TW200404535A - Pharmaceutical composition for maintaining circulation through fetal ductus arteriosus during treatment or prevention of preterm labor - Google Patents

Abstract

The invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating preterm labor. In particular, the invention describes the pharmaceutical composition for preventing and treating preterm labor in a subject, said pharmaceutical composition comprising a therapeutically-effective amount of a compound of formula I or II, wherein R1, R2, R3 R4, R5 and R6 are as described in the specification provided that the compound in not 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (celecoxib).

Description

200404535 (1) Description of the invention: [Technical Field] The present invention belongs to the scope of preventing and treating full-term delivery. More specifically, the present invention relates to the use of a cyclooxygenase-2 inhibitor or a derivative thereof for the prevention and / or delivery of a second-treatment patient before term. [Previous technology] Prostaglandins play a major role in the inflammation process, and the inhibition of prostaglandin production, especially the inhibition of PPG2, PGH2 'and PGE2 production, has been the common goal of discovering anti-inflammatory drugs. However, general nonsteroidal anti-inflammatory drugs (NSAID's), which are active in reducing pain caused by prostaglandins and swelling caused by inflammatory processes, are also active in influencing other prostaglandin-regulated non-inflammatory processes. Therefore, the high-dose use of most NSAIDs can cause serious side effects, including life-threatening ulcers, and this side effect limits their therapeutic use. Instead of NSAID, s is a corticosteroid, which also has side effects, especially when used for long-term treatment. It has been found that NSAIDis prevents the production of prostaglandins by inhibiting the enzymes in the human peanut four_ / prostaglandin pathway, including cyclooxygenase (COX). Recent discoveries of inducible enzymes (called, cyclooxygenase_2 (COX ·]), or "prostaglandin G / Η synthase", caused by inflammation have provided practical targets for inhibition This inhibition more effectively reduces inflammation and has fewer side effects. The natural preterm term delivery during pregnancy is an important and increasing problem in medicine. There is little progress in understanding the causes of childbirth before ^ months, and in the examination and general management of childbirths. Safely stop term, then give birth and then have the ability to reach full term pregnancy

O: \ 90 \ 90006.DOC 200404535

Sought after. Term month before decision even # ~ Production accounts for the major part of the death during childbirth, and the main problem of child defects 屋, so it is better to maintain the fetus and the uterus without giving birth before term. Suddenly accounted for the factors. Term delivery is also a limitation of the maintenance of various types of fetuses ^ The occurrence of delivery depends on many factors. Pregnancy progresses normally; luteal β-muscles are required to maintain relaxation and release to sub-pull, but the mechanism of uterine smooth muscle relaxation during pregnancy is unknown. Just .. f Parturition begins with childbirth. Childbirth includes the right stroke of the uterus and train 丨 Lexi i has regular, progressive contractions, which leads to child +

Neck shortening and expansion. Yu Zhengtang Risks Λ In the pregnancy of Zheng Zheng, the childbirth usually starts two days before the due date. Once a diagnosis of full-term delivery is made, the benefits of restraining the split-birth and allowing them to give birth are measured. The risk of suppressing childbirth is mainly related to the side effects of childbirth suppressing drugs. -Once you have diagnosed childbirth ^ months ago and determine that the age of gestation is suitable for birth suppression, you must decide the contraindications for full-term labor, such as child pain; preeclampsia, placental rupture., Death or abnormalities of platform children, fetus Repression or domain

Amniotic meningitis, and then select a specific convenient anti-birth agent (tocolytic agent). The different anti-birth agents with different pharmacological properties have been tried to control preterm delivery. The most commonly used anti-birth agents now include adrenergic receptor stimulants, such as epinephrine or its synthetic analogs and derivatives salbutamol, terbutaline, isoxuprin (iS0XSUprine) ), Menstrual ephedrine (ritodrine), and fenboterine (sulfonate), sulphate, prostaglandin inhibitors such as aspirin, indomethacin (incj〇inethacin) and methoxy tea propyl Acid (naproxen), ethanol and calcium channel blockers such as nipedifine

O: \ 90 \ 90006.DOC 200404535 or nicardipine 〇 Even the best anti-labor drugs currently in use are not satisfactory in preventing or inhibiting full-time recovery before term. In addition to proven ineffectiveness, such standard abortions may have severe side effects on the mother and fetus. Halogenated inhaled anesthetics used to relax the uterus have been shown to produce significant myocardial depression in the mother and fetus. It is clear that active treatment of postpartum delivery with the highest doses of magnesium and betamimetics is very toxic to the mother. In this clinical situation, trying to avoid pulmonary edema will cause the mother's blood volume to be too low. The uterine arteries experience a countercurrent during diastole. Studies have been conducted with NSAIDs to treat and prevent preterm delivery. Clinical evaluations of indomethacin and sulindac were performed. However, the use of these compounds is obviously limited because of its side effects, including fetal arterial catheter contraction and mitral valve return, which can cause fetal right heart failure, and so on. These side effects limit the use of NSAIDs, especially during the most important last trimester of pregnancy. Cyclooxygenase-2 was recently found to increase during childbirth (Zuo et al. J. Clin.

Endoc Metab, 79, 894-9 (1994), Slater et al., Am J. Obstet Gynecol. 172, 77-82 (1995)). In addition, COX-2 also plays a role in preterm labor due to spontaneous abortion or infection by a mother (§ilver et al., J.

Clin. Invest., 95, 725-3 1 (1995)). Sawdy et al. Describe the use of nimesulide in preventing preterm labor (Ding He Lancet, 35, 265-6 (1997)). W094 / 26731, published on November 24, 1994, illustrates the use of COX-2 inhibitors in the treatment of full-term delivery.丨 W097 / 31631, published in September 997, indicates that COX-2 inhibitors

O: \ 90 \ 90006.DOC 200404535 Use in childbirth and uterine contraction. Prostaglandins have been shown to be used in the last three trimesters of pregnancy to control the closure of arterial catheters. U.S. Patents 5,380,738; 5,344,991; 5,393,790; 5,434,178; 5,474,995; 5,510,368; and WO 96/06840, WO 96/03388, WO 96/03 3 87, WO 96/25405, WO 95/153 16, WO 94/15932, WO 94/27980, WO 95/005 (H, WO 94/13635, WO 94/20480, and WO 94/26731 describe compounds that selectively inhibit cyclooxygenase-2. It has been described that [pyrazole-1 -Yl] sulfenazamide is a cyclooxygenase_2 inhibitor and can be used to treat inflammation, arthritis, and pain. Preclinical and clinical trials have shown few side effects. US Patent No. 5,466,823 shows that it can be used to treat inflammation. However, no one has previously stated that it can be used to treat and prevent preterm term. The present invention uses these compounds that selectively inhibit cyclooxygenase_2 to treat and prevent preterm term delivery while maintaining fetal arterial ducts. Circulation of blood. [Abstract] The present invention provides

Pharmaceutical composition of vascular circulation, on the patient,

Wherein the composition comprises a therapeutically effective amount of a compound of formula I 1

O: \ 90 \ 90006.DOC 200404535 where A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated hetero and carbohydrates, where R1 is at least one substituent selected from heterocyclic , Cycloalkyl, cycloalkenyl, and aryl, where R1 is optionally substituted with one or more groups at a substitutable position, such groups are selected from the group consisting of alkyl, alkyl, cyano, and alkyl Alkoxy, alkynyl, alkynyl, alkynyl, ^ iS alkoxy, amine, alkynyl, aryl, aryl, amine, alkoxy, alkynyl, alkynyl, S & II, alkoxy, and alkylthio, where R2 is selected from the group consisting of alkyl and amine; and R3 is a group selected from the group consisting of i, alkyl, alkyl, alkenyl, alkynyl, oxygen, cyano Alkyl, carboxyl, cyanoalkyl, heterocyclicoxy, alkylthio, alkylthio, cycloalkyl, cycloalkyl, aryl, alkyl, heterocyclyl, cycloalkenyl, aralkyl Aryl, heterocycloalkyl, alkynyl, sulfanylthio, alkynyl, alkynyl, arylalkyl, aralkylcarbonyl, arkenyl, alkoxyalkyl, aryl Thioalkyl, aryloxyalkyl, aralkylthio Alkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminecarbonyl, aminecarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl , N-alkylarylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkylaralkyl Amine, N-Alkylarylamino 5Aminoalkyl'Alkylaminoalkyl 'N-Arylaminoalkyl' N_aralkylaminoalkyl, N-alkyl-N-aryl Alkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkyl Sulfosulfanyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-O: \ 90 \ 90006.DOC -10- 200404535 arylaminosulfonyl; or a pharmaceutically acceptable salt thereof. The invention can be used for, but not limited to, the treatment and prevention of pre-term division. The present invention can also be used, but not limited to, the prevention and maintenance of arterial catheter closure and circulation of fetal arterial catheters during preterm delivery. These compounds are useful in the treatment of humans, as well as mammals, including pets and farm animals, such as, but not limited to, horses, dogs, weeds, cattle, sheep, and pigs. [Embodiment] πTreatment π — The term includes partial or full inhibition of preterm delivery. The term `` prevention '' includes the prevention of the occurrence of all preterm full-term deliveries or the prevention of preterm full-term deliveries in individuals at risk of preterm full-term delivery. The term "therapeutically effective" is used to describe each dose. This amount can improve the severity and frequency of the disease, while avoiding side effects in treatment.

