，3H)，2.04(m，2H)，4.20(t，2H)，7.04(d，1H)， 8.00(d，1H)，8.08(d，1H)，8.65(d，1H)，10.20(s，1H)， 10.57(s，1H) CDCl 3
2b20b 1.04(t，3H)，1.85(m，2H)，4.00(t，2H)，6.73(d，1H)， 7.20(d，1H)，7，42(m，2H)，8.40(d，1H)，9.50(s，1H) CDCl 3
2b21c 1.04(t，3H)，1.50(s，9H)，1.80(m，2H)，2.75(t，2H)， 3.60(t，2H)，3.90(t，2H)，4.50(s，2H)，6.60(d，1H)， 7.31(d，1H) CDCl 3
2b21d 1.06(t，3H)，1.50(s，9H)，1.85(m，2H)，2.80(t，2H)， 3.62(t，2H)，4.00(t，2H)，5.00(s，2H)，6.80(d，1H)， 7.62(d，1H)，10.00(s，1H) CDCl 3
2b23 1.00(t，3H)，1.06(t，3H)，1.82(m，4H)，3.92(t，2H)， 4.00(t，2H)，6.40(s，1H)，6.50(d，1H)，7.80(d，1H)， 10.30(s，1H) CDCl 3
2b25 1.06(t，3H)，1.85(m，2H)，2.12(s，3H)，4.00(t，2H)， 6.50(d，1H)，7.30(d，1H)，9.65(s，1H)，11.40(s，1H) CDCl 3
2b28 1.08(t，3H)，1.86(m，2H)，2.20(s，3H)，3.45(s，3H)， 3.75(m，2H)，4.00(t，2H)，4.08(m，2H)，6.71(d，1H)， 7.71(s，1H)，10.25(s，1H) CDCl 3
2b29b 1.10(t，3H)，1.65(br s，1H)，1.87(m，2H)，2.20(s，3H)， 4.00(m，6H)，6.69(d，1H)，7.62(d，1H)，10.06(s，1H) CDCl 3
2b32 1.08(t，3H)，1.60(br s，1H)，1.80(m，4H)，1.92(m，2H)， 2.15(s，3H)，3.73(t，2H)，3.92(t，2H)，4.00(t，2H)， 6.65(d，1H)，7.65(d，1H)，10.20(s，1H) CDCl 3
2b35 1.04(t，3H)，1.80(m，2H)，2.12(s，3H)，4.00(t，2H)， 4.31(s，2H)，6.60(br s，1H)，6.70(d，1H)，7.40(br s，1H)， 7.60(d，1H)，9.90(s，1H) CDCl 3
2b40 1.08(t，3H)，1.27(t，3H)，1.86(m，6H)，2.16(s，3H)， 2.39(m，2H)，3.90(m，2H)，4.00(t，2H)，4.12(q，2H)， 6.67(d，1H)，7.67(d，1H)，10.20(s，1H) CDCl 3
2b41 1.00(t，3H)，1.73(m，6H)，2.08(s，3H)，2.27(t，2H)， 3.85(t，2H)，4.04(t，2H)，6.88(d，1H)，7.58(d，1H)， 10.04(s，1H)，12.00(br s，1H) DMSO-d 6
2b54 1.00(t，3H)，1.80(m，3H)，2.10(s，3H)，2.70(m，2H)， 3.85(m，1H)，3.95(m，3H)，4.35(m，1H)，6.70(d，1H)， 7.50(s，1H)，9.80(s，1H) CDCl 3
11b 2.20(s，3H)，3.46(s，2H)，7.31(m，4H)，11.0(br s，1H) DMSO-d 6
12a1 1.00(t，3H)，1.73(m，2H)，2.13(s，3H)，2.38(s，3H)， 4.04(t，2H)，6.90(d，1H)，8.00(s，1H)，8.85(d，1H)， 10.29(br s，2H) DMSO-d 6
12a3 1.00(t，3H)，1.69(m，6H)，2.54(m，2H)，2.85(m，2H)， 4.00(t，2H)，6.85(d，1H)，7.96(s，1H)，8.92(d，1H)， 10.27(br s，2H) DMSO-d 6
Embodiment 16:P2Y 12Receptors bind is estimated
In 24 a holes-Tissue Culture Plate, cultivate and have human P2Y 12Chinese hamster ovary (CHO) cell that the recombinant of receptor is expressed.(1mM EDTA 0.5%BSA) washes cell three times for 50mM Tris pH7.4,100mMNaCl to use binding buffer liquid.(the 2-methyl-S-ADP) (100'000～300'000dpm/ hole) and the test compounds of variable concentrations are cultivated this cell to use 2-methyl-sulfo--adenosine 5 '-bisphosphate of the tritium-labelling that contains binding buffer liquid in 0.5ml/ hole then.After at room temperature cultivating 2 hours, use binding buffer liquid to wash this cell 3 times.Then, by adding 0.5ml solubilising buffer (SDS, NaOH, EDTA) with cell solutionization.Then the content in each hole is transferred in the beta counting bottle, and added Ultima Gold scintillation solution.The signal that pair cell is relevant carries out quantitatively, calculates the degree with respect to the inhibition of the inhibition of passing through the shown maximum possible of the excessive cold 2-methyl-S-ADP of adding then.
Embodiment 17: with platelet ADP receptor P2Y 12The test of bonded antagonist
Test by method mentioned above.In this test, the IC of formula I compound exhibits 50Value between about 0.001 and about 10 μ M between.The IC of preferred compound exhibits 50Value is lower than 1 μ M, the IC of particularly preferred compound exhibits 50Value is lower than 0.1 μ M, the IC of preferred compound exhibits 50Value is lower than 0.01 μ M.Exemplary IC 50Be worth as follows.
The chemical compound of embodiment IC 50(μM)
1 0.024
2a7 0.19
2a12 0.47
2a25 0.03
2a30 0.01
2a35 0.037
2a39 0.015
2a43 0.005
2a52 0.0016
2a63 0.001
2a64 0.0008
2a71 0.003
4a2 0.14
8a 0.083
12a3 0.055
12a9 0.04
15 9.6
The platelet aggregation that embodiment 18:ADP brings out
18a) the preparation of richness-hematoblastic blood plasma (PRP)
After must obtaining formal agreement, the sodium citrate of the final concentration of use 108mM is as anticoagulant, by obtaining blood from healthy volunteer's venipuncture.Under 20 ℃, under 160g, richness-hematoblastic blood plasma (PRP) was carried out centrifugalize 10 minutes.Under 5000g, the part centrifugal blood was separated 10 minutes, obtain poor-platelet blood plasma (PPP).
18b) the platelet aggregation brought out of ADP
At 37 times, the Chronolog fluorescence concentration class instrument that uses band to stir (900rpm) is measured platelet aggregation.PRP is put into cuvette, and 37 ℃ of following balances 2 minutes.In first stage, measure the accumulative ADP concentration that obtains optimum degree of the PRP of each donor.In second stage, used inhibitor hatching PRP down 2 minutes at 37 ℃, adding final concentration then is the antagonist ADP of 1～5 μ M.