Patient-like master. Metabolic tetraenoic acid metabolism in cyclooxygenation for the prevention and treatment of flowers delivered before term

Enzyme activity can be inhibited by a variety of mechanisms using inhibitors that directly block the enzymatic pathways that NSAIDs may occur. For example, the biggest advantage of selective inhibitors in Yanxue 2 is that it is the lowest. Such side effects are the use of non-selective, especially for long-term prophylactic treatment.

O: \ 90 \ 90006DOC -11-200404535 "· Cyclooxygenase-2 inhibitor" refers to a compound that can inhibit cyclooxygenase rrj ^ ,. 叩 on ^ oxygenation ... significant inhibition. Preferably it includes Cyclooxygenase

制 的 IC5。 IC5. Less than about 0-2 μM, and inhibiting cyclooxygenase_2 is better than inhibiting cycloplus P, and the ratio of enzyme-1 is at least 50, more preferably at least 100 compounds. In particular: yes, yes, the cyclooxygenase-1 ICsG of these compounds is greater than about 1 μM, and more preferably greater than 10 μM. The present invention provides a medicine for treating or preventing fetal arterial duct circulation during preterm delivery. A composition for use in a patient in need of such treatment or prevention. This composition can be administered to pregnant women who experience childbirth before full term, wherein the composition consists essentially of the compound of formula j alone or in combination with other anti-birth agents, and the amount given can effectively inhibit or Stop uterine contractions. These anti-birth agents include / 5-adrenergic receptor stimulants, such as epinephrine or its synthetic analogs and derivatives, asthma, terbutaline, isoxsuprine, hydroxystilbine Nephedrine (ntodnne) and fenbuterol, magnesium sulfate, ethanol, activin antagonists, cardiac antiarrhythmic agents such as lidocaine or ocainide ' Nitrogen oxide supply agents such as s-nitrosoacetamidinyl penicillamine, oxidizing I nucleophiles and adducts, nitroglycerin 'hydroxylamine, sodium azide, diethylamino nitric oxide and the like, and oxidation Nitrogen precursors such as L-arginine, and channel blockers such as nipedifine or nicardipine. O 'derivatives include any structurally related to cyclooxygenase_2 inhibitors The compound or compound that is equivalent to the biological activity of 彡 衣 气 气 气 -2 inhibitor. By way of example, such inhibitors may include, but are not limited to, their prodrugs. O: \ 90 \ 90006.DOC -12- 200404535 Preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, where A is selected from oxazolyl, isoxazolyl, thienyl, dihydrofuranyl , Fur. Southern, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl and pyridyl; wherein R1 is a heterocyclic group selected from 5- and 6-membered, lower ring Alkyl, lower cycloalkenyl, and aryl selected from phenyl, biphenyl, and fluorenyl, where R1 is optionally substituted with a lower alkyl, lower haloalkyl, cyano, carboxyl, lower Alkoxycarbonyl, hydroxy, lower hydroxyalkyl, lower haloalkoxy, amine, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkyl, halogen , Substituted with low alkoxy and low thiol groups; wherein R2 is selected from low alkyl and amine groups; and R3 is selected from halogen, low alkyl, oxygen, cyano, carboxyl, low cyanoalkyl, hetero Aryloxy, lower alkyloxy, lower cycloalkyl, heteroaryloxy, lower alkyloxy, lower cycloalkyl, phenyl, lower ialkyl, 5- or 6-membered heterocyclic ring Alkyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl, lower alkoxyalkyl, heteroaryloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aminoalkyl Alkyl, alkylamino Aryloxy, and aralkyloxy; or a pharmaceutically acceptable salt thereof. More preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, wherein A is selected from oxazolyl, isoxazolyl, dihydrofuryl, imidazolyl, and pyrazolyl; wherein R1 is selected from 5 -And 6-membered heterocyclyl, lower cycloalkyl, lower cycloquinyl 'and aryl selected from the radicals' biphenyl and naphthyl, where R1 is optionally substituted at one or more positions with one or more Substituted by a group selected from the group consisting of a low-density group 'lower 1¾-alkynyl' cyano, a condensed group, a lower alkoxy group, a mesityl group, a lower hydroxyalkyl group, a lower alkoxy group, an amine group, and a lower alkyl group. Amino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halogen, lower alkoxy O: \ 90 \ 90006.DOC -13-200404535 and lower alkyl sulfur Where R2 is an amine group; and wherein R3 is selected from the group consisting of oxygen, cyano, weidyl, low alkyloxy, low alkyl, low cyano, halogen, low alkyl, low alkyl, Lower cycloalkyl, phenyl, lower alkyl, 5- or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6 -Membered heteroaryloxy, aminocarbonyl, low Alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylamino alkyl, phenyloxy, and aralkyloxy; or pharmaceutically acceptable salts thereof. Particularly preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, wherein A is selected from the group consisting of oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl; wherein R1 is optionally substituted at a position to One or more phenyl groups substituted with: methyl, ethyl, isopropyl, butyl, tertiary-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl , Trifluorofluorenyl, chloromethyl, difluoromethyl, trichlorofluorenyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, Dichloropropyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluorofluorenyloxy, amine, N-methylamino, N, N-dimethylamino, N-ethyl Amino, N, N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, nitro, methoxymethyl, fluorenyl Ruthenium, fluorine, gas, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, and fluorenylthio; its card R2 is an amine group; and R3 is Selected from oxygen, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl , Carboxymethyl, carboxyethyl, cyanofluorenyl, fluorine, gas, bromine, methyl, ethyl, isopropyl, butyl, tertiary-butyl, isobutyl, pentyl, hexyl, fluorofluorene Base, difluorofluorenyl, trifluorofluorenyl, trimethylol, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoro O: \ 90 \ 90006.DOC -14- 200404535 ethyl, difluoropropyl, dichloroethyl, dichloropropyl, methyloxy, ethoxy, propoxy, n-butoxy, pentyloxy, cyclohexyl, phenyl, Pyridyl, thienyl 'pyrazolyl, oxazolyl, furyl, pyridoxyl, hydroxymethyl, hydroxypropyl' benzyl, formamyl, phenylcarbonyl, methoxymethyl, furylmethyl Oxy'aminocarbonyl, N · methylaminocarbonyl, N, N-diamidinoaminocarbonyl 'N, N-diamidinoamino, N-ethylamino, N, N-dipropyl Amino, N-butylamino, N-methylethylamino, aminomethyl, N, N_dimethylaminomethyl, N-fluorenyl-N_ethylaminomethyl, Fluorenyloxy, and phenyloxy; or a pharmaceutically acceptable salt thereof. A particularly interesting group of compounds of formula I includes the compounds shown below and their pharmaceutically acceptable salts: 3- (3,4-difluorobenzyl) -4- (4-methylsulfonylbenzene ) -2- (5H) -furanone; 3-phenyl-4- (4-methylsulfonylphenyl) -2- (5H) -furanone; ) -3- (trifluoromethyl) -1Η-pyrazole β1_yl] benzenesulfonamide; 4_ [5- (4-fluorenylbenzyl) | (trifluoromethyl) _1Η_pyrazole + yl ] Benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluorofluorenyl) -1Η ^ pyzol-1-yl] benzsulfonamide; 3- [1- [4- (methylsulfonyl) phenyl] -4_trifluoromethyl-1fluoren-imidazol-2-yl] pyridine; 2-methyl-5- [1- [4_ (methyl Sulfonyl) phenyl] · 'trifluoromethyl-1 甲基 _imidazol-2-yl] ρ specific bite; 4- [2- (5-methylpyridin-3-yl) -4_ (trifluorofluorenyl) _1Η_pyrazol- ^ yl] benzenesulfonamide; O: \ 90 \ 90006.DOC -15- 200404535 4- [5-fluorenyl-3-phenylisoxazol-4-yl] benzenesulfonamide; 4- [5-hydroxyethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; [2-trifluoromethyl-5- (3,4-difluorophenyl) _4_oxazole Yl] benzenesulfonamide; 4- [2-fluorenyl-4-phenyl-5-pyrazolyl] benzenesulfonamide; and 4- [5 -(3-fluoro-4-fluorenoxyphenyl-2-tris (methyl) -4-sialyl] benzite scutamine. In formula 有 一 there is a long class of directional interesting compounds represented by formula II