In 5 minutes, monitor indicating the variation that continues the accumulative light absorption carried out.The degree of platelet aggregation is calculated in light absorption with respect to PRP (not assembling) and PPP (assembling fully).
Embodiment 19: functional test (FLIPR)
Under the control of cytomegalovirus promoter, in expression vector pcDNA3 (Invitrogen), stably express Chinese hamster ovary (CHO) cell of human P2Y12 receptor, under the mammalian cell condition of culture (37 ℃ and 5% carbon dioxide) of standard, grow near the point among Ham ' the s F-12 that is supplemented with 10% hyclone (making) by Switzerland Bioconcept company.Use is dissolved in phosphate ester buffer agent saline, and (PBS, 0.02%EDTA Gibco) handled cell 10 minutes, separate by puncture, and by collection in centrifugal 5 minutes under 200g, aforesaid operations at room temperature carried out all.At 37 ℃ and 5%CO 2Down, use is dissolved in estimates buffer (4 μ M Fluo-3,0.04% pluronic F-127 (being molecular probe), 5mM benemid (Sigma), 20mM HEPES (Gibco) hatching among the Hank ' sBSS of identical deal (HBSS, Bioconcept) and Ham ' s F-12) 1 hour.Washing of in-service evaluation buffer and resuspending are in estimating buffer then.50,000 cell transfer of 60 μ l are estimated in the plate (Gray receives) to 384-hole FLIPR, and deposited by centrifugalize.Stereotyped command operation FLIPR384 instrument (molecular device) according to manufacturer adds the chemical compound that is dissolved in the 10 μ l of DMSO with the concentration of 10mM, and be diluted to resulting ultimate density before the test of estimating buffer.Add the ADP solution of the 10 μ l that are dissolved in the evaluation buffer that is supplemented with bovine serum albumin (content of fatty acid＜0.02%, Sigma company makes) then, thereby obtain the ultimate density of 3 μ M and 0.1% respectively.During twice adding, write down fluorescent emission.
Embodiment 20: gelatin solution
With one of the chemical compound of the formula (III) described in the foregoing description (for example embodiment 8a) as active component and contain 2% cyclodextrin sterilization-filtering solution as solubilizing agent, under aseptic condition, under heating condition, mix as the sterilization gelatin solution of antiseptic with a kind of phenol that comprises, the solution of 1.0ml has following composition:
Active component 3mg
Gelatin 150.0mg
Phenol 4.7mg
Contain of the distillation of 20% cyclodextrin as solubilizing agent
1.0ml
Water
Embodiment 21: the sterilizing-drying material that is used to inject
One of formula (III) chemical compound described in 5mg the foregoing description (for example embodiment 12a1) is dissolved in containing in 20mg mannitol and the aqueous solution of 20% cyclodextrin as solubilizing agent of 1ml.This is dissolved in sterilization-misgivings, and under aseptic condition, it is joined in the ampoule of a 2ml, the degree of depth-solidify and lyophilizing.Before the use, lyophilized products is dissolved in 1ml distilled water or the 1ml physiological solt solution.This solution is by intramuscular injection or intravenous administration.Said preparation can also be put into a two-chamber injection ampoule.
Embodiment 22: thin film-sugar coated tablet
Following compositions is used to prepare the tablet of 10,000 each self-contained 100mg active component:
Active component 1000g
Corn starch 680g
Colloidal silica 200g
Magnesium stearate 20g
Stearic acid 50g
Carboxyl sodium methide starch 250g
Water is an amount of
Use a kind of starch paste of making by 250g corn starch and 2.2kg demineralization water to handle the mixture of one of the chemical compound of the general formula (III) described in the foregoing description (for example embodiment 4a2), thereby form a wet piece as active component, 50g rice starch and colloidal silica.Then with its pressurization by mesh size sieve of 3mm not, and under 45 ℃ in fluid-bed dryer dry 30 minutes.With this dried particles pressurization sieve that is 1mm by a mesh size, and mixes with pre-sieve (sieve of the 1mm) mixture of 330g corn starch, magnesium stearate, stearic acid and carboxyl sodium methide starch, and one of compression formation biconvex tablet a little.
Embodiment 23: soft capsule
Prepare 5000 soft capsules in the following manner, its one of chemical compound that comprises the general formula described in 0.05g the foregoing description (III) respectively is as active component:
Active component 250g
2 liters of lauroglycol 
Be suspended in the active component of being pulverized among the Lauroglykol  (propylene glycol laurate, Glattefoss é S.A., Saint Priest, France) and in wet crushing mill, pulverize to make the particle diameter of 1～3 μ m.Use capsule filling machine that the mixture of 0.42g part is joined in the Perle then.