Where R4 is selected from the group consisting of hydrogen ion, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkyl, aminocarbonyl, arylamine Carbonyl group, carboxyalkylaminocarbonyl group, carboxyalkyl group, aralkyloxyalkylaminocarbon group, aminemethylamino group, alkoxyalkylamino group, dialkyl group, and mesityl group; Wherein R5 is selected from the group consisting of sulfonium ions, alkyl, cyano, cycloalkyl, cycloalkyl, and functional groups; and R6 is selected from the group consisting of arkenyl, aryl, and cycloalkyl, Cycloalkenyl, and heterocyclyl; where R4 is optionally substituted with one or more groups selected from the group consisting of halogen, alkylthio, alkylsulfonyl, cyano, nitrate Base, iS base, alkenyl, alkenyl, alkenyl, alkenyl, alkenyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkenyl \ 90 \ 90006.DOC -16- 200404535 Oxyhalohalooxy, amidino, heterocyclic and amine; or a pharmaceutically acceptable salt or derivative thereof. A particularly interesting group of compounds of formula II is this σ ', where R4 is selected from lower alkyl; where R5 is a hydrogen ion: and where R6 is optionally substituted at one or more positions in the substitutable position. Each is selected from the following: Group substituted phenyl · halogen, lower, lower acceptable salt or derivative. 1 low base; or medically compatible = ::: group two is exciting_ 疋 k from difluoromethyl and difluoromethyl; among them, ions; Substituted positions are substituted with one or more groups selected from the group consisting of: chloro, methyl, and its pharmaceutically acceptable derivatives. Qian, or compounds of particular interest in the compound include the following compounds and their acceptable salts:-] phenyl) _3_ (trifluoromethyl) xan-1-yl] benzene continuous amine; [Phenyldifluoromethyl) _1H-pyrazol-1-yl] benzenesulfonamide; 4 [5- (Heartamyl) 1 (trifluoromethyl) _thoraxyl group] Benzylamine ; 4 [5 (4-Methenylphenyl)> 3- (trifluoromethyl) -1′-pyrazol-1-yl] benzylamine; ”chlorobenzyl) _3_ (difluoromethyl ratio) -1-yl] benzylamine; 4 [5 · (4-methylbenzyl) _3_ (trifluoromethyl) · 1Η • pyrazole- 丨 -yl] benzylsulfonamide; '

4-[3-(1 m m «X amine earth) methylphenylpyrazole-1-yl]

O: \ 90 \ 90006.DOC -17- 200404535 4- [3- (difluoromethyl) _5-phenyl_1H-, pyrazolyl] benzenesulfonamide; 4- [3- (difluoromethyl ) _5_ (4-methoxyphenyl) _1Η_pyrazolyl] benzenesulfonamide; 4- [3 _ (-fluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -ih -Pyrazole · fluorenyl] benzylsulfonamide; and 4- [5- (3_fluoro-4_methoxyphenyl) -3- (trifluoromethyl > 1} • pyrazole_ 丨 _yl Benzsulfazone. A group of compounds of particular interest in Formula II includes the compounds shown below and their pharmaceutically acceptable salts ... 4- | > (4-methylphenyl) _3_ (tri Fluoromethyl) small group] Benzamidine; ', 4- [5- (4-Gasphenyl) _3_ (difluoromethyl) _1Η_asehal + yl] benzamine; 4- [5 -(3-Fluoro-4-methoxyphenyl) _3_ (difluoromethyl) · 1Η_pyrazolyl] Benzoflavin. The term " hydrogen ion " refers to a single hydrogen atom (Η ). This hydrogen ion group can be linked, for example, to form a hydroxyl group on an oxygen atom, or two hydrogen ions can be linked to a carbon atom to form a methylene group (even-). In other words 'such as " _ 烧 基', "” 基 姐 基 ", &Quot; Hydroxyl radical " and " Cycloalkynyl radical, " In the alkyl radical, the alkyl radical includes a linear or branched group of one to about 20 carbon atoms 'or' preferably one to twelve. Carbon atoms. More preferred alkyl groups are lower alkyl groups having from-to about ten carbon atoms. Most preferred lower alkyl groups are having from-to about six carbon atoms. Examples of such groups include forma & , Ethyl, n-propyl, isopropyl'-n-butyl, pentyl, iso-pentyl, hexyl, etc. The term "alkenyl" includes linear divisors of φ-magic and knife. Of one to about twenty carbon atoms

0 \ 90 \ 90006.DOC -18-200404535, or preferably a group having from two to about twelve mountain τ, and having at least one carbon 妷 double bond. Better dilute 4 soils, "low olefins" of one to about six carbon atoms. Examples of the alkenyl group include a vinyl group, a propenyl group, an allyl group, a propenyl group, a butenyl group, and a methyl ethyl butylene group. The term "alkynyl" refers to a linear or branched group having at least one slave-carbon triple bond and having two to about twenty carbon atoms, preferably two to about twelve carbon atoms. More preferred alkynyl is a "low alkynyl" having two to about ten carbon atoms. The most preferred alkynyl has two to about six carbon atoms. Examples of such fast radicals include propylene radical, butadiyl radical, and the like. The terms "alkenyl" and "lower alkenyl" include groups having "cis" and, and "reverse" directions, or groups that are azimuth or τ ^. "Cycloalkyl" includes% -shaped groups having three to about twelve carbon atoms. More preferred cycloalkyl groups are three to about eight carbon atoms, and lower cycloalkyl groups. " Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. "'Balkenyl"-Yanji includes partially unsaturated carbocyclic groups having three to twelve carbon atoms. More preferred cycloalkenyl is " lower alkenyl "having four to about eight carbon atoms. Examples of such groups include cyclobutenyl, cyclopentenyl, and cyclopentenyl. The term halogen means fluorine 'gas, bromine or iodine. The term "_alkyl" includes groups in which any one or more of the alkyl carbon atoms are substituted with a halogen as described above. Examples of special fluorenes include monoalkyl, dihalo, and polyhaloalkyl. A monohaloalkyl group, for example, may have an iodine, bromine, gas or fluorine atom in the group. Dihalo and polyhaloalkyl groups may have two or more of the same halogen atoms or a mixture of different halogen atoms. "Low-haloalkyl, including groups of one to six carbon atoms. Examples of iialkyl include fluoromethyl, difluorofluorenyl, trifluorofluorenyl, trifluoromethyl, trifluoromethyl, trifluoromethyl , Pentafluoroethyl, heptafluoropropyl, difluoromethyl, 'difluorofluoromethyl, difluoroethyl, difluoropropyl, difluoroethyl,

O: \ 90 \ 90006.DOC -19- 200404535 and dipropylamine. The term "alkylene" includes linear or branched alkyl groups having from one to about ten carbon atoms, any of which may be replaced by one or more hydroxyl groups. More preferred radicals are "low hydroxyalkyl" radicals having one to six carbon atoms and one or more radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl 2 dihydroxypropyl, Hydroxybutyl, and hydroxyhexyl. &Quot; Alkoxy " and " alkoxy " include oxygen-containing groups having an alkyl moiety of from one to about ten carbon atoms. More preferred alkoxy groups are "low alkoxy" having one to six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tertiary-butoxy The term "alkoxyalkynyl" includes one or more alkynyl radicals bonded to a thienyl radical, that is, a monoalkoxyalkyl radical and a dialkoxyalkyl radical are formed. This " alkoxy group may also be substituted by one or more prime atoms, such as fluorine, gas or bromine, to form a haloalkoxy group. More preferred haloalkoxy groups are one to six carbon atoms and one or more halogen, low haloalkoxy groups. "Examples of such groups include fluoromethoxy, gasmethoxy, and trifluoromethyl. Oxy, difluoroethoxy, fluoroethoxy, and fluoropropoxy. "Aryl ,, whether used alone or in combination, means a carbocyclic aromatic containing one, two, or three rings Systems in which sub-rings can be draped or fused together. The term "aryl" includes aromatic groups such as phenyl, fluorenyl, tetrahydrofluorenyl, imprint and biphenyl. The aryl moiety may also be substituted with one or more substituents at a substitutable position. These substituents are independently selected from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxy Carbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amine, halo, nitro, alkylamino, fluorenyl, cyano, carboxyl, aminocarbonyl, alkoxy Carbonyl and alkoxy. The term "heterocyclyl" includes saturated, partially unsaturated and unsaturated heteroatom-containing cyclic groups, wherein the heteroatom may be selected from nitrogen, 0 \ 90 \ 90006 DOC -20- 200404535 sulfur and oxygen. Saturated Examples of heterocyclic groups include saturated heterocyclic rings having 3 to 6-carbon atoms containing 4 to 5 nitrogen atoms (for example, ^ each fluorenyl group). Sitting silk 3 Hexachloropyridine, Hexahydropyridyl , Etc.); saturated 3 to 6-membered ^ / to 2 ^ milk atoms and 1 to 3 nitrogen atoms of heteromonocyclic groups (for example, morpholinyl = saturated 3 to 6-membered containing 1 To 2 sulfur atoms and 1 to 3 gaseous heteroearly bad groups (such as fluorene, etc.). Partially unsaturated heterocyclic groups include dihydrofluorene 'dihydrofluorene' dihydro and dihydro ^ .. Heteroaryl-5 Division includes heterocyclic heterocyclic groups. Examples of heteroaryl include unsaturated 3- to 6-membered heteromonocyclic groups containing! To 4 nitrogen atoms, for example Each group, stilbene, mizolyl, pyrazolyl, pyridyl 'pyrimidinyl, pyrimidinyl, pyridyl, trisyl (for example, 2, trisialyl, trisialyl, 2H 1, 2,3-Difluorenyl, etc.) , 2Η · 4. Sorry 'and so on); Unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms, such as + lyl, isofluorenyl, xyl, benzimidyl, Xinlinji, .Isofluorenyl, benzotrisyl, tetrabenzyl, tetrabenzyl (such as tetrathalo ^ b] pyridyl ', etc.), etc .; unsaturated with oxygen atoms Heterocyclic monocyclic groups of 3 to 6-belt, such as pyranyl, furanyl, etc .; unsaturated 3- to 6-membered heteromonocyclic groups containing sulfur atoms, e.g., cephenyl, etc. Unsaturated 3 to 6-membered heterogeneous early% groups containing 12 oxygen atoms and 1 to 3 nitrogen atoms, such as the number "salyl 'and the number" iso ". 1,2,4 τ monozolyl, humidizolyl, I, "-" diazolyl, etc.); ^ atoms and unsaturated fused heteromonocyclic groups of 1 to 3 nitrogen atoms, (Such as j £ U 歹 J such as 5 azolyl, benzodiaxazolyl, etc.); containing 5 to 2 sulfur atoms and 彳 $, > nitrogen derived unsaturated 3 to 6- Miscellaneous