Claims (33)

1. the purposes of the Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors of following general formula
Figure A2004800177170002C1
Wherein
R 1Be hydrogen, optional alkyl, cycloalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl or the alkanoyl that replaces; With
R 2Be aryl or heteroaryl;
And tautomer;
The tautomer of its geometric isomer and these geometric isomers comprises each formula (I) chemical compound or the mixture of its tautomer and geometric isomer or its tautomer;
The pharmaceutically-acceptable acid addition of alkali compounds;
Comprise the chemical compound of acidic-group and the pharmaceutically acceptable salt of alkali;
The pharmaceutically acceptable ester that comprises the chemical compound of hydroxyl or carboxyl;
The prodrug that wherein has the chemical compound of prodrug formation property group; And hydrate or solvate;
As be used to prevent and/or treat the peripheral vessel relevant, heart with platelet aggregation-, liver-and kidney-blood vessel, cardiovascular and cerebrovascular disease and disease, comprise thrombosis, and be used to make relative medicine, platelet adenosine diphosphate receptor antagonist.
2. purposes as claimed in claim 1, wherein R 1It is not alkanoyl.
3. purposes as claimed in claim 1 or 2, wherein this disease or disease are thrombosis.
4. as claim 1 or 3 described purposes, wherein R 1Be hydrogen, alkyl, aryl, heteroaryl or alkanoyl.
5. purposes as claimed in claim 4, wherein R 1Be hydrogen, alkyl, phenyl, bromophenyl, chlorphenyl, fluorophenyl, aminomethyl phenyl, methoxyphenyl, cyano-phenyl, alkoxycarbonylphenyl, pyridine radicals or alkanoyl.
6. purposes as claimed in claim 5, wherein R 1Be hydrogen, methyl, phenyl, 2-pyridine radicals, 4-pyridine radicals, 2-aminomethyl phenyl, 4-aminomethyl phenyl, 4-methoxyphenyl, 2-chlorphenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyano-phenyl, 4-ethoxy carbonyl phenyl or acetyl group.
7. as claim 1～6 times-described purposes, wherein R 2Be naphthyl, thienyl or pyridine radicals.
8. purposes as claimed in claim 7, wherein R 2Be naphthalene-2-base, pyridin-3-yl or thiene-3-yl-.
9. as each described purposes of claim 1～3, wherein this chemical compound is following general formula compound:
Comprise their geometric isomer and tautomer and composition thereof as claimed in claim 1, and their salt, ester and prodrug, wherein
R 1The definition as claim 1,2 and 4～6 each;
R 3Be hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy, cycloalkyl alkoxy or alkylsulfonyloxy;
R 4Be hydrogen, halogen, hydroxyl, alkyl or alkoxyl; With
R 5Be hydrogen, halogen, hydroxyl, alkyl, alkoxyl, the alkoxyl alkoxyl, the hydroxy alkoxy base, the dihydroxy alkoxyl, the alkanoyloxy alkoxyl, the carboxyl alkoxyl, carboxyl-hydroxy alkoxy base, carboxyl-dihydroxy alkoxyl, the alkoxy carbonyl alkoxyl, alkoxy carbonyl-hydroxy alkoxy base, alkoxy carbonyl-dihydroxy alkoxyl, the carbamoyl alkoxyl, N-alkyl-carbamoyl alkoxyl, N, N-dialkyl amido alkoxyl, morpholine-4-base alkoxyl, piperidines-1-base alkoxyl, morpholine-4-base carbonylic alkoxy, 2,2-dialkyl group [1,3] dioxolanes-4-base alkoxyl or 2,2-dialkyl group-4-carboxyl [1,3] dioxolanes-5-base alkoxyl; Or
R 4And R 5Form the carbocyclic ring or the heteroaryl ring system of a condensed optional replacement with the phenyl ring that they connected.
10. purposes as claimed in claim 9, wherein R 1It is not alkanoyl;
R 3Be hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy or cycloalkyl alkoxy; With
R 4And R 5Be hydrogen, halogen independently of one another, hydroxyl, alkyl or alkoxyl; Or
R 4And R 5, form the carbocyclic ring or the heteroaryl ring system of a condensed optional replacement with the phenyl ring that they connected.
11. as claim 9 or 10 described purposes, wherein R 3Be alkyl, thiazolinyl, alkynyl, alkoxyl, cycloalkyloxy, cycloalkyl alkoxy, hydroxy alkoxy base or alkoxyl alkoxyl, and R 4And R 5All be hydrogen, perhaps R 4Be halogen, alkyl or alkoxyl and R 5Be hydrogen, perhaps R 4And R 5Be alkyl or alkoxyl independently of one another.
12. purposes as claimed in claim 11, wherein R 3Be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, but-1-ene base, penta-1-thiazolinyl, fourth-1-alkynyl, penta-1-alkynyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, 3-methyl-butoxy, amoxy, cyclopentyloxy, hexyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, 2-hydroxyl-ethyoxyl, 2-methoxyl group-ethyoxyl, and R 4And R 5All be hydrogen, perhaps R 4Be chlorine, bromine, methyl or methoxy and R 5Be hydrogen, perhaps R 4And R 5Be methyl or methoxy independently of one another.
13. as claim 9 or 10 described purposes, wherein R 3Be hydrogen or alkoxyl and R 4With R 5Can form optional naphthalene, naphthane, indane, 1H-indenes, isoquinolin, dihydrobenzo [1,4] two oxines (dioxin dioxine) or benzo [1,3] Er Evil luxuriant (dioxolane dioxole) residue that replaces with the phenyl ring that they connected.
14. purposes as claimed in claim 13, wherein R 3Be propoxyl group and R 4With R 5Can form a naphthalene-1-base, indane-4-base, isoquinolin-5-base, isoquinolin-8-base, 1,2,3 with the phenyl ring that they connected, 4-tetrahydroisoquinoline-8-base, 2-alkoxy carbonyl-1,2,3,4-tetrahydroisoquinoline-8-base or 5,6,7,8-naphthane-1-base residue.
15. as claim 9 or 10 described purposes, wherein
R 3, R 4And R 5The hydrogen of respectively doing for oneself; Perhaps
R 3And R 5Hydrogen and R respectively do for oneself 4Be methoxyl group; Or
R 3And R 4Hydrogen and R respectively do for oneself 5Be methoxyl group; Or
R 4And R 5Hydrogen and R respectively do for oneself 3Be the tert-butyl group, ethyoxyl, propoxyl group or butoxy; Perhaps
R 3Be hydrogen, R 4Be methoxyl group, and R 5Be hydroxyl; Or
R 4Be hydrogen, R 3Be methoxyl group or propoxyl group and R 5Be methoxyl group or propoxyl group; Perhaps
R 5Be hydrogen, R 3Be methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, amoxy, hexyloxy, 3-methyl butoxy, 2-hydroxyl-oxethyl, 2-methoxy ethoxy, cyclo propyl methoxy or cyclobutyl methoxy base and R 4Be methyl, methoxyl group, chlorine or bromine.
16. as claim 9 or 10 described purposes, wherein
R 3Be methoxyl group, propoxyl group, cyclopentyloxy, penta-1-alkynyl or ethanesulfonyloxy group;
R 4Be methyl;
R 5Be hydroxyl, methyl, amyl group, methoxyl group, propoxyl group, the 2-methoxy ethoxy, the 2-hydroxyl-oxethyl, 3-hydroxyl propoxyl group, 4-hydroxyl butoxy, 2,3-dihydroxy propoxyl group, 4-acetoxyl group butoxy, the carboxyl methoxyl group, 3-carboxyl propoxyl group, 4-carboxyl butoxy, 3-carboxyl-2-hydroxyl propoxyl group, 3-carboxyl-2,3-dihydroxy propoxyl group, ethoxycarbonyl methoxy, 3-ethoxy carbonyl propoxyl group, 4-ethoxy carbonyl butoxy, 3-ethoxy carbonyl-2-hydroxyl propoxyl group, 3-ethoxy carbonyl-2,3-dihydroxy propoxyl group, carbamyl ylmethoxy 3-N-ethylamino formoxyl propoxyl group, 4-N-ethylamino formoxyl butoxy, 2-N, the N-dimethylamino ethoxy, 3-N, the N-dimethylamino propoxy, 2-(morpholine-4-yl)-ethyoxyl, 2-(piperidines-1-yl)-ethyoxyl, 3-(morpholine-4-yl)-carbonyl propoxyl group, 4-(morpholine-4-yl)-carbonyl butoxy, 2,2-dimethyl [1,3] dioxolanes-4-ylmethoxy or 2,2-dimethyl-4-carboxyl [1,3] dioxolanes-5-ylmethoxy; Or
R 4And R 5,, form a naphthalene-1-base, 5,6,7 with the phenyl ring that they connected, 8-naphthane-1-base, indane-4-base, 1,2,3,4 ,-four isoquinolin-8-base or 2-tert-butoxycarbonyl-1,2,3,4 ,-four isoquinolin-8-base residue.
17. as claim 1 or 3 described purposes, wherein said chemical compound is:
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-methoxyl group-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-3-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,4-dimethoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-naphthalene-2-methylene-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(the 4-tert-butyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-methoxyl group benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,4-dimethoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-bromo-4-methoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-butoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-ethyoxyl-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-butoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-hexyloxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-4-amoxy-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclobutyl methoxy base-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[3-methyl-4-(3-methyl-butoxy)-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-isobutoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[4-(2-methoxyl group-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-chloro-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[4-(2-hydroxyl-ethyoxyl)-3-methyl-benzal]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclo propyl methoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(7-propoxyl group-indane-4-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(8-propoxyl group-isoquinolin-5-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-ethanesulfonyloxy group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2,6-dipropoxy-pyridin-3-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2-hydroxy-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(2-methoxyl group-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-(3-methyl-2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(ethoxy carbonyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(carboxyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-amino-2-oxo-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-carboxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethylamino-4-oxo-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethoxy carbonyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-carboxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(5-ethylamino-5-oxo-amoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-ethoxy carbonyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3,5-diketone and formates thereof;