O: \ 90 \ 90006DOC -21-200404535 Early% groups, such as pyrazolyl, pyrimidiazolyl (eg 1,2,4 oxadiazolyl, = 4% disialyl, disialyl, etc.) Etc .; unsaturated fused heteromonocyclic groups containing 1 to 2 melons and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzothiadiazolyl, etc.) and the like. "Heteroaryl" also refers to a heterocyclic group and an aryl group. Such fused bicyclic groups include benzofuran, benzofluorene, and the like. The heterocyclic group may be There are i to 3 substituents, such as alkyl, hydroxyl, halide, alkoxy, oxygen, amine, and alkylamino. The term "alkylthio" includes one to one attached to a divalent sulfur atom. A linear or branched alkyl group of about ten slave atoms. A more preferred alkylthio group is a "low alkylthio" group of one to six carbon atoms. Examples of such low alkylthio groups Methylthio, ethylthio, propylthio, butylthio, and hexyl μ. The term "thioalkylthio" includes one to about ten carbon atoms linked via a divalent sulfur atom. An alkylthio group on an alkyl group. A more preferred alkylthioalkyl group is a "low-alkylthio group" having an alkyl group of one to six carbon atoms. This type of low-carbylthio group is Examples of radicals include fluorenylthiomethyl. &Quot; Branylsulfinyl "includes linear or branched radicals having an alkyl group of one to about ten carbon atoms bonded to a divalent _S (= 〇) _ group. group. More preferred alkylsulfinylsulfonyl groups are "low alkylsulfinylsulfonyl" alkyl groups having one to six carbon atoms. Examples of such lower alkylsulfinylsulfenyl groups include methylarylenesulfinyl, ethylsulfinylfluorenyl, butylsulfinylfluorenyl, and hexylsulfinylfluorenyl. The term "sulfonyl", whether used alone or in combination with other words such as "alkylsulfonyl" refers to a divalent -so2-yl group. "Alkylsulfonyl" includes sulfonyl Alkyl, wherein alkyl is as defined above. More preferred alkylsulfonyl groups are "low alkylsulfonyl groups" having one to six carbon atoms. Examples of such low alkylsulfonyl groups include methylsulfonyl, ethylsulfonylrt O: \ 90 \ 90006.DOC-22-200404535 and propylsulfonyl. This "alkylsulfonyl" may also be substituted with one or more halogen atoms such as fluorine, gas or bromine to form a haloalkylsulfonyl "" Aminosulfonyl, ", πaminosulfonyl" and "mothylamino", the terms refer to NH202S-. The term ", fluorenyl" refers to the residue formed after organic radicals have been removed. Examples of such alkynyl groups include calcined aryl and aryl fluorenyl. Examples of such low-carbon fluorenyl include fluorenyl and ethyl Propyl, propyl fluorenyl, butyl fluorenyl, isobutyl fluorenyl, pentyl fluorenyl, isopentyl fluorenyl, trimethylethyl fluorenyl, hexyl fluorenyl, trifluoroethyl fluorenyl. The term "carbonyl", either alone or in combination Words such as "alkoxycarbonyl" are used in combination to mean-(C = 0 >. ,, aralkyl). The term includes aryl groups having the above-mentioned carbonyl group. Examples of arylmethyl include benzyl, And the like, and the aryl group on the arylfluorenyl group may be substituted again. The term "hydroxyl", whether used alone or in combination with other words such as "carboxyalkyl", means -C02H., "Carboxyalkyl" includes an alkyl group substituted with a carboxyl group. More preferably, it includes a "low carboxyalkyl group" having the above-mentioned low alkyl group. The low alkyl group may also be substituted. Examples of the above low alkyl group include carboxyethyl and Carboxypropyl. The term "alkoxycarbonyl" means that the alkoxy group described above is bonded to a carbonyl group through an oxygen atom. Group. More preferred are "low alkoxycarbonyl groups" of alkyl groups having one to six carbon atoms. Examples of such low alkoxycarbonyl groups (esters) include substituted or unsubstituted methoxycarbonyl groups , Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl. "Alkylcarbonyl", "arylcarbonyl," and "aralkyl" include the foregoing Radicals of aryl, aryl, and aromatic radicals. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl, and benzylcarbonyl. The term "aralkyl" includes aryl-substituted alkyl groups such as benzyl, diphenylfluorenyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in this aralkyl The radical can be O: \ 90 \ 90006.DOC -23- 200404535, which is substituted by i element, alkyl group, alkoxy group, _alkyl group and _alkoxy group. The term "heterocycloalkyl" includes saturated and partially unsaturated heterocyclyl-substituted alkyls, such as pyrrolidinyl, its 5 TX earth, and heteroaryl-substituted alkyls, such as Pyridylmethyl, quinolylmethyl, fluorenylmethyl, furylethyl, and 4-phosphonylethyl. The heteroaryl group in the heteroaralkyl group may be halogen, alkyl, or haloalkyl Group, and i-alkoxy substituted. The term "aralkyloxy" includes an alkyl group bonded to other groups via an oxygen atom. The term "aralkyloxy group" includes an alkyl group bonded to The term "aralkyl" refers to an aryl group attached to another group via a sulfur atom. The term "aralkyl" refers to an aryl group attached to a group via a sulfur atom. Arylthio on a radical. The term "aminoalkyl" includes an alkyl group substituted with an amine group. More preferred is " low aminoalkyl ". Examples of such groups include aminomethyl The term 'aminoethyl, etc.' refers to an amine group substituted with one or two alkyl groups. "Low alkylamino" having an alkyl moiety of one to six carbon atoms is preferred. Suitable 'low alkylamino groups may be mono-substituted N-alkylamino or di-substituted N, N-alkylamino, such as N-methylamino, N-ethylamino, N, N -Dimethylamino, N, N-diethylamino and the like. The term "arylamino" refers to an amine group substituted with one or two aryl groups, such as an N-benzylamino group. This " arylamino group " may also be on the aryl ring of this group There are further substitutions. The term "aralkylamino" includes amino groups substituted with one or two aralkyl groups. The terms "N-arylaminoalkyl" and "N-aryl-N-alkylaminoalkyl" refer to aminoalkyl substituted with an aryl or an aryl and an alkyl, respectively. This class Examples of groups include N-phenylaminomethyl and N-benzyl-N-methylaminofluorenyl. The term `` πaminocarbonyl '' refers to an amine group of the formula -C (= 〇) NH2. ' The term 'alkylaminocarbonyl' refers to an amino nitrogen atom

O: \ 90 \ 90006.DOC -24- 200404535 Aminocarbonyl substituted with one or two alkyl groups. Preferred are "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl". More preferred are "low N-alkylaminocarbonyl" and "low N, N-dialkylaminocarbonyl", the alkyl portion of which is the aforementioned lower alkyl., The word includes a group having one or more alkyl groups attached to an amine alkyl group. The aryloxy group π-the word includes a group having an aryl group attached to the alkyl group via a divalent oxygen atom. Ffarylthio group The term "radical" includes groups in which an aryl group is linked to an alkyl group via a divalent sulfur atom. The compound used in the method of the present invention may be in the form of a free state base or a pharmaceutically acceptable acid addition salt thereof. The term "pharmaceutically acceptable salts" includes salts that are used to form metal salts and to form free acid or acid addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compound of formula j can be made from inorganic or organic acids. Examples of the inorganic acid are hydrochloric acid, hydrobromic acid, hydrolysic acid, acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic 'aromatic, aromatic fatty groups, heterocyclic, weilic acid, and sulfonic acid organic acids. Examples are acetic acid, acetic acid, propionic acid, succinic acid, and ethanol. Acid, glucose, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, propionic acid, aspartic acid, ammonium acid, benzyl acid, amine Anisic acid, methanesulfonic acid, 4-hydroxyphenylarsinic acid, phenylacetic acid, mandelic acid, dihydroxyarsinic acid, pinanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, Toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, / 5-hydroxybutyric acid, salicylic acid, galacturonic acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of formula I include salts made from aluminum, calcium, lithium, potassium, potassium, sodium and zinc, and N, Nf-diethylideneethyl: 90006.DOC -25- 200404535 Monoamine 'chloroprocaine, Neck Choline, Choline, Diethanolamine, Ethylenediamine,' :: N f-Glucosamine) and Procaine's salt . All available methods use corresponding formulas! Compounds are prepared by, for example, -experimental reactions. Tendency or middle method Two methods of inhibiting cyclooxygenase_2 of the present invention can be slaughtered according to the following methods, unless otherwise stated, such as the formula:

Ux preparation as described. Its scheme

Synthesis scheme illustrates the preparation of cyclooxygenase-2 inhibitors,

O: \ 90 \ 90006 DOC Such as US patent -26- 200404535 5,521207 and WQ95 / 15316 related formula! As shown, today—and attached for reference. In step 1, the test is performed with _ 丨, preferably ⑽ 仏 or touch, and brewing or infusion treatment to form the intermediate duckol form), this intermediate is used without purification. In hydrazone 2, the free ketone of ketone 2 in an anhydrous protic solvent such as pure ethanol or acetic acid with hydrochloride or substituted hydrazine was subjected to reflux treatment to obtain m and 4. After recrystallization or chromatography analysis, 3 is obtained, which is usually solid. Similar pyrazoles can be prepared by the methods described in U.S. Patent Nos. 4,146,72; 5,05i, 5i8; 5,134,142, and 4,914,121, which are hereby incorporated by reference. Scheme Π

Scheme II illustrates a four-step process for the preparation of cyclooxygenase-2 to inhibit pyrazole 8 using silk 5 as described in U.S. Patent No. 5,486,534 (wherein Ra is a hydrogen ion or an alkyl group). In step 1, a ketone 5 is reacted with lithium such as lithium bis (trimethylsilyl) thiamine or lithium diisopropylamidamine (LDA) to form an anion. In step 2, the anion is reacted with an acetating agent to prepare a dione 6. In step 3, diazole 6 is reacted with substituted hydrazine to form pyrazole 7. In step 4, emulsify tons of 7 O: \ 90 \ 90006.DOC -27- 200404535 to emulsify "1 ~ 〇XGne® (potassium peroxymonosulfate), 3. · gas permanganic acid (MCPBA) or over gas Chlorination, the reaction yields the required 3-benzyl) phenyl_pyridine. A mixture of 8 and 5- (alkylsulfonyl) phenyl_esalyl isomers. Can be analyzed by chromatography or recrystallized It is obtained as a white or gray-yellow solid ㈣ leaf blade 8.

Square HI 30-R:

Δ Mono or dione 6 can also be prepared by using hydrazone 5 with a base, such as sodium hydride, in a solvent, such as monofluorenamide, and then reacting with nitrile to obtain an amino ketone. This amine ketone is then reacted with an acid to obtain 6. Similar salamanders can also be prepared as described in U.S. Patent No. 3,984,4 ^ 1, which is incorporated herein by reference.

O: \ 90 \ 90006.DOC -28- 200404535 Cyclooxygenase-2 inhibitor diaryl / heteroarylthiophene (where τ is s and Rb is alkyl) 玎 US Patent 4,427,693; 4,3. 2,461; 4,381,311; 4,590,205; and 4,820,827 and PCT documents WO95 / 0050i and WO94 / 15932, which are hereby incorporated by reference for reference. Similar pyrrole (where T is N), furanone and furan (where T is 0) can be prepared by the methods described in pCT documents WO 95/00501 and wo 94/15 932, and EP799,823.

Scheme IV? / S

NaH T3SC1

OTBS 17 MCPBA t

O: \ 90 \ 90006.DOC -29- 200404535 Cyclooxygenase-2 inhibitor diaryl / heteroaryloxazole can be used in US patents 3,743,656; 3,644,499 and 3,647,858 and PCT documents WO 95/00501 and WO 94/27980 Prepared by the method, and attached for reference. Similar pyrazole compounds can be prepared by the methods described in WO 96/19463 and WO 96/19462.

Option V

22 23

1) CiS〇3H

2) NH.OH 1

O: \ 90 \ 90006.DOC-30-Μ — * Ο

24 200404535 Cyclooxygenase-2 inhibitor diaryl / heteroarylisocyanide can be prepared by the methods described in US Patent 5,633,272, PCT documents WO 92/05 162 and WO 92/19604, and European Publication EP 26928, Attached here for reference. Sulfonamide 24 can be prepared from hydrated isoxazole 23 in two steps. First, hydrated isoxazole 23 is treated with two or three equivalents of chlorosulfonic acid at 0 ° C to form sulfonyl chloride to dust. In the second step, the sulfonium gas thus generated is treated with concentrated ammonia to obtain a sulfonamide derivative 24.

Option VI

O: \ 90 \ 90006 DOC -31-200404535 Scheme VI shows a three-step method for preparing the cyclooxygenase_2 inhibitor imidazole 29 of the present invention. In step 1, nitrile (RiCN) 25 and primary phenylamine 26 are present in the presence of an alkyl aluminum reagent such as trimethyl aluminum, triethyl aluminum, vaporized dimethyl aluminum, and vaporized monoethyl aluminum. Reaction in an inert solvent such as toluene, benzene and xylene to obtain 脒 27. In step 2, 脒 27 and 2-halone (where X is Br or Cl) in a base such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or a hindered tertiary amine such as N, N, It is reacted in the presence of isopropylethylamine to make 4,5-monohydrogen sigma glutamate 28 (where Rb is an alkyl group). Suitable solvents for this reaction are isopropanol 'acetone and dimethylformamide. This reaction can be carried out at a temperature of 20 to 90 ° C. In step 3 ', 4,5-dihydroweisal 28 is dehydrated in the presence of an acid catalyst such as methanesulfonic acid or mineral acid to form the di-substituted imidazole 29 of the present invention. Suitable solvents for this dehydration step are, for example, toluene, dimethylbenzene and benzene. This dehydration step uses trifluoroacetic acid as a solvent and catalyst. In some cases (for example, when R3 = fluorenyl or phenyl), this intermediate 2 8 may not be easily separated. Under the above conditions, the target miso can be directly produced. Similarly, it is also possible to prepare an imidazole having a sulfonylphenyl moiety attached to the 2-position 'and R1 attached to the nitrogen atom at the 1-position. Diaryl / heteroarylimidazoles can be prepared by the methods described in U.S. Patent No. 4,822,805, U.S. Patent Application Serial No. 08 / 282,395, and PCT Document WO 93/14082, and are incorporated herein by reference. O: \ 90 \ 90006.DOC -32- 200404535 .Λ Catalyst Case VII CTMS 丨 .c ::

SF / 3 4

NH ^ OAcR3CHO I HOAc

R s

R

o s

R 5 3 6 3

O: \ 90 \ 90006 DOC 200404535 The subject-flavored sialoxygenase-2 inhibitor compound% can be synthesized according to the order listed in the scheme νπ. They can be converted into trialkylsilyl cyanide, such as trimethylmethoxyl cyanide (TMSCN), in the presence of a catalyst such as zinc iodide (ζηΐ2) or potassium cyanide (KCN). Protected cyanohydrin 3m. The cyanohydrin 31 is reacted with the strong test ', and then treated with benzyl 32 (wherein R2 is an alkyl group), and treated with acid and alkali in this order to obtain a stupid marriage 33. Examples of strong tests suitable for this reaction are lithium diisopropylammonium amine (LDA) and lithium hexamethyldisulfite. Benzoin 33 can be converted to benzoin 34 by reacting it with a suitable oxidizing agent such as bismuth oxide or manganese digas, or by performing Swern oxidation with dimethylsulfinium (DMSO) and trifluoroacetic anhydride. Benzozone 34 can be prepared by directly reacting the anion of cyanohydrin 31 with a substituted benzamidine gas. The compounds 33 and 34 can be converted as intermediates according to the chemical reactions known to those skilled in the art and the method described by M.R. Grimmett in Advances in Heterocyclic Chemistry, 12, 104 (1970) "Advances in Imidazole Chemistry". Imidazole 35 (where R is an alkyl group). The conversion of 34 to 35 is accomplished by reaction with ammonium acetate and a suitable aldehyde (r3cho) in acetic acid. Benzoin 36 can be converted to form saliva 38 by reaction with formaldehyde. In addition, Benzoin 36 can be converted to imidazole by first sulfonation with a suitable fluorenyl group (114〇_) and treatment with ammonium hydroxide. Those skilled in the art will understand that the oxidation of sulfides (where R2 is fluorenyl) into sulfones Completed starting with compound 35 at any reaction stage, including oxidation of imidazole 38 with, for example, oxidants such as hydrogen peroxide, acetic acid, m-peroxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE®) Diaryl / heteroarylimidazole can be used in U.S. Patents 3,707,475; 4,686,23 1; 4,503,065; 4,472,422; 4,372,964; 4,576,958; 3,901,908

O: \ 90 \ 90006DOC -34- 200404535, US Application Serial No. 09 / 281,903, European Publication E〇372,445, and PCT document WO 95/00501 were prepared by the method described herein, and are hereby attached for reference. Scheme νιπ

O: \ 90 \ 90006 DOC -35- 42 200404535 One-group / heteroaryl +, x-threon cyclooxygenase_2 inhibitor can be US patent 5,3 4 4,9 91 and pc τ Order and WO Prepared by the method described in 95/00501, Bayi is attached for reference. 7

Wanlai JX

• 3 r-f R

H

crΔ h ,,?: j: J 00 / -r, c c H 2, c2 a F c N

5 samples, synthetic scheme IX shows that the basic enzymatic aspirinase 2 inhibitor 44 is prepared from brominated biphenyl intermediate 43 (prepared by a method similar to that described in synthetic scheme VIII) and a suitable substituted phenylboronic acid. A coupling agent similar to the one exhibited by Suzuki et al. [Synth · commun, u, 513 (1981)] was used, with intermediate 43 and terephthalic acid in toluene / ethanol and Pd. A catalyst, such as reflux reaction in the presence of (triphenylphosphine) palladium (0) and 2M sodium carbonate, produces the corresponding 1,2-diarylbenzene anti-inflammatory agent 44 of the present invention. This terphenyl compound can be prepared by the method described in PCT Patent Document No. WO 96/16934, and is hereby attached for reference. ^

Option X

O: \ 90 \ 90006.DOC

2 R 〇 f ons

43 46 -36- 47 200404535 / heteroaryl cardiocyclic oxygenase-2 _ The preparation can be prepared by the method described in the US patent state number, European patent application called PCT document WO 3339 and purchase 95/00501, today Call and attach for reference. Eccentric sitting can be prepared by the method described in PCT file W09 Huzhou, which is attached for reference. The diaryl ^ heteroaryl ° cyclooxygenase-2 preparation can be prepared by the methods described in US Patent No. 4'011328 '4,533,666 and WO 96/24584 and wo 96/24585. for reference. The biological evaluation of the effect of cyclooxygenase-2 inhibitors on preterm labor can be determined by the following model: 'The method described by Slater et al. [Am. J. 〇bstet Gynec〇1., 172, 77_82 (1995) ] The materials, reagents and methods are used to make human fetal membrane models. Cox_2 inhibitors should be active at a dose of 20 mg / kg. The effect of the mounted oxygenase-2 inhibitor on the prevention of arterial duct closure is determined by the following model: According to the method described by Velvis et al. [Pediatr · Res ·, 30, 62-8 (1991)] Materials, reagents and methods are used to make sheep model. The COX_2 inhibitor should be active at a dose of 20 mg / kg. Materials and Methods The compounds of the present invention can be administered in any desired route known in the art, preferably in a pharmaceutical composition suitable for the route of administration, in the desired therapeutically effective amount. For example, the active compounds and compositions can be administered orally, intravascularly, intraperitoneally, intranasally, intratracheally, subcutaneously, intramuscularly or topically (including aerosols). r ·, O: \ 90 \ 90006.DOC -37- 200404535 The administration of the present invention can prevent or treat. The methods and compositions used herein can be used alone or in combination with other treatments known in the art for the prevention and treatment of term labor. Alternatively, the methods and compositions described herein can be used as adjuvant therapy. For example, cyclooxygenase-2 inhibitors can be administered alone or in combination with other agents that treat or prevent preterm delivery. The term `` adjuvant therapy '' (or 'combination therapy,') is used to define cyclooxygenase-2 inhibitors and other medicinal agents, which means that each dose of the combined drug is administered sequentially, and that these agents are administered simultaneously, For example, a single formulation is given a fixed proportion of live clams, or a single formulation is given multiple doses of each formulation. The present invention also includes a pharmaceutical composition to assist in the prevention and treatment of full-term preterm delivery. The composition contains a therapeutically effective amount of a compound of formula "Material"), and other agents or other growth inhibitors or other drugs or nutritional agents. For oral administration, the pharmaceutical composition may be, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in a unit dosage form, which contains the active ingredient in teriary. Examples of such dosage units are capsules, tablets, powders, granules or suspensions, which contain additives such as lactose, mannitol, corn flour or potato starch; binding agents such as crystalline cellulose, cellulose Derivatives, gum arabic, corn flour or gelatin; there are disintegrating agents such as corn flour, 'potato starch or sodium methylcellulose; there are smooth or stearic acid calming. The active ingredient may also be administered as a composition by injection, for pelvic use, e.g., saline, dextrose or water as a suitable vehicle. When given intravenously, intramuscularly, subcutaneously, or intraperitoneally, the person can be combined with a sterilized aqueous solution. This aqueous solution is preferably compatible with the receiving blood

O: \ 90 \ 90006.DOC -38- 200404535 isotonic. Such formulations can be made into aqueous solutions by dissolving solid active ingredients in physiologically compatible substances such as sodium chloride 'glycine and the like' and physiologically compatible pH, in aqueous solutions of granules. Sterilize again. This formulation can be contained in a unit-dose or multi-dose container β, such as a closed ampoule or vial. Formulations suitable for parenteral administration generally include a sterile aqueous preparation of the active compound, which preparation is preferably made isotonic. Formulations for injection can also be formulated by suspending or dispersing the compounds in aqueous solvents such as vegetable oils, synthetic fatty acid glycerides, high fatty acid esters or polyethylene glycols. Formulations for topical use include gels, creams, oils, and the like. For spray administration, the compound can be formulated with a known aerosol vehicle, such as physiological saline, and administered using a commercially available sprayer. Bioavailability can be enhanced with formulations of fatty acid sources. Therefore, when administered rectally, the active ingredient can be formulated into a suppository, which is used as a base for substances that are solid at room temperature but soluble in body temperature. Commonly used bases include coconut oil, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of different molecular weights, and polyethylene stearate. The dosage form and 1 can be confirmed by referring to known medicines for treatment or prevention of full-term preterm delivery. The amount of therapeutically active compound to be administered and the dosage of the drug used to treat the disease using the compounds and / or compositions of the present invention will depend on a number of factors, including age, weight, gender and patient health, the severity of the disease, the route and frequency of administration, The particular compound used, as well as the pharmacokinetic properties of the individual patient to be treated, will therefore vary. If the compound is administered topically rather than systemically, and if it is intended for prevention rather than treatment, O: \ 90 \ 90006.DOC -39- 200404535 will require a therapeutically effective amount given by 'lower dose and time required for treatment . The frequency of treatment given may be determined by the attending physician. Those skilled in the art will understand that it can be adjusted to an appropriate amount depending on the individual. This pharmaceutical composition may contain about 0.1 to about 2000 mg of active ingredient, preferably about 0.5 to 500 mg, and most preferably about 1 To about 200 mg. The dosage per day is about 0.01 to 100 mg / kg body weight, preferably about 0.1 to 50 mg / kg body weight, and most preferably about 1 to 20 g / kg body weight, more preferably. The daily dose may be given in one to four times / day. All references are attached for reference. Although the invention has been described in terms of specific embodiments, the detailed description of these specific embodiments does not limit the invention.

O: \ 90 \ 90006.DOC 40-

Claims (1)

200404535 The scope of patent application: 1 · A type of treatment or prevention for the maintenance of fetal arteries during the treatment of patients with pre-term delivery or prevention of full-term labor. General theory, > 财 # 疋 勒 脉 V 官 次 ％ A pharmaceutical composition, i. A composition comprising a therapeutically effective amount of a compound of formula I Wherein A is selected from the group consisting of pyrazolyl, isoxazolyl, thienyl, dihydrofuranyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isopyrazolyl, cyclopentenyl, benzene And pyridyl groups; wherein R1 is at least one substituent selected from heterocyclic, cycloalkyl, cycloalkenyl and aryl, where R1 is optionally substituted with one or more groups Substituted, these groups are selected from the group consisting of alkyl, haloalkyl, cyano, carboxy'alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amine, alkylamino, arylamino, A nitro group, an alkoxyalkyl group, an alkylsulfinite group, an i element, an alkoxy group and an alkynylthio group; wherein R2 is selected from an alkyl group and an amine group; and R3 is a group selected from the group consisting of Halogen, alkyl, alkenyl, fastyl, oxygen, cyano, weyl, cyanoalkyl, heterocyclooxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, Fluorenyl, heterocyclyl, cycloalkenyl, aralkyl, heterocycloalkyl, fluorenyl, alkylthioalkyl, hydroxyalkyl, alkoxy, aryl, aryl Alkyl, arylalkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthio O: \ 90 \ 90006.DOC 200404535 alkyl, aralkoxyalkyl , Alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkylarylamino Carbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl_N-aralkylamino, N-alkane Arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-arylalkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl , N-alkyl-N-arylaminoalkyl, aryloxy, aralkyloxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, Aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl; or pharmaceutically acceptable Accepted salt, but the compound is not 4- [5- (4-fluorenylphenyl) -3- (trifluoromethyl) -1Η-Houbi σ sitting-1-yl] benzamine ; C elecoxib). 2. The composition according to item 1 of the scope of patent application, wherein A is selected from the group consisting of oxazolyl, isoxazolyl, fluorenyl, dihydrofuranyl, succinyl, pyrrolyl, sigma sitting group, and Fluorenyl, misoyl, isosalyl, cyclopentyl, phenyl and pyridyl; wherein R1 is a heterocyclic group selected from 5- and 6-membered, lower cycloalkyl, lower cycloalkenyl, and An aryl group selected from phenyl, biphenyl, and fluorenyl, where R1 is optionally substituted at one or more positions selected from lower alkyl, lower haloalkyl, cyano, carboxy, and lower alkoxy Carbonyl, hydroxy, lower hydroxyalkyl, lower i alkoxy, amine, lower alkyl amine, phenylamino, nitro, lower alkoxyalkyl, lower alkyl sulfinyl, halogen, low Alkoxy and lower alkylthio groups are substituted; wherein R2 is selected from lower alkyl and amine groups; and R3 is selected from halogen, lower alkyl, O: \ 90 \ 90006.DOC -2- 200404535 oxygen, cyano, weyl, lower cyanoalkyl, heteroaryloxy 'lower alkyloxy, lower cycloalkyl, phenyl, lower alkyl, 5- or 6-membered heterocyclic group, Lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl Lower alkoxyalkyl, heteroaryloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, aminoalkyl, alkylaminoalkyl, aryloxy, And aralkoxy; or a pharmaceutically acceptable salt thereof. 3. The composition according to item 2 of the scope of patent application, wherein A is selected from the group consisting of oxazolyl, isoxazolyl, diargyryl, imidazolyl, and pyrazolyl; wherein R1 is selected from 5- and 6- Membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl, and aryl selected from phenyl, biphenyl, and fluorenyl, where R1 is optionally substituted at one or more positions selected from the following: Group substituted: low alkyl, low halogen, cyano, alkyl, low alkyl, hydroxy, low hydroxyalkyl, low iS alkoxy, amine, low alkylamino, phenyl Amine, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halogen, lower alkoxy and lower alkylthio; wherein R2 is amine; and wherein R3 is selected from oxygen and cyano 'Jiji' low alkoxy alkoxy, low weikyl radical, low cyano alkynyl, II element, low alkynyl, low alkynyloxy, lower cycloalkyl, phenyl, lower i alkyl, 5- or 6 -Membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, lower alkyl Alkylaminocarbonyl Alkyl, lower alkylaminoalkyl, phenyloxy, and aralkyloxy; or pharmaceutically acceptable salts thereof. 4. The composition according to item 3 of the scope of patent application, wherein A is selected from the group consisting of a sigma sigma group, an odd sigma sigma group, a sigma sigma group, and a salyl group; where R1 is as needed 0: \ 90 \ 90006 DOC 200404535 To be substituted at the substitutable position with one or more phenyl groups selected from the group consisting of methyl, ethyl, isopropyl, butyl, tertiary-butyl, isobutyl, pentyl, Hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, gas methyl, dichloromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl'di Pyropropyl 'diaminoethyl, diaminopropyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amine, N-methylamino, N, N- Dimethylamino, N-ethylamino 'N, N-dipropylamino' N-butylamino 'N-methyl-N-ethylamino, phenylamino, nitro, Methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, and methylthio; where R2 is Amine group; and R3 is selected from oxygen, cyano, carboxyl, methoxycarbonyl, ethyl Carbonyl, carboxypropyl, carboxyfluorenyl, carboxyethyl, cyanomethyl, fluorine, gas, bromine, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl Methyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dimethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, diethyl 'Dioxopropyl' dioxoethyl, dioxopropyl, methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, cyclohexyl, phenyl, outer stilbyl, p Sephine, Soul 17 Sitki, 4. Seat group, sigma succinyl group, p-well group, hydroxy fluorenyl, hydroxypropyl, benzyl, fluorenyl, phenylcarbonyl, fluorenyl fluorenyl, sulfanyl fluorenyloxy, aminoamino , N-methylaminocarbonyl, N, N-diamidinoaminocarbonyl, N, N-diamidinoamino, N-ethylamino, N, N-dipropylamino, N-butane Amino, N-methyl-N-ethylamino, aminomethyl, N, N-dimethylaminofluorenyl, N-methyl O: \ 90 \ 90006.DOC 200404535 ethylamino Methyl, unyloxy, and phenyloxy; or a pharmaceutically acceptable salt thereof. 5. The composition according to item 丨 of the declared patent scope, wherein the compound is a compound selected from the group consisting of the following, and a pharmaceutically acceptable salt thereof: 6- [0 (4-chlorobenzylsulfonyl) " · 1H-pyrrole_2_yl] methyl] -3 (2H) -takken_; 3- (3,4-monofluorophenyl) _4_ (4-methylsulfazinylphenyl) _2_ (5 ^ 1) _Furanos; 3-phenyl-4- (4-methylsulfonylphenyl) -2- (5H) -furanone; 4- [5- (4-Gaphenyl) -3- ( Trifluoromethyl) -iH-pyrazol-1-yl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -iH- Pyrazol-1-yl] benzamide; 3- [1- [4- (methylsulfonyl) phenyl] -4-trifluorofluorenyl-1H-imidazol-2-yl] 2-methyl-5- [1- [4- (methylcontinyl) phenyl] -4-tri-Imethyl-1fluoren-imidazol-2-yl] pyridine; 4- [2- (5-methyl Pyridin-3-yl) -4- (trifluorofluorenyl) -fluorene-pyrazol-1-yl] benzylsulfonamide; 4- [5-methyl-3-phenylisohumazol-4-yl ] Sulfasulfonamide; 4- [5-hydroxyethyl-3-phenylisohumazol-4-yl] benzenesulfonamide; [2-trifluorofluorenyl-5- (3,4-difluorobenzene ) -4-oxazolyl] benzenesulfonamide; 4- [2-methyl-4-phenyl-5-humazolyl ] Benzenesulfonamide; and 4- [5- (3-fluoro-4-fluorenyloxyphenyl-2-dimuryl). Syl] benzene O: \ 90 \ 90006.DOC 200404535 sulfonamide. 6. · A pharmaceutical composition for treating or preventing fetal arterial duct circulation during the treatment of a patient in need of such treatment or prevention of full-term delivery, wherein the composition comprises a therapeutically effective amount of a compound of formula II See where R4 is selected from hydrogen ion, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl Aminocarbonyl, carboxyalkylaminocarbonyl, weikyl ', alkynyl, alkynyl, amino', amine, alkynyl, alkoxycarbonyl, cyanoalkenyl, and hydroxyalkyl; Wherein R5 is selected from the group consisting of hydrogen ion, alkyl, cyano, mesityl, cycloalkyl, alkylsulfonyl, and halogen; and R6 is selected from the group consisting of arkenyl, aryl, cycloalkyl, and cyclo. Alkenyl, and heterocyclic; where R4 is optionally substituted with one or more groups selected from the group consisting of halogen, alkylthio, alkylsulfonyl, cyano, nitro , Haloalkyl, alkyl, hydroxy, alkenyl, hydroxyalkyl, weyl 'cycloalkyl', alkylamino, dialkylamino, alkyloxycarbonyl, aminocarbonyl, alkoxy 'haloalkyl Oxy 'sulfamoyl, heterocyclyl and amine; or a pharmaceutically acceptable salt or derivative thereof, but the O: \ 90 \ 90006.DOC 5 is not 4 [5- (4-methyl Phenylbenzene Group) _3_ (trifluoromethyl) _ih_pyrazole-1-yl] benzenesulfonamide (Herofluorene). According to the claim, the composition of item 6 of the patent scope, wherein R4 is selected from the group consisting of low-density burned groups, wherein R5S hydrogen ion, and R6 is optionally substituted at a position with-or more groups selected from Group-substituted phenyl: a low-carbon group, and a low-carbon group; or a pharmaceutically acceptable salt or derivative thereof. 8. The composition according to item 7 of the scope of application for a patent, wherein the compound is selected from the following compounds and their pharmaceutically acceptable salts: Heart [5- (4-Gaphenyl) -3- (trifluoromethyl) _1Η-pyrazolyl] benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -iH-pyrazol-1-yl] benzenesulfonamide; 4- [5- (4- Fluorophenyl) -3- (trifluoromethyl than fluoren-1-yl) benzite yellow amine; Heart [5- (4 • methoxyphenyl) -3- (trifluoromethyl) -iH- Pyrazol-1-yl] bensulfonamide;, 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1Hw than salan-1-yl] benzite scutamine; 4- [3- (difluorofluorenyl) -5- (4-fluorenylphenyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5 -Phenyl-1'-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methoxyoxyphenyl) -1'-pyrazol-1-yl ] Benzylsulfonamide; 4- [3- (difluorofluorenyl) -5- (3-fluoro-4-methoxyphenyl) -1Η_pyrazole-1-O: \ 90 \ 90006 DOC -7 -200404535 group] Benzoamine; and 4- [5- (3-fluoro-4-methoxyphenyl) _3- (trifluoromethyl) · 1Η-pyrazole-; μ group] benzenesulfonamide 9. The composition according to item 7 of the scope of patent application, wherein the compound 4_ [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-speakazol-1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof. I. According to the scope of the patent application The composition of item 7, wherein the compound is 4- [5- (3-fluoro-4-fluorenyloxyphenyl) _3_ (difluoromethyl) -iH-pyrazolyl) benzylsulfonamide or its A pharmaceutically acceptable salt. II. A pharmaceutical composition for treating or preventing term delivery to a subject in need of such treatment or prevention, wherein the composition comprises a therapeutically effective amount of a compound of formula I Wherein A is selected from 4-fluorenyl, iso-0 salyl, dihydrosulfanyl, amidazolyl, pyridyl, and pyrazolyl; wherein R1 is a heterocyclic group selected from 5- and 6-membered, lower ring Alkyl, lower cycloalkenyl, and aryl selected from phenyl, biphenyl, and fluorenyl, where R1 is optionally substituted with one or more groups selected from the following, lower alkyl Base, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxy, lower hydroxyalkyl, lower haloalkoxy, amine, lower alkylamino, phenylamino, nitro, lower alkyl Oxyalkyl, lower alkylsulfinyl, sulfonium, lower alkoxy and lower alkyl O: \ 90 \ 90006.DOC 200404535; wherein R2 is an amine group; and wherein R3 is selected from oxygen, Cyano, weyl, low alkoxycarbonyl, low alkynyl, low cyano alkynyl, halogen, low alkynyl, low alkynyloxy, low cyclic alkynyl, phenyl, low halogen alkyl, 5- or 6 -Membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl, lower alkoxyalkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, lower alkyl Aminoamino carbonyl , Lower alkylamino group, a phenyl group, an alkoxy group, and aryloxy; or a pharmaceutically acceptable salt thereof treating the primary disease. 12. A composition according to item 11 of the scope of patent application, wherein A is selected from the group consisting of oxazolyl, isoxazolyl, imidazolyl, pyridyl, and pyrazolyl; wherein R1 is optionally substituted at a position of one or A plurality of phenyl substituted with a group selected from methyl, ethyl, isopropyl, butyl, tertiary-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, Trifluoromethyl, trifluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, difluoroethyl, dichloro Propyl, cyano, sulphydryl, methoxyl, meridian, mesityl, trimermethoxy, amine, N-fluorenylamino, N, N-dimethylamino, N -Ethylamino, N, N-dipropylamino, N-butylamino, N-fluorenyl-N-ethylamino, phenylamino, nitro, methoxymethyl, methyl Sulfinylsulfenyl, fluorine, gas, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, and methylthio; where R2 is an amine group; and where R3 is Selected from the group consisting of fluorene, cyano, carboxyl, fluorenyloxycarbonyl, ethoxycarbonyl, carboxypropyl, Methyl, carboxyethyl, cyanomethyl, fluorine, gas, molybdenyl, ethyl, isopropyl, butyl, tertiary-butyl, isobutyl, pentyl O: \ 90 \ 90006DOC- 9- 200404535 group 'hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, gas methyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, 1 Ethyl, difluoropropyl, dichloroethyl, dichloropropyl, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl, phenyl, ratio σ 疋Selenium, VT sephenyl, alpha alpha, 4 sigma, sigma sigma, P to p yl, .methyl, hydroxypropyl, benzyl, formamyl, phenylcarbonyl, methoxy Methyl, furanyloxy, aminocarbonyl, N-methylaminocarbon ', N, N_dimethylaminocarbonyl, N, N_dimethylamino, N_ethylamine , N, N-dipropylamino, ν-butylamino, N-methyl-N-ethylamino, aminomethyl, N, N-dimethylaminomethyl, N-methyl -N-ethylaminomethyl, fluorenyloxy, and phenyloxy; or a pharmaceutically acceptable salt thereof. 13. The composition according to item i 丨 of the scope of patent application, wherein the compound is a compound selected from the group consisting of the following compounds, and a pharmaceutically acceptable salt thereof: 6-[[5- (4-Gabenzyl) -i , 4-dimethyl_1H_pyrrole · 2-yl] methyl] -3 (2H) -tagongone; 3- (3,4_difluorophenyl) _4- (4-methylgarthretinylbenzene ) _2- (5Η) -syrone; 3-phenyl-4- (4-fluorenylsulfonylphenyl) _2- (5Η) -furanone; '[5- (4-Gaphenyl) _3_ (trifluorofluorenyl) _1Η-pyrazole- 丨 _yl] benzenesulfonamide; 4- [5- (4-methylbenzyl) -3- (trifluoromethyl) -iHw than salyl] benzene Berberamine; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) _1H_pyrazole O: \ 90 \ 90006.DOC -10- 200404535 group] Benzylsulfonamide; 3- [1- [4- (fluorenylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazol-2-yl]; 1- [4_ (fluorenylsulfonyl) phenylphenyl 4-trifluorofluorenyl- 丨 shitolu-2-yl] ring bite; 4- [2- (5-fluorenylpyridylphenyl 4fluorotrifluoro Fluorenyl) _1Η_pyrazol- ^ yl] benzite yellow amine; 4- [5-methyl-3-benzylisoxazol-4-yl] benzenesulfonamide; 4- [5-hydroxyethyl Phenylisozazol_4_yl] benzene Fluorenamine; [2-trifluorofluorenyl-5- (3,4-difluorophenyl) -4-oxazolyl] benzenesulfonamide; 4- [2-methyl_4-benzyl-5- Pyrazolyl] benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-'oxazolyl] benzenesulfonamide. 14. A pharmaceutical composition for the treatment or prevention of full-term delivery to a subject in need of such treatment or prevention, wherein the composition comprises a therapeutically effective amount of a compound of formula II Where R4 is selected from the group consisting of hydrogen ion, alkyl, haloalkyl, alkoxy, cyano, cyano, carboxy, amine, carbonyl, carbamoylaminocarbonyl, cycloalkylaminocarbonyl, aryl Aminocarbonyl, carboxyalkylaminocarbonyl, O: \ 90 \ 90006.DOC -11-200404535 carboxyalkyl, aralkyloxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyano Alkenyl, and hydroxyalkyl; wherein R5 is selected from the group consisting of hydrogen ion, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl, and halogen; and wherein R6 is selected from arylalkenyl, aromatic Group, cycloalkyl group, cycloalkenyl group, and heterocyclic group; wherein R4 is optionally substituted with one or more groups selected from the group consisting of iS element, alkylthio group, and alkylsulfonic acid. Fluorenyl 'cyano, cyano, halo, alkyl, alkenyl, alkenyl, alkenylalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxyrotranyl' Amine group, alkoxy group, halooxy group, amine group, heterocyclic group and amine group; or a pharmaceutically acceptable salt or derivative thereof for treating the patient. 15_ The composition according to item 14 of the scope of patent application, wherein r4 is selected from the group consisting of low-halogenated alkyl groups; wherein R5 is a hydrogen ion; and R6 is optionally substituted at one or more positions selected from Group-substituted phenyls: oxane, lower alkyl, and lower alkoxy; or pharmaceutically acceptable salts or derivatives thereof. 16. The composition according to item 14 of the scope of application, wherein the compound is selected from the following compounds and their pharmaceutically acceptable salts: chlorophenyltrifluorofluorenyl) _1 曱 _pyrazol-1-yl] benzenesulfonamide ; 4- [5-Phenyltrifluoromethyl: MH-dazol-1-yl] benzenesulfonamide; 4- [5-('fluorophenyl) _3_ (trifluoromethyl) -1Η-ρ ratio Azole-; [_yl] benzenesulfonamide; O: \ 90 \ 90006.DOC -12- 200404535 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1Η- ρbizol-1-yl] benzite xanthanamine; 4- [5- (4 -Gaphenyl) -3- (dioxomethylyl) benzite xanthanamine; 4- [5- (4- Methylphenyl) -3- (trifluoromethyl) -1Η-speakazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-fluorenylphenyl) ) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide; 4- [ 3- (difluoromethyl) -5- (4-methoxyphenyl) -1Η-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluorofluorenyl) -5- ( 3-fluoro-4-methoxyphenyl) -1'-pyrazol-1-yl] benzenesulfonamide; and 4- [5- (3-fluoro-4-methoxyphenyl) -3- ( Trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide. 17. According to the application The composition of item 14 of the patent, wherein the compound is 4- [5- (4-fluorenylphenyl) -3- (trifluorofluorenyl) -1Η-pyrazol-1-yl] benzenesulfonamide or its A pharmaceutically acceptable salt. 18. The composition according to item 14 of the scope of application for a patent, wherein the compound is 4- [5- (4-phenyl) -3- (difluorofluorenyl) -1H-toxazole- 1-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof. 19. The composition according to item 14 of the scope of patent application, wherein the compound is 4- [5- (3-fluoro-4-fluorenyloxyphenyl) ) -3- (difluorofluorenyl) -1Η-ρbiazol-1-yl] benzsulfonamide or a pharmaceutically acceptable salt thereof. O: \ 90 \ 90006.DOC -13-200404535 柒, designated representative Figures: (1) The designated representative figure in this case is: (). (II) Brief description of the element representative symbols in this representative figure: (none) 捌 If there is a chemical formula in this case, please reveal the chemical formula that can best show the characteristics of the invention: I O: \ 90 \ 90006.DOC