4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-2,3-dihydroxy-3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-3-carboxyl-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-benzal-3,5-dioxo-pyrazolidine-1-yl) ethyl benzoate;
4-[4-(2-hydroxyl-3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-[4-(2-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-[4-(3-methoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-(3,5-dioxo-4-pyridin-3-yl methylene-pyrazolidine-1-yl) ethyl benzoate;
4-(3,5-dioxo-4-thiene-3-yl-methylene-pyrazolidine-1-yl) ethyl benzoate;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate;
4-(3-methyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
1-(4-bromo-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methoxyl group-phenyl)-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] phenylcyanide;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
1-(2-chloro-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-(7-propoxyl group-indane-4-methylene)-pyrazolidine-3, the 5-diketone;
4-(2-methoxyl group-3-methyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(3-methyl-2,4-dipropoxy-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-methyl-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridin-4-yl-pyrazolidine-3, the 5-diketone;
1-acetyl group-4-[1-(2,3-dimethyl-4-propoxyl group-phenyl)-methylene]-pyrazolidine-3, the 5-diketone.
18. the chemical compound of following general formula:
Comprise their geometric isomer and tautomer and composition thereof as claimed in claim 1, and their salt, ester and prodrug, wherein
R 1The definition as claim 1,2 and 4～6 each;
R 3' be alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy, cycloalkyl alkoxy or alkylsulfonyloxy;
R 4' be halogen, hydroxyl, alkyl or alkoxyl; With
R 5' be halogen, hydroxyl, alkyl, alkoxyl, the alkoxyl alkoxyl, the hydroxy alkoxy base, the dihydroxy alkoxyl, the alkanoyloxy alkoxyl, the carboxyl alkoxyl, carboxyl-hydroxy alkoxy base, carboxyl-dihydroxy alkoxyl, the alkoxy carbonyl alkoxyl, alkoxy carbonyl-hydroxy alkoxy base, alkoxy carbonyl-dihydroxy alkoxyl, the carbamoyl alkoxyl, N-alkyl-carbamoyl alkoxyl, N, N-dialkyl amido alkoxyl, morpholine-4-base alkoxyl, piperidines-1-base alkoxyl, morpholine-4-base carbonylic alkoxy, 2,2-dialkyl group [1,3] dioxolanes-4-base alkoxyl or 2,2-dialkyl group-4-carboxyl [1,3] dioxolanes-5-base alkoxyl; Or
R 4' and R 5' phenyl ring-rise to form-individual condensed, optional carbocyclic ring or the heterocyclic ring system that replaces that is connected with them;
Condition is: R 1Be phenyl and R 3' be methoxyl group, R 4' and R 5' can not be methoxyl group simultaneously.
19. chemical compound as claimed in claim 18, wherein
R 1It is not alkanoyl;
R 3' be alkyl, thiazolinyl, alkynyl, alkoxyl, hydroxy alkoxy base, alkoxyl alkoxyl, alkene oxygen base, cycloalkyloxy or cycloalkyl alkoxy; With
R 4' and R 5' be halogen independently of one another, hydroxyl, alkyl or alkoxyl; Or
R 4' and R 5', form the carbocyclic ring or the heteroaryl ring system of a condensed optional replacement with the phenyl ring that they connected.
20. as claim 18 or 19 described chemical compound, wherein R 3' be alkyl, thiazolinyl, alkynyl, alkoxyl, cycloalkyloxy, cycloalkyl alkoxy, hydroxy alkoxy base or alkoxyl alkoxyl, R 4' be halogen, alkyl or alkoxyl and R 5' be alkyl or alkoxyl.
21. chemical compound as claimed in claim 20, wherein R 3' be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, but-1-ene base, penta-1-thiazolinyl, fourth-1-alkynyl, penta-1-alkynyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isobutoxy, 3-methyl-butoxy, amoxy, cyclopentyloxy, hexyloxy, cyclo propyl methoxy, cyclobutyl methoxy base, 2-hydroxyl-ethyoxyl, 2-methoxyl group-ethyoxyl, R 4' be chlorine, bromine, methyl or methoxy, and R 5' be methyl or methoxy.
22. as claim 18 or 19 described chemical compound, wherein R 3' be alkoxyl and R 4' and R 5' phenyl ring that is connected with them is common forms optional naphthalene, naphthane, indane, 1H-indenes, isoquinolin, dihydrobenzo [1,4] two oxines or a luxuriant loop systems of benzo [1,3] two Evil that replaces.
23. chemical compound as claimed in claim 22, wherein R 3' be propoxyl group and R 4' and R 5' form a naphthalene-1-base, indane-4-base, isoquinolin-5-base, isoquinolin-8-base, 1,2,3 with the phenyl ring that they connected, 4-tetrahydroisoquinoline-8-base, 2-alkoxy carbonyl-1,2,3,4-tetrahydroisoquinoline-8-base or 5,6,7,8-naphthane-1-base residue.
24. as claim 18 or 19 described chemical compounds, wherein
R 3' be methoxyl group, propoxyl group, cyclopentyloxy, penta-1-alkynyl or ethanesulfonyloxy group;
R 4' be methyl;
R 5' be hydroxyl, methyl, amyl group, methoxyl group, propoxyl group, the 2-methoxy ethoxy, the 2-hydroxyl-oxethyl, 3-hydroxyl propoxyl group, 4-hydroxyl butoxy, 2,3-dihydroxy propoxyl group, 4-acetoxyl group butoxy, the carboxyl methoxyl group, 3-carboxyl propoxyl group, 4-carboxyl butoxy, 3-carboxyl-2-hydroxyl propoxyl group, 3-carboxyl-2,3-dihydroxy propoxyl group, ethoxycarbonyl methoxy, 3-ethoxy carbonyl propoxyl group, 4-ethoxy carbonyl butoxy, 3-ethoxy carbonyl-2-hydroxyl propoxyl group, 3-ethoxy carbonyl-2,3-dihydroxy propoxyl group, carbamyl ylmethoxy 3-N-ethylamino formoxyl propoxyl group, 4-N-ethylamino formoxyl butoxy, 2-N, the N-dimethylamino ethoxy, 3-N, the N-dimethylamino propoxy, 2-(morpholine-4-yl)-ethyoxyl, 2-(piperidines-1-yl)-ethyoxyl, 3-(morpholine-4-yl)-carbonyl propoxyl group, 4-(morpholine-4-yl)-carbonyl butoxy, 2,2-dimethyl [1,3] dioxolanes-4-ylmethoxy or 2,2-dimethyl-4-carboxyl [1,3] dioxolanes-5-ylmethoxy; Or
R 4' and R 5', form a naphthalene-1-base, 5,6,7 with the phenyl ring that they connected, 8-naphthane-1-base, indane-4-base, 1,2,3,4 ,-four isoquinolin-8-base or 2-tert-butoxycarbonyl-1,2,3,4 ,-four isoquinolin-8-base residue.
25. chemical compound, it is selected from:
4-[1-[2-((2S)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-carboxyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-carboxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-carboxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-3-carboxyl-2,3-dihydroxy-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(5-ethylamino-5-oxo-amoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2S, 3R)-2,3-dihydroxy-3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(ethoxy carbonyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone; With
4-[1-[3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone.
26. chemical compound, it is selected from:
1-phenyl-4-[1-(5-propoxyl group-isoquinolin-8-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-[2-(4-ethylamino-4-oxo-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-ethoxy carbonyl-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((2R)-3-ethoxy carbonyl-2-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-ethoxy carbonyl-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
1-phenyl-4-[1-(8-propoxyl group-isoquinolin-5-yl)-methylene]-pyrazolidine-3, the 5-diketone;
4-[1-[2-(2-amino-2-oxo-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R, 5S)-4-carboxyl-2,2-dimethyl-[1,3] dioxolanes-5-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
1-phenyl-4-[1-(7-propoxyl group-indane-4-yl)-methylene]-pyrazolidine-3, the 5-diketone;
1-phenyl-4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
1-phenyl-4-[1-(5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-pyrazolidine-3,5-diketone and formates thereof;
4-[1-[2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-[1-[2-(carboxyl-methoxyl group)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-[1-[2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(3-methyl-2,4-dipropoxy-benzal)-pyrazolidine-3, the 5-diketone;
4-[1-(3-methyl-2,4-dipropoxy-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-(2-methoxyl group-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2-methoxyl group-3-methyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(7-propoxyl group-indane-4-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-(2-tert-butoxycarbonyl-5-propoxyl group-1,2,3,4-tetrahydrochysene-isoquinolin-8-yl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone; With
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-fluoro-phenyl)-pyrazolidine-3, the 5-diketone.
27. chemical compound, it is selected from:
1-phenyl-4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[1-[3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-phenyl]-methylene]-1-phenyl-pyrazole alkane-3,5-diketone and hydrochlorate thereof;
4-(2,4-dimethoxy-3-methyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-ethanesulfonyloxy group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-methoxyl group benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(4-propoxyl group-naphthalene-1-methylene)-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] phenylcyanide;
4-[1-(2-hydroxy-3-methyl-4-propoxyl group-phenyl)-methylene]-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-amyl group-benzal)-pyrazolidine-3, the 5-diketone;
1-(2-chloro-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-penta-1-alkynyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-pyridin-4-yl-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-pyrazolidine-3, the 5-diketone;
4-(4-cyclopentyloxy-2,3-dimethyl-benzal)-1-phenyl-pyrazole alkane-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(4-methoxyl group-phenyl)-pyrazolidine-3, the 5-diketone;
1-(4-bromo-phenyl)-4-(2,3-dimethyl-4-propoxyl group-benzal)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-(2-methyl-phenyl)-pyrazolidine-3, the 5-diketone;
4-(2,3-dimethyl-4-propoxyl group-benzal)-1-methyl-pyrazolidine-3, the 5-diketone;
4-[4-(2,3-dimethyl-4-propoxyl group-benzal)-3,5-dioxo-pyrazolidine-1-yl] ethyl benzoate; With
1-acetyl group-4-[1-(2,3-dimethyl-4-propoxyl group-phenyl)-methylene]-pyrazolidine-3, the 5-diketone.
28. as active constituents of medicine as each described chemical compound of claim 18～27.
29. a pharmaceutical composition, it comprises as each described chemical compound of claim 18～27 and pharmaceutically inert carrier.
30. as claim 1 or 3 described purposes, wherein said chemical compound is each described chemical compound of claim 18～23.
31. a method for preparing as each described chemical compound of claim 18～27, it comprises shown in following reaction scheme, the pyrazolidinedione of general formula (IV) and the al of logical formula V is closed, wherein R 1, R 3 ', R 4 'And R 5 'Define as claim 18,
Figure A2004800177170021C1
In the chemical compound of formula IV and V any reactive group that may exist suitably protected, and, if desired, any unwanted blocking group is sloughed from condensation product.
32. as the pyrazolidinedione of the general formula (IV) of claim 31, it is selected from:
1-pyridine-2-base-pyrazolidine-3, the 5-diketone;
4-(3,5-dioxo-pyrazolidine-1-yl) phenylcyanide; With
1-pyridin-4-yl-pyrazolidine-3, the 5-diketone.
33. the aldehyde of logical formula V as claimed in claim 31, it is selected from:
4-cyclopentyloxy-2,3-dimethyl-benzaldehyde;
4-propoxyl group-5,6,7,8-tetrahydrochysene-naphthalene-1-aldehyde;
2,3-dimethyl-4-penta-1-alkynyl-benzaldehyde;
2,3-dimethyl-4-amyl group-benzaldehyde;
7-propoxyl group-indane-4-formaldehyde;
5-propoxyl group-isoquinolin-8-formaldehyde;
8-propoxyl group-isoquinolin-5-formaldehyde;
2-tert-butoxycarbonyl-8-formoxyl-5-propoxyl group-1,2,3, the 4-tetrahydroisoquinoline;
2,3-dimethyl-4-ethanesulfonyloxy group benzaldehyde;
2-hydroxy-3-methyl-4-propoxyl group-benzaldehyde;
2-methoxyl group-3-methyl-4-propoxyl group-benzaldehyde;
2-(2-methoxyl group-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde;
2-(2-hydroxyl-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde;
2-(3-hydroxyl-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde;
2-(4-acetoxyl group-butoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-(4-hydroxyl-butoxy)-3-methyl-4-propoxyl group-benzaldehyde;
(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl acetate;
(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetic acid;
2-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-acetamide;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl n-butyrate.;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid;
4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-butanoic acid acetamide;
3-methyl-2-(4-morpholine-4-base-4-oxo-butoxy)-4-propoxyl group-benzaldehyde;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-ethyl valerate;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid;
5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-valeric acid acetamide;
3-methyl-2-(5-morpholine-4-base-5-oxo-amoxy)-4-propoxyl group-benzaldehyde;
2-(2-dimethylamino-ethyoxyl)-3-methyl-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
3-methyl-2-(2-morpholine-4-base-ethyoxyl)-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
3-methyl-2-(2-piperidines-1-base-ethyoxyl)-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
2-(3-dimethylamino-propoxyl group)-3-methyl-4-propoxyl group-benzaldehyde and hydrochlorate thereof;
2-(2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-((4R)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
2-((4S)-2,2-dimethyl-[1,3] dioxolanes-4-ylmethoxy)-3-methyl-4-propoxyl group-benzaldehyde;
(3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.;
(3R)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid;
(3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-ethyl n-butyrate.;
(3S)-4-(6-formoxyl-2-methyl-3-propoxyl group-phenoxy group)-3-hydroxyl-butanoic acid;
(4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylate methyl ester;
(4R, 5S)-5-(6-formoxyl-2-methyl-3-propoxyl group-phenoxymethyl)-2,2-dimethyl-[1,3] dioxolanes-4-carboxylic acid.
CNA2004800177171A 2003-06-24 2004-06-16 Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors Pending CN1812782A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP03/006616 2003-06-24
PCT/EP2003/006616 WO2005002574A1 (en) 2003-06-24 2003-06-24 Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors

Publications (1)

Publication Number Publication Date
CN1812782A true CN1812782A (en) 2006-08-02

Family

ID=33547562

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2004800177171A Pending CN1812782A (en) 2003-06-24 2004-06-16 Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors

Country Status (6)

Country Link
EP (1) EP1638540A2 (en)
JP (1) JP2007506661A (en)
CN (1) CN1812782A (en)
AU (1) AU2003249865A1 (en)
CA (1) CA2529436A1 (en)
WO (2) WO2005002574A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070276011A1 (en) * 2003-09-11 2007-11-29 Susumu Muto Plasminogen Activator Inhibitor-1 Inhibitor
JPWO2007020935A1 (en) * 2005-08-17 2009-02-26 小野薬品工業株式会社 Pain therapeutic agent comprising P2Y12 receptor and / or P2Y14 receptor blocker
TWI391378B (en) 2006-03-16 2013-04-01 Astellas Pharma Inc Quinolone derivative or pharmaceutically acceptable salt thereof
JP5560202B2 (en) 2007-12-26 2014-07-23 サノフイ Pyrazole-carboxamide derivatives as P2Y12 antagonists
WO2009080226A2 (en) 2007-12-26 2009-07-02 Sanofis-Aventis Heterocyclic pyrazole-carboxamides as p2y12 antagonists
JP6016788B2 (en) * 2011-05-16 2016-10-26 国立大学法人九州大学 Low molecular weight compound controlling Rac activation by DOCK-A subfamily molecule and use thereof
WO2017038650A1 (en) * 2015-08-28 2017-03-09 積水メディカル株式会社 Benzyl compound
US10730830B2 (en) 2016-01-29 2020-08-04 Ono Pharmaceutical Co., Ltd. Tetrahydronaphthalene derivative
TWI765002B (en) * 2017-03-15 2022-05-21 瑞士商愛杜西亞製藥有限公司 Receptor antagonist
US11584710B2 (en) 2017-07-31 2023-02-21 Horitzonts Tecnologics Hungary Korlátolt Felelosségu Társaság Compounds for treating infections

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2012634A1 (en) * 1990-03-20 1991-09-20 Hassan Salari Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases
CA2380644A1 (en) * 1999-07-30 2001-02-08 Basf Aktiengesellschaft 2-pyrazolin-5-ones
IL159354A0 (en) * 2001-06-18 2004-06-01 Applied Research Systems Use of alklidene pyrazolidinedione derivatives in polycystic ovary syndrome, some novel such derivatives, their preparation and pharmaceutical compositions containing them
WO2003002569A1 (en) * 2001-06-29 2003-01-09 Novo Nordisk A/S Method of inhibiting ptp 1b and/or t-cell ptp and/or other ptpases with an asp residue at position 48
AU2003213673A1 (en) * 2002-03-01 2003-09-16 Pintex Pharmaceuticals, Inc. Pin1-modulating compounds and methods of use thereof

Also Published As

Publication number Publication date
WO2005000281A3 (en) 2005-04-14
JP2007506661A (en) 2007-03-22
EP1638540A2 (en) 2006-03-29
WO2005002574A1 (en) 2005-01-13
WO2005000281A2 (en) 2005-01-06
AU2003249865A1 (en) 2005-01-21
CA2529436A1 (en) 2005-01-16

Similar Documents

Publication Publication Date Title
CN1252067C (en) Benzazole derivatives and their use as JNK modulators
CN1256326C (en) Novel 4- (oxoxyphenyl) -3-oxopiperidines for the treatment of cardiac and renal insufficiency
CN1259307C (en) Acylated indanyl amines and their use as pharmaceuticals
CN1297550C (en) Benzofuran derivatives, process for the preparation of the same and uses thereof
CN1124262C (en) Indole derivatives useful as endothelin receptor antagonists
CN1934091A (en) Imidazole compounds for the treatment of neurodegenerative disorders
CN1052672A (en) Benzofuran derivative
CN1045769C (en) Sulphurous derivatives of imidazole, their preparation process, intermediates obtained, their use as medicaments and pharmaceutical compositions containing them
CN1514828A (en) Pyrazole derivatives for treating HIV
CN101039938A (en) Diphenyl substituted alkanes as flap inhibitors
CN1681811A (en) Azolidinone-vinyl fused-benzene derivatives
CN1993347A (en) Potassium channel inhibitors
CN1897936A (en) Cyclic guanidines, compositions containing such compounds and methods of use
CN1933830A (en) Indole derivatives and use thereof as kinase inhibitors in particular ik. k.2 inhibitors
CN1688583A (en) Organic compounds as agents for the treatment of aldosterone mediated conditions
CN1251589A (en) Substituted triazolo-pyridazine derivatives as ligands for GABA receptors
CN1031057C (en) Triazolo [4.3-a][1,4] benzodiazepine and thiopheno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine
CN1909902A (en) Triazole, oxadiazole and thiadiazole derivatives as PPAR modulators for the treatment of diabetes
CN101031296A (en) Modulators of muscarinic receptors
CN1443173A (en) Substituted imidazoles as TAFI a inhibitors
CN1662498A (en) Novel tetrahydropyridine derivatives as renin inhibitors
CN1812782A (en) Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors
CN1049219C (en) Fused heteroaromatic cyclopentene derivative having endothelin-antagonist activity
CN1498218A (en) Imidazo-pyrimidine derivatives as ligands for GABA receptors
CN1097752A (en) Benzocyclohepta alkene, benzoxepines and benzo thia

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication