TW577739B - Pharmaceutical composition comprising celecoxib for maintaining circulation through fetal ductus arteriosus during treatment or prevention of preterm labor - Google Patents

Abstract

This invention relates to a pharmaceutical composition for maintaining circulation through the fetal ductus arteriosus during treatment or prevention of preterm labor in a subject in need of such treatment or prevention, comprising a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (celecoxib) or a pharmaceutically-acceptable salt or derivative thereof.

Description

577739 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (Scope of the invention The invention belongs to the scope of prevention and treatment of full-term childbirth. More specifically, the invention relates to cyclooxygenase_2 inhibitors Or its derivatives to prevent and treat patients before and after full-term use. BACKGROUND OF THE INVENTION For example, repaglin plays a major role in the inflammation process, and inhibits the production of prostaglandins, especially the inhibition of PGG2, PGH2, and PGE2. The common goal of anti-inflammatory drugs has been discovered. However, general nonsteroidal anti-inflammatory drugs (NSAID'S), which are active in reducing pain caused by prostaglandin and swelling caused by the inflammatory process, affect other prostaglandin-adjusted and It is also active in the process without inflammation. Therefore, the high doses of most NSAID'S can cause serious side effects, including life-threatening ulcers, which limit their therapeutic use. Instead of NSAID, s is Corticosteroids, and this also has side effects, especially when used for long-term treatment. It has now been discovered that NS AID's is by inhibiting human peanut Enzymes in the / prostaglandin pathway, including cyclooxygenase (COX), prevent the production of prostaglandins. Recently defamable enzymes caused by inflammation (called "cyclooxygenase_2 (c〇X-2y The discovery of "prostaglandin G / Η synthase II") provided the actual target for inhibition, and this kind of inhibition more effectively reduced inflammation and had fewer side effects. Natural preterm full-term delivery during the suspect period is medical Facing important and increasing problems. Little is known about the causes of preterm delivery, and little progress has been made in the examination and general management of preterm delivery. It is safe to stop preterm delivery and achieve pregnancy. Full-term capacity has always been pursued by the medical and scientific communities. Production before full-term accounted for the major part of death during postpartum period, and was also postpartum. 4- This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (please First read the precautions on the back to write this page)-Packing · 577739 A 7 V. Invention Description (3 Even if the most anticipated anti-laboratory drug used today is rich or inhibited from dying a long time ago, it is unsatisfactory ... except that it has proved ineffective, Such standard music pair Mothers and fetuses may also have serious side effects. Μ Inhaled anesthetics that achieve relaxation of the uterus have been shown to produce significant myocardial depression in the mother and fetus. It is clear that the largest doses of magnesium and betamimetlcs are administered to the child after delivery. Active treatment is very toxic to the mother. In this clinical situation, trying to avoid pulmonary edema will cause the mother's second volume to be too low. The literature reports that the uterine artery has diastolic reflux. The NSAIDs have been used to treat and prevent term. Studies have been done before childbirth. Clinical evaluations of indomethacin and sulindac have been conducted. However, the use of these compounds is obviously limited because of their side effects, including fetal arterial duct contraction and tricuspid valve return, This can cause fetal right heart failure, and so on. These side effects limit the use of NS AIDs, especially during the most important last trimester of pregnancy. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, recently found an increase in cyclooxygenase_2 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 delivery due to spontaneous abortion or mother infection (Silver et al., J. Clin. Invest., 95, 725-3 1 (1995)). Sawdy et al. Describe the use of nimesulide in preventing preterm labor (The Lancet, 350, 265-6 (1997)). W094 / 26731, published on November 24, 1994, illustrates the use of phenphene COX-2 inhibitors in the treatment of full-term delivery. W097 / 31631, published in September 1997, illustrates the use of COX-2 inhibitors in the management of labor and uterine contractions. -6-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 577739 A7 _________ B7 V. Description of the invention (5) where A is 5- or 6- Member of the ring substituents, selected from partially saturated or unsaturated heterocyclic and carbocyclic rings; wherein R1 is at least one substituent, selected from heterocyclic, cycloalkyl, cycloalkenyl and square groups, where R 疋 as required These groups are substituted with 'one or more groups' at a substitutable position. These groups are selected from alkyl groups, alkyl groups, amino groups, amino groups, fluorinated oxycarbonyl groups, via groups, #ialkylalkyl groups, since Alkoxy, amine, alkylamino, arylamino, nitro, alkoxyalkyl, alkylidene, alkylene, alkoxy and alkylthio; where R2 is selected from Alkyl, and amine; and R3 is a group selected from the group consisting of prime, alkyl, alkenyl, alkynyl, oxygen, cyano, carboxyl, cyanoalkyl, heterocyclooxy, and alkyloxy Alkyl, alkylthio, alkylcarbonyl, cycloalkyl, aryl, alkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocycloalkyl, fluorenyl, alkylthioalkyl , Hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, arylalkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl , Aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminecarbonyl, aminecarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N -Alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N _Aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkylarylaminoalkyl, aryloxy, aralkyloxy, arylthio, aralkylthio, alkylene Sulfonyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-8- This paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back first ^ Write this page)-Packing. 577739 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (6-N-arylaminosulfonyl; or a pharmaceutically acceptable salt thereof. The present invention can be used for, but not limited to, treatment and prevention. Preterm delivery. The present invention can also be used for, but not limited to, the prevention of arterial duct closure and the retention of circulating blood flow in fetal arterial ducts during preterm delivery. These compounds are useful in addition to human treatment. In the treatment of mammals, including pets and farm animals, such as, but not limited to, horses, dogs, horses, cows, sheep, and pigs. &Quot; Treatment " includes partial or full term delivery inhibition. "Prevention" a Words include preventing the occurrence of preterm full-term labor in individuals at risk of preterm full-term labor or preventing the occurrence of pre-clinical full-term labor. The term "therapeutically effective" is used to describe the amount of each dose, which can improve the severity and frequency of the disease, while avoiding side effects in therapy. The term " patient " is used in the treatment to include humans or animals who have given birth before term, and more often means a human patient. When used in a preventive method, the subject refers to any human or animal that is more likely to be a human subject whose stomach is pregnant and who is expecting to deliver before term. Inhibitors of the cyclooxygenase pathway in arachidonic acid metabolism used to prevent and treat arachidonic acid delivered before term can inhibit enzyme activity through a variety of mechanisms. For example, inhibitors useful in the methods described herein can be used as enzyme substrates: to block enzyme activity. The greatest advantage of using cyclooxygenase-2 selective carcinogenesis is that it can minimize gastric side effects. Such secondary domain M effects may occur using non-selective NSAIDs. , Especially when used for long-term preventive treatment under county control. "Cyclooxygenase · 2 inhibitor" refers to a compound that can inhibit the enzyme I and licease-2, but significantly inhibits the cyclooxygenase-1. It is preferred that the main ingredients include the Oxygenase_2 inhibition table paper size applies the Chinese National Standard (CNS) Α4 specification (210χ ^^ (please read the notes on the back first to write this page)-loaded · printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 577739 A7 B7 5 Explanation of the invention (8) group, phenyl and pyridyl; wherein R1 is a heterocyclic group selected from 5- and 6-membered, lower cycloalkyl, lower cycloalkenyl, and selected from phenyl, biphenyl and Aryl of fluorenyl, where R1 is optionally substituted with a lower alkyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower alkoxy, Amine group, low alkylamino group, phenylamino group 'nitro' low alkyloxy group, low alkylsulfinylsulfonyl group, # element, low alkoxy group and low alkylthio group; where R2 is optional From lower alkyl and amine groups; and wherein R3 is selected from halogen, lower alkyl, oxygen, cyano, carboxyl, lower cyanoalkyl, heteroaryloxy, lower alkyloxy, lower cycloalkane , Heteroaryloxy, lower alkyloxy, lower cycloalkyl, phenyl, lower alkyl, 5- or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, Phenylcarbonyl, lower alkoxyalkyl, heteroaryloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, aryloxy, and Arylalkoxy; or a pharmaceutically acceptable salt thereof. More preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, wherein A is selected from the group consisting of azinoyl, isosinyl, and dihydrocranyl , Imidyl, and pidyl; where R1 is a heterocyclic group selected from 5- and 6-membered, lower cycloalkyl, lower cycloalkenyl, and selected from phenyl, biphenyl, and fluorenyl Aryl, where R1 is optionally substituted with one or more groups selected from substitutable groups, low alkyl, low alkyl, cyano, alkyl, alkoxycarbonyl, hydroxy, low Hydroxyalkyl, lower alkoxy, amine, lower alkylamino, phenylamino, nitro, lower oxolanyl, lower alkylene, fluorenyl, 1¾, lower alkyl, and lower alkyl Thio; where R2 is amine And R3 is selected from the group consisting of oxygen, cyano, and low-pitched alkoxy, low-pitched pit, low-amino sulphur-based, self-priming, -11-This paper is in accordance with China National Standard (CNS) A4 (210X297 mm) (please read the precautions on the back of this page first ^ write this page)-installed ·, is 577739 A? B7 printed by the Central Consumers' Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 5. Description of invention (9) Low-burn base, Low-burning radical oxygen curtain, low-ring cyclyl 'phenyl' low-pitting '5-or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, fluorenyl, phenylcarbonyl, lower alkoxy Alkyl, 5- or 6-membered heteroaryloxy, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower alkylaminoalkyl, phenyloxy And aralkoxy; or a pharmaceutically acceptable salt thereof. Particularly preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, wherein A is selected from the group consisting of oxazolyl, isoroxazolyl, 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 Methyl, trifluoromethyl, chloromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl —Phenylpropyl, phenylamino, methoxycarbonyl, hydroxy, hydroxymethyl, trifluoromethoxy, amine, N-methylamino, N, N-dimethylamino, N -Ethylamino, N, N-dipropylamino, N • butylamino, N-methyl-N-ethylamino, phenylamino, nitro, methoxymethyl, methyl Alkylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, and methylthio; where R2 is an amine group; and R3 is Selected from oxygen, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxyl Methyl, carboxymethyl, carboxyethyl, cyanomethyl, fluorine, gas, bromine, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluorine Methyl, difluoromethyl, trifluoromethyl, trimethyl, dichloromethyl, trimethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl Digas ethyl 'dichloropropyl' methoxy, ethoxy, propoxy, n-butoxy, pentyloxy, cyclohexyl, phenyl, -12- This paper size applies to Chinese national standards (CNS ) A4 size (210X297mm) j ......... ** (please read the notes on the back ^ write this page first). · 1T line 577739 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (10) For p-dienyl, p-sedenyl, p-sedyl, stilbenyl, sulfanyl, p-biyl, several methyl groups, per-propyl group, benzyl group, and Fluorenyl, phenylfluorenyl, methoxymethyl, furylmethyloxy, aminocarbonyl, N-methylaminocarbonyl, n, N-dimethylaminocarbonyl, N, N-dimethyl Amino, n-ethylamino, N, N-dipropyl 'N-butylamino, N-methyl · N-ethylamino, aminomethyl, N, N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl Group, benzyloxy, and phenyloxy; or a pharmaceutically acceptable salt thereof. A particularly interesting group of compounds of formula I includes compounds shown below and their pharmaceutically acceptable salts: -difluorophenyl) -4- (4-methylcontinylphenyl) -2 · (5Η) -macrotonone; 3 · dongyl · 4- (4-methylphenylmethylphenyl) -2- (5Η) -anhydropyridine; 4- [5- (4-chlorophenyl) -3 · (trifluorofluorenyl) -1ρ-ρbitul_1_yl] benzodiazepine; 4 · [5_ (4-methylphenyl) -3_ (trifluoromethyl) -1Η_ρbijun- 1-yl] benzylidene amine; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) _1Η-pyrazol-1-yl] benzoate amine; 3- [1- [4- (methylsulfonyl) phenyl] -4 · trifluoromethyl · ιη-imidazol-2-yl] pyridine; 2-methyl-5 · [1- [4- ( Methylsulfonyl) phenyl] -4_trifluoromethyl-1fluoren-imidazol-2-yl] ether; 4- [2_ (5 · methylpyridin-3-yl) -4- (trifluoromethyl ) -LH-pyrazol-1-yl] benzenesulfonamide; 4- [5-methyl-3-phenylisohumazol-4.yl] benzenesulfonamide; 4- [5-unylethyl -3-phenylisoamycin-4-yl] benzylamine; [2-difluoromethyl-5- (3,4-difluorophenyl) -4 -ρbenzyl] benzenezincamine -13- The paper size is suitable for financial standards (CNS) A4 (21Gx297) (Please read the notes on the back first to write this page.) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed by 577739 A7 ____— B7 V. Description of the Invention (12) _ ~ --- compound, where R4 is Is selected from the group consisting of a lower haloalkyl group; wherein R5 is a hydrogen ion; and wherein R6 is a phenyl group substituted with one or more groups selected from the group consisting of: Alkoxy; or a pharmaceutically acceptable salt or derivative thereof. A particularly interesting group of compounds of formula II is the compound wherein R4 is selected from trifluoromethyl and difluoromethyl; where R5 is a chloride ion; and wherein R6 is a substitutable position as required Phenyl substituted with one or more groups selected from the group consisting of fluorine, chlorine, methyl, and methoxy; or a pharmaceutically acceptable salt or derivative thereof. A particularly interesting group of compounds in Formula II includes compounds shown below and their pharmaceutically acceptable salts: 4- [5 · (4-Gaphenyl) _3 • (trifluoromethyl) -1Η- ρ Bijun-1-yl] benzylidene; 4_ [5_benyl_3- (trifluoromethyl) _ΐΗ-ρbijun-1 · yl] benzylidene; 4- [5- (4 -Fluorophenyl) _3 • (trifluoromethyl) -1Η-pyrazol-1-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) · 3 · (trifluoromethyl ) · 1Η · Ejun _ι · yl] benzidine amine; 4_ [5 · (4-fluorophenyl) _3- (bis said methyl) -1Η-ρ 比 Jun-1-yl] benzimidamine ; 4- [5 · (4 · methylphenyl) -3- (trifluoromethyl) -lH-pyrazole-1 · yl] benzenesulfonamide; 4- [3- (difluoromethyl)- 5- (4-methylphenyl) _1Η-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-1Η-pyrazol-1-yl] Benzylsulfonamide; 4- [3_ (difluoromethyl) _5- (4 · methoxyphenyl) -1 {-pyrazol-1-yl] benzenesulfonamide; 4- [3_ (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1Η-pyrazol-1-yl] benzenesulfonamide; and __-15- This paper size applies to the Chinese National Standard (CNS) M specifications ( 21〇χ 297 mm) --------- ^ — (Please read first Note on the back page :) Line 577739 A? B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and the invention description (13 4_ [5- (3-Fluoro-4-methoxyphenyl) -3 · (Trifluoromethyl) -1H-pyrazol-yl] benzenesulfonamide. A particularly interesting group of compounds of formula II includes the compounds shown below and their pharmaceutically acceptable salts: 4 [ 5_ (4-methylphenyl) -3- (trifluoromethylbicyclo-1-yl] benzodiazepine; 4_ [5_ (4-chlorophenyl) -3_ (difluoromethyl) _1H_py Oxazolyl] benzenesulfonamide; 4 [5- (3-fluoro-4-methoxyphenyl) -3 · (difluorofluorenyl) -1Η_ρ than sialo-i_yl] benzamide. The term "hydrogen ion" refers to a single hydrogen atom (H). This hydrogen ion group can be linked to, for example, an oxygen atom to form a hydroxyl group, or two hydrogen ions can be linked to a carbon atom to form a methylene group (-CH2 ·) "The term" alkyl ", whether used alone or in other words, such as" alkyl "," alkylsulfonyl, "," alkoxyalkyl "and radical-free" Radicals include linear or branched groups having one to about 20 carbon atoms, or, preferably, Up to twelve carbon atoms. More preferred pit groups are low-carbon groups having one to about ten carbon atoms. The most preferred low alkyl group is one to about six carbon atoms. Examples of such groups include methyl , Ethyl, n-propyl, isopropyl, n-butyl, pentyl, iso-pentyl, hexyl, and the like. The term "alkenyl" includes linear or branched groups having two to about twenty carbon atoms, or preferably two to about twelve carbon atoms, having at least one carbon · carbon double bond. More preferred alkenyl groups are "low fluorenyl" groups having two to about six carbon atoms. Examples of fluorenyl include vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutylfluorenyl. The term "alkynyl" refers to a linear or branched group having at least one carbon-carbon triple bond and having two to about twenty carbon atoms, preferably one to about eleven carbon atoms. A better block base is two to about ten carbons. 16- This paper size applies to the Chinese National Standard (CNS) six-four specifications (210X297 mm) (Please read the precautions on the back first to write this page}-577739 A7 B7 V. Description of the invention (14-atom "low alkynyl". The most preferred low-block group is two to about six carbon atoms. Examples of such alkynyl groups include propynyl, butynyl, and the like. The words "alkenyl" and, "lower alkenyl" include groups having "cis" and "reverse" directions, or "E," or z " directions. The term "cycloalkyl" Includes cyclic groups of three to about twelve carbon atoms. More preferred cyclic alkyl groups are "lower cyclic alkyl groups" which have three to about eight interfering atoms. Examples of such groups include cyclopropyl, cyclobutyl Groups, cyclopentyl and cyclohexyl. The term "cycloalkenyl" includes highly unsaturated carbocyclic groups having three to twelve carbon atoms. More preferred cyclofluorenyl groups are those having four to about eight carbon atoms. "Lower alkenyl". Examples of such groups include cyclobutenyl, cyclopentyl, and cyclopentenyl. The term "halogen" means fluorine, chlorine, bromine or "The term" halohalo, "includes groups in which any one or more of the alkyl carbon atoms are substituted with the halogens described above. Specific examples include mono-, alkyl-, and di-alkyl groups, and Multi-halogen pit group. Mono-carbon group, for example, this group may have a broken, stream, gas or fluorine atom. Di- and poly-alkyl groups may have two or more of the same halogen atom or Mixed different halogen atoms. "Low haloalkyl" includes groups of one to six carbon atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and dimethyl. , Trifluoromethyl, pentafluoroethyl, heptafluoropropyl 'monogas methyl' * monogas methyl 'digas ethyl, difluoropropyl, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please first Read the notes on the back to write this page} Ethylethyl 'and monochloropropyl. The term "Cycloalkyl" includes linear or branched alkyl groups of one to about ten carbon atoms, any of which can be Substitution of one or more hydroxyl groups. More preferred hydroxyalkyl groups are "lower hydroxyl groups" having one to six carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. "Alkoxy" and "alkyloxy" include from one to about ten carbon atoms The oxygen content of the alkyl part of the 17- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 577739 A? B? V. Description of the invention (15-based group. A better alkoxy group is "Low alkoxy" groups having one to six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tertiary-butoxy. "Alkoxyalkyl The term "includes one or more alkoxy groups attached to an alkyl group, that is, a monoalkyloxy group and a dioxooxy group. This" alkoxy "may also consist of one or more halogen atoms, such as Fluorine, chlorine or bromine is substituted to form a haloalkoxy group. More preferred haloalkoxy groups are "low-alkoxy" groups having one to six carbon atoms and one or more halogens. Examples of such groups include fluoroamyloxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy. The term "aryl", whether used alone or in combination, means a carbocyclic aromatic system containing one, two, or two J-coats, in which sub-rings can be linked or fused together in a pendant manner. "Aromatic The term "aryl" includes aromatic groups such as phenyl, fluorenyl, tetrahydronaphthyl, indan and biphenyl. The aryl moiety may also be substituted with one or more substituents at a substitutable position, etc. The substituent is independently selected from the group consisting of alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amine , Halogen, nitro, alkylamino, fluorenyl, cyano, carboxyl, aminocarbonyl, alkoxycarbonyl and aralkyloxycarbonyl. The term "heterocyclyl" includes saturated, partially unsaturated And unsaturated heteroatom-containing cyclic groups, wherein the heteroatom may be selected from nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromono groups containing 1 to 4 nitrogen atoms Ring groups (eg, pyrrolidinyl, miridinyl, hexahydrop-p-bityl, hexahydrop-p-pyl, etc.); saturated 3 to 6- Heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl, etc.); saturated 3 to 6-membered groups containing 1 to 2 sulfur atoms and i to 3 Heteromonocyclic group of nitrogen atom (such as pyrazolidinyl, etc.). Partially unsaturated-18 This paper size applies Chinese National Standard (CNS) A4 specification (2 丨 〇 > < 297 mm) Please read the back first Note I Binding Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 577739 Five Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Λ 7 Β7, Invention Description (16 Heterocyclic Groups Including Dihydro farphene, Dihydro Onan, dihydrofuran and dihydrofar 4. The term "heteroaryl" includes unsaturated heterocyclic groups. Examples of heteroaryl include unsaturated 3 to 6 members containing 1 to 4 nitrogen atoms Heteromonocyclic groups, such as pyrilyl's-loweryl, imidazolyl, erazolyl, pyridyl, pyrimidinyl'-eryl, pyrenyl, triazolyl (eg 4H-1, 2, 4 -Triazolyl, 1H_1,2,3-triazolyl, 2H-1,2,3_triazolyl, etc.) tetrazolyl (eg ih_tetramethyl '2H-tetrazolyl', etc. ); Contains 1 to 5 Unsaturated fused heterocyclic group of nitrogen atom, for example, indolyl, isoindolyl, hydrazone, benzimidyl 'π-quinyl, iso4-lyl, indium, Benzene trikidyl, tetrabenzyl radical (such as tetrasalyl [1,5-b] pyrenyl, etc.), etc .; unsaturated 3 to 6-membered hetero-mono with oxygen atoms Ring groups, such as pyranyl, furanyl, etc .; unsaturated 3 to 3-membered heteromonocyclic groups containing sulfur atoms, such as pyrenyl, etc .; containing 1 to 2 oxygen atoms and 1 to Unsaturated 3 to 6-membered heteromonocyclic group of 3 nitrogen atoms, such as humazolyl, isoxazolyl, oxadiazolyl (for example, H4_oxadiazolyl, i, 3,4_hum Diazolyl, 1,2,5-diadiyl, etc.); unsaturated fused heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as phenylhydrazone Oxazolyl, benzimidazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic groups containing i to 2 sulfur atoms and i to 3 nitrogen atoms, such as p-Seryl Is a dijunyl group (for example, 1,2,4-pyrimadiazolyl, t, 3,4 · diamidazolyl, υ,% oxadiazolyl, etc. Etc.), etc .. Unsaturated fused heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, (eg, benzimidazolyl, benzopyrimidazolyl, etc. )and many more. "The term" heteroaryl "also includes a group in which a heterocyclic group is fused to an aryl group. Such fused bicyclic groups include phenylhydrazone, phenylhydrazone, and the like.

-19 577739 A7 B7 V. Description of the invention (17 The heterocyclic group printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs "may have 1 to 3 substituents, such as alkyl, oxo, halogen, kineoxy, oxygen "Amine and alkylamino." The term "alkylthio" includes linear or branched alkyl groups of one to about ten carbon atoms attached to a divalent sulfur atom. Better alkylthio "Low alkylthio" which is an alkyl group having one to six carbon atoms. Examples of such low alkylthio groups are methylthio, ethylthio, propylthio, butylthio, and Hexylthio. The term "fluorenylthioalkyl" includes radicals having an alkylthio group attached to an alkyl group having one to about ten carbon atoms via a divalent sulfur atom. More preferred alkylthioalkanes The group is a "low alkylthioalkyl" group having one to six carbon atoms. Examples of such low alkylthioalkyl groups include methylthiomethyl. "Alkylsulfinyl" includes A linear or branched group having an alkyl group of one to about ten carbon atoms attached to a divalent -S (= 0)-group. A more preferred alkylsulfinyl group is an alkyl group of one to six carbon atoms "Low alkylsulfinyl sulfenyl". Examples of such low alkyl sulfinyl sulfinyl include methylsulfinyl sulfinyl, ethylsulfinyl sulfinyl, butylsulfinyl sulfinyl, and hexylsulfinyl sulfinyl. The term "sulfonyl", whether used alone or in combination with other words such as "alkylsulfonyl" refers to a divalent -so2-yl group. "Alkylsulfonyl" includes linkages to sulfonyl Alkyl group, wherein the definition of pit group is as described elsewhere. A better alkyl group is a "lower oxonyl" group having one to eight carbon atoms. Examples of such a low oxonyl group include a methyl group Sulfosulfenyl, ethylsulfenyl, and propylsulfonyl. This "alkylsulfonyl" may also be substituted with one or more halogen atoms such as fluorine, gas, or brook to form a halogenated sulfonyl. &Quot; Amine continyl group "," Amino group ", and" Amino group "refers to NH202S-." Amino group "refers to the residue formed by removing the hydroxyl group from an organic acid. Examples of fluorenyl groups include alkyl fluorenyl and aryl fluorenyl. Examples of such low alkyl fluorenyl include methyl fluorenyl, ethyl fluorenyl, propyl fluorenyl, butyl fluorenyl, isobutyl fluorenyl, pentyl fluorenyl • 20- Paper size Please read the first note with the Chinese National Standard (CNS) Α4 Specification (2l〇X297 public Chu)

II · I Page η Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 577739 A? P --- _B? V. Description of the invention (18) — ^ ^-, isoamyl, trimethylacetamyl, Hexyl, trifluoroethenyl. The term "carbonyl", whether used alone or in combination with other words such as "alkoxycarbonyl", means-(c = 0)-. The term "arylfluorenyl" includes aryl groups containing the above carbonyl groups, Examples of arylfluorenyl include benzamidine, fluorenyl, and the like, and the aryl group on the arylfluorenyl may be substituted again. The term "hydroxy", whether used alone or in combination with other words such as' "Acid alkyl" is used in combination to refer to -CO2H. "Carboxyalkyl" includes alkyl substituted with carboxy. More preferred is a "low carboxyalkyl group" including the above-mentioned lower alkyl group, and the lower alkyl group may be substituted with halogen. Examples of the upper carboxyalkyl group include a carboxyethyl group and a carboxypropyl group. The term "alkoxycarbonyl" means a group in which the above-mentioned alkoxy group is bonded to a peptidyl group through an oxygen atom. More preferred are "low alkoxycarbonyl" alkyl groups having one to six carbon atoms. Examples of such lower alkoxyfluorenyl (S) groups include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include the above-mentioned alkyl, aryl, and aralkyl-linked groups on carbonyl. Examples of such groups include Substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl, and fluorenylcarbonyl. The term "aralkyl" includes aryl-substituted alkyl groups such as fluorenyl, diphenylmethyl, triphenyl Phenylmethyl, phenylethyl, and dibenzylethyl. The aryl group in the aralkyl group may be substituted with a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group, and a alkoxy group. The terms benzyl and phenylfluorenyl are interchangeable. The term 'heterocyclyl' includes saturated and partially unsaturated heterocyclyl-substituted alkyl groups such as p-pyridylmethyl and hetero An aryl-substituted pit group such as p-pyridylmethyl, P-quinylmethyl, P-sethenylfluorenyl, uranylethyl, and. Quinyl 4-ylethyl. The heteroaryl group in the heteroaralkyl group may be self-priming, alkyl group, -21-mound paper standard applicable to China National Standard (CNS) A4 specifications (210x297 mm) " " (Please read the back Precautions written on this page)-Packing 577739 A7 —____________ B? 5. Description of the invention (19) haloalkyl, and _alkoxy substituted. The term "aralkoxy" includes aralkyl groups attached to other groups via an oxygen atom. "The term" aralkoxyalkyl "includes an aralkyloxy group attached to an alkyl group through an oxygen atom. The term" aralkylthio group "includes an aryl group attached to another group via a sulfur atom." The term "aralkylthioalkyl" includes an aralkylthio group attached to an alkyl group through a sulfur atom. The term "aminoalkyl" includes an alkyl group substituted with an amine group. More preferred is "low aminoalkyl". Examples of such groups include aminomethyl, aminoethyl, and the like. The term "alkylamino" 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 alkylamines may be mono-substituted N-alkylamino or di-substituted N, N-alkyl Amine groups such as N-methylamino, N · ethylamino, N, N-dimethylamino, N, N-diethylamino, etc. The term "arylamino" refers to a Or two aryl-substituted amino groups, such as N-phenylamino. This "arylamino" may also be substituted on the aryl ring of this group. The term "aralkylamino" Includes amine groups substituted with one or two aralkyl groups. The "N-arylaminoalkyl" and "N-aryl-N-alkylaminoalkyl" printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs refer to an aryl group or an aryl group and a aryl group, respectively. Alkyl-substituted aminoalkyl. Examples of such groups include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term "aminocarbonyl" refers to an amine group of the formula -C (= 0) NH2. The term "alkylaminocarbonyl" refers to an aminocarbonyl group substituted with one or two alkyl groups on an amino nitrogen atom. 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 term "alkylaminoalkyl" Includes groups having one or more alkyl groups attached to an amine alkyl group. The term "aryloxyalkyl" includes groups having an aryl group attached to an alkyl group via a divalent oxygen atom. "Arylsulfur-22 -This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm)-577739 A7-B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (2) The term "alkylalkyl" includes aromatic A group 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. "Pharmaceutically acceptable salt"- The term includes salts generally used to form alkali metal salts and to form free-form acid or base addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable. A suitable pharmaceutically acceptable compound of formula i Accepted acid addition salts can be made from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, hydrogen Bromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, aromatic aliphatic groups, heterocyclic, carboxylic acids, and sulfonic organic acids. Examples are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvate, and Aspartic acid, ammonium acid, benzoic acid, anthranilic acid, methanesulfonic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, dihydroxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, Pantothenic acid, 2-side acetosulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid 'alginic acid, /?-Hydroxybutyric acid, salicylic acid, galactic acid and galactose Alkyds. Suitable pharmaceutically acceptable addition salts of compounds of formula I include salts made from sodium, zinc, noodles, magnesium, potassium, sodium, and zinc, as well as N, N, bis; Amine, chlorojincaine, bile test, diethanolamine, diethylamine, meglumine (N-methylglucamine) and procaine All of these salts can be prepared by conventional methods using the corresponding compound of formula I with, for example, a suitable acid or assay reaction. General Synthesis Methods The cyclooxygenase-2 inhibitor of the present invention can be prepared according to the following scheme ΐ-χ -23- The national standard (CNS) A4 specification of this paper standard (21〇χ 297 public attack 1 ^ —- (Please read the precautions on the back first to write this page) Item-Binding · Thread (21) RLr3 substituents, unless stated otherwise, as described in Formula I

Option I

3 Η ONC I 3 R

2f First read the notes on the back 1? 1 ^ Writing a hundred C ifp packs _ • ---- Ί Order synthetic scheme I to explain the preparation of Cyclops q lice and lice inhibitors, 5,521,207 and WQ95 / 153 16 ; ^ National patent goes, Renfeng® + 'Guanshi No. 1', attached here for test. In step Su1, the same 1 is treated with λ ,, ′ ^, preferably NaOMd ester or ester analog, to produce medium contact milk. # And Wang Feng T interstitial monoketone 2 (enol form), this is used without purification. In step 2+, diketone 2 is pre-dissolved in anhydrous substance, such as pure ethanol or acetic acid, internally treated with hydrochloride or substituted hydrazone free base at reflux to obtain pyrazoles 3 and 4. Then recrystallize or analyze the color layer -24- This paper size is applicable to China National Standard (CNS) A4 specification (21〇X 297 gigabytes) -Line · Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics // jy A ? B7 V. Description of the invention (22 is 3, which is generally solid. Use .ct 圏 Patent 4,146,721; 5,051,5 18 to make similar pyrazoles' 5,134,142 and 4,914,121. Attached for reference.

SRZ

〇 6

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economics. Scheme II illustrates a four-step method for preparing cyclooxygenase-2 to inhibit pyrazole 8 using ketone 5 as described in US Patent 5,486,534 (where Ra is a hydrogen ion or an alkyl group). In step 1, ketone 5 is reacted with a base, such as lithium bis (trimethylsilyl) thiamine or lithium diisopropylammoniumamine (LDA), to form an anion. In step 2, this anion is reacted with an acetating agent to prepare dione 6. In step 3, di-6 is reacted with substituted fluorene to form pyrazole 7. In step 4, Ejun 7 is reacted with an oxidant, such as 0 × 〇ne® (potassium peroxymonosulfate), 3-gas perbenzoic acid (MCPBA) or hydrogen peroxide, to obtain the desired 3- (alkyl Sulfonyl) phenyl _ Leaf dagger 8 and 5 · (Entertainer: yl-continyl) phenyl-a mixture of isomers. Can be borrowed 25- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 577739 A7 B7 V. Description of the invention (23 Color layer analysis or recrystallization to obtain pure white or gray-yellow solid pure mouth Bisha 8. Alternatively, dione 6 can also be prepared by using ketone 5 with a base, such as sodium hydride, in a solvent, such as dimethylformamide, and then reacting with nitrile to obtain an amine ketone. Then use this amine group The reaction of a ketone with an acid yields a dione 6. Similar pyrazoles can also be prepared as described in US Patent 3,984,43 1 and are attached here for reference. Please read the memorandum on this page for employees Printed by the Consumer Cooperative 26- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 577739 A 7 B1 V. Description of the invention (24)

Rb0,

13 (Please read the precautions on the back first and write this page)

27 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 577739 A7 B7 V. Description of the invention (25 Cyclooxygenase-2 inhibitor diaryl / heteroaryl p-phene (where T is S 'And Rb are alkyl) can be US Patent 4,427,693; 4,302,461;

4,381,311; 4,590,205; and 4,820,827 and PCT documents WO 95/00501 and WO 94/15932, which are hereby incorporated for reference. Similar p-pyrroles (where T is N), bitanone and squeak (where T is 0) can be prepared by the methods described in PCT documents WO 95/00501 and WO 94/15932, and EP799,823.

Option IV Please read the back i thing 1 «

R ^ S

16

NaH TBSC1

OTBS MCPBA

H + h2〇 TBSO r2o2s

R ^ COCl alkali printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇 r2o2s

-28 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 577739 A7 B7 V. Description of the invention (26) Cyclooxygenase_2 inhibitor diaryl / heteroarylhumidazole can be US patent 3,743,656 ; 3,644,499 and 3,647,858 and PCT documents WO 95/00501 and WO 94/27980 were prepared and are hereby incorporated by reference. Similar pyrazole compounds can be prepared by the methods described in WO 96/19463 and WO 96/19462.

Option V, please read the note on the back

NOH

I) 2 eq. N-BuLi i 2) (R3C〇), 〇

Write this page 23 22

1) ClSO.H

2) NH4〇H

I Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ''

29- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 577739 Λ7 B? 5. Description of the invention (27) Cyclooxygenase-2 inhibitor diaryl / heteroarylisoxazole can be used in the United States Patents 5,633,272, PCT documents WO92 / 〇5162 and WO 92/19604, and the method described in European Publication EP 26928 are hereby incorporated by reference. Sulfonamide 24 can be prepared using hydrated isozaki 23 in two steps. First, the hydrated isoxazole 23 is treated with two or three equivalents of chlorosulfonic acid at 0 ° C to generate sulfonium gas to dust. In the second step, the sulfonium chloride generated in this way is treated with concentrated ammonia to obtain a sulfonamide derivative 24.

Solution VI (Please read the notes on the back to write this page first) • Equipment _ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

29 28 -30- This paper size applies the Chinese National Standard (CNS) M specification (210 X297 mm) 577739 A7 B7 V. Description of the invention (28) Printed Alchemy VI by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A three-step method for the production of the oxygenase_2 inhibitor imidazole 29. In step 1, nitric acid (ricn) 25 and primary phenylamine 26 are used in the presence of an alkyl aluminum reagent such as trimethyl aluminum, triethyl aluminum, dimethyl aluminum chloride, and diethyl aluminum chloride. It is reacted in an inert solvent such as toluene, benzene, and xylene to obtain 脒 27. In step 2, 脒 27 and 2-halone (where χ is Br or Cl) in the presence of a base such as sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate or a hindered secondary amine such as n, n '· di It is reacted in the presence of isopropylethylamine to produce 4,5_ monohydroimidazole 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 °. In step 3, 4,5-dihydroimidazole 28 is dehydrated in the presence of an acid catalyst such as 4-methanesulfonic acid or mineral acid to form the substituted imidazole 29 of the present invention. Suitable solvents for this dehydration step are, for example, toluene, xylene and benzene. This dehydration step uses trifluoroacetic acid as a solvent and catalyst. In some cases (for example, when R3 = methyl or phenyl), this intermediate 28 may not be easily separable. Under the above conditions, the target microphone can be directly obtained. Similarly, imidazoles can also be prepared in which the sulfofluorenylphenyl moiety is linked to the 2-position and R1 is linked 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 Series 08 / 2§2,395 and PCT document WO 93/14082, and are hereby incorporated by reference. Please read the note on the back-P. Binding, Line-31-This paper size is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm) 577739 A7 B7 V. Description of the invention (29 〇r1Ah _tmscn_ ^ Rl catalyst

Option VII

OTMS CN Η 30

SRZ 34 HOAc

NH.OAc, R5CHO Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs

Oxygenation

32 This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 577739 Λ7 __B7 V. Description of the invention (30) The subject of the present invention is an imidazole-framed oxygenase-2 inhibitor compound 36. Column sequential composition. Aldehyde 30 can be converted to protected by reaction with trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN), in the presence of a catalyst such as zinc iodide (Znl2) or potassium cyanide (KCN) Cyanohydrin 3 1. The cyanohydrin 31 is reacted with a strong base, and then treated with benzaldehyde 32 (wherein R2 is an alkyl group), and treated with acid and alkali in this order to obtain benzoin 33. Examples of strong bases suitable for this reaction are lithium diisopropylamidamine (LDA) and hexamethyldiazepine. Benzoin 33 can be converted into benzoin 3-4 by reacting it with a suitable oxidizing agent such as bismuth oxide or manganese digas, or by performing swern oxidation with dimethylsulfinium oxide (DMSO) and trifluoroacetic anhydride. Benzophenanthrene 3 4 can be prepared by directly reacting cyanohydrin 3 anion with substituted benzamidine gas. According to chemical reactions known to those skilled in the art and MR Grimniett's Advances in Iterazole Chemistry in Advances in Heterocyclic Chemistry, 12, 104 (1970), the method can be used to print compounds. 33 and 34 are converted into imidazole 35 (where R2 is an alkyl group). The conversion of 34 to 35 is completed by reaction with ammonium acetate and a suitable aldehyde (R3CHO) in acetic acid. Benzoin 36 can be converted by reaction with formaldehyde Into imidazole 38. In addition, benzoin 36 can be converted into imidazolium by first dehydration with a suitable amidino group (r3c0-), and then treated with ammonium hydroxide. Skilled in this field, the skilled person will understand the sulfide (where R2 is The oxidation of methyl) to amidine can be completed starting with compound 35 at any reaction stage, including using, for example, oxidants such as hydrogen peroxide, acetic acid, methane peroxybenzoic acid (MCPBA) and potassium peroxymonosulfate ( OXONE®) oxidizes imidazole 38. Diaryl / heteroarylimidazole can be used in US patents 3,707,475; 4,686,23 1; 4,503,065; 4,472,422; 4,372,964; 4,576,958; -33- ) A4 specifications (21〇xi97 & t) '; 577739

A7 B7 V. Description of the invention (31) No. 3,901,908, US application series 09/28 1,903, European publication E0 3 72,445, and PCT document WO 95/00501. Attached for reference. Scheme VIII r so. • n-BuLi, THF, -78 ° C R2g.

ZnCl Please read the notes first. ZnCl-! 37

38

40 Write this page

Pd 'R ^ r Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

-34- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 577739 A? R7 V. Description of the invention (32 Diaryl / heteroarylcyclopentene cyclooxygenase-2 inhibitor can The method described in U.S. Patent No. 5,344,991 and PCT document WO95 / g (5) is attached for reference. SO.R2

R · Β (〇H)

Option IX

S0oR " pd〇, PhCH3, C2H5〇H # Na2C〇3, △ Similarly, 'Synthesis Scheme IX represents that it is made from bromobiphenyl intermediate 43 (prepared in a manner similar to that described in Synthesis Scheme VIII) and a suitable substituted phenylboronic acid 1,2-diarylbenzene cyclooxygenase_2 inhibitor 44. A coupling agent similar to that developed by Suzuki et al. [Synth Commun, 11, 5 13 (198 1)] was used, with intermediate 43 and boric acid in toluene / ethanol and in presence of pd. Catalysts, such as the presence of (triphenylphosphine) red (0) and 2M sodium carbonate. The reaction is carried out under reflux to prepare the corresponding 1,2-aphthylbenzene anti-inflammatory agent 4 4 of the present invention. This terphenyl compound can be prepared by the method described in the p c τ patent document WO 96/16934, which is hereby incorporated by reference.

Scheme X Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

s + H2N person R3 2 46

• 35 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 577739 A7 R7 • w ··: · — * ·. · W. One by one 丨丨, · |-—-. · «Li ·, •••• You still ——————__ V. Description of the invention (33) Diaryl / heteroarylpyrazole cyclooxygenase · 2 inhibitor can US Patent Nos. 4,051,250; 4,632,930, European Patent Application Nos. EP 592,664 and PCT documents WO 96/03 3 92 and wo 95/00501 are prepared and are hereby incorporated by reference. Isopyrazole can be prepared by the method described in PCT document wo 95/00501, 4-- and attached for reference. Diaryl / heteroarylpyridine cyclooxygenase_2 inhibitors can be prepared by the methods described in U.S. Patent Nos. 5,169,857; 4,011,328; 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: Materials described by Slater et al. [Am. J. Obstet. Gynecol., 172, (1995)] 'Reagents and methods to make human fetal membrane models. Cox_2 inhibitors should be active at a dose of 20 mg / kg. The effect of cyclooxygenase-2 inhibitors on the prevention of arterial duct closure was determined by the following model: Sheep models were made according to the method described by Velvis et al. [Pediatr Res, 30, 62_8 (1991)] using materials, reagents, and methods. 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). ___ _36_ This ^ paper size applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) " ------— (Please read the precautions on the back first to write this page} -Pack-11 577739 Description of the invention (34 A? B7 The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs prints out that the administration of the present invention can be prevented or treated for the purpose. The methods and compositions used herein can be used alone or other treatments and preventative feet known to this skill. Concomitant treatments may be used in combination. Alternatively, the methods and compositions described herein may be used as adjuvant treatments. For example, cyclooxygenase inhibitors may be administered alone or in combination with other treatments or preventions of preterm delivery. The term "adjuvant therapy" (or "combination therapy") is used to define cyclooxygenase-2 inhibitors and other medicinal agents, which mean that each dose of the combined drug is administered sequentially, and that these are given simultaneously. Agents, such as a single formulation given in a fixed proportion of the 'tongue agent' or 疋 given each formulation multiple times. The present invention also includes pharmaceutical compositions that assist in the prevention and treatment of preterm delivery, this combination Contains a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or diluent (collectively referred to herein as a "carrier" substance), and other agents or other growth inhibitors or other drugs or nutrients mixed therewith When administered orally, the pharmaceutical composition may be, for example, a tablet, a capsule, a suspension or a liquid. The pharmaceutical composition is preferably made in a unit dosage form containing a specific amount of the active ingredient. Such dosages Examples of units are capsules, tablets, granules or suspensions, & conventional additives such as lactose, mannitol corn starch or potato starch; binding agents such as crystalline cellulose, cellulose derivatives, Gum acacia, corn starch, or degrading agents such as corn starch, yam starch, or sodium carboxymethyl cellulose; lubricants such as talc or tincture of stearate. The active ingredients can also be administered as a composition by injection, of which Use, for example, physiological saline, dextrose or water as a suitable carrier. ', For intravenous, intramuscular, subcutaneous, or intraperitoneal administration, the compound may be combined with a bactericidal aqueous solution. Aqueous solution is preferred with the recipient (please read the note on the back first to write this page)-loading · ¼ ^ ----------

Specifications of this paper A4 (210X297 mm) " 739 Λ " __________R7 5. Description of the invention (35) —— Isotonic. Such formulations can be made into aqueous solutions by dissolving solid active ingredients in an aqueous solution containing physiologically compatible substances such as sodium gaseous, glycine, and pH buffering agents compatible with physiological conditions, and then Sterilize. This formulation can be contained in unit-dose or multi-dose containers such as closed ampoules or vials. 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 administered in a known aerosol vehicle, such as physiological saline, p weekly, and using a commercially available mouth sprayer. Bioavailability can be enhanced with formulations of lipid- and acid-resistant 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 fatty esters. The dosage form and quantity printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can be determined by referring to the known drugs used for treatment or prevention of full-term 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's health, severity of the disease, 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 by the bureau instead of systemically, and if it is for prevention rather than treatment, this paper size applies the Chinese National Standard (CNS) A4 specification (210x ^ 97 male feet) ~~ ---- 577739 Λ 7 Β7 V. Description of the invention (36) The dose is lower. The frequency of treatment given can be determined by the treating doctor as needed and the required treatment time. Those skilled in the art will understand that the therapeutically effective amount given can be adjusted to an appropriate amount depending on the individual. The pharmaceutical composition may contain from about 0.1 to about 2000 milligrams of active ingredient, preferably from about 0.5 to 500 milligrams, and most preferably from about 1 to about 200 milligrams. The dosage per day is about 0.001 to 1,000 mg / kg body weight, preferably about 0.1 to 50 mg / kg body weight, and most preferably about 1 to 20 mg / kg body weight. 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. (Please read the note on the back first to write this page) Item-Equipment · Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs-39 This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Date ^ 9 'v 〇 ^ ^ ° Case No. ____ 0871180Q4 Category Na m; A4 C4 C) ZA. Γ (Ώ ^ 577739 Chinese manual replacement page (December 1992) $ I Patent specification, $ 1 name text Pharmaceutical composition containing CELECOXIB for maintaining fetal arterial duct circulation during the treatment and prevention of full-term delivery

PHARMACEUTICAL COMPOSITION COMPRISITION CRISCOXIB FOR MAINTAINING CIRCULATION THROUGH FETAL DUCTUS ARTERIOSUS DURING TREATMENT OR PREVENTION OF PRETERM LABOR 326 New Celler Road, Quefcol, Missouri, United States2. Blair Cher Road, Berwyn, Missouri, U.S.A. 13 American Gidi Cyril Nationality U.S. Applicant Post Office Box 5110, Chicago, Illinois, USA 2 Table i Roger A. Williams Paper scale towel making @ ϋ 家 标准 (CNS) M specifications (training 297 public love) 577739 Patent Application No. 87118094 Revised Chinese Manual (October 89)

And the main cause of children's defects, it is better to maintain the fetus and the uterus rather than allow full-term babies to give birth. "Delivery before the month is also the limiting factor for maintenance-free types. The occurrence of childbirth depends on many factors. Pregnancy normally progresses to term and requires the smooth muscles of child-guests to be relaxed to a certain percentage ’but the mechanism of uterine smooth muscle dimension relaxation during pregnancy is unknown. Parturition begins with childbirth. Childbirth involves a series of regular, progressive contractions of the uterus, which cause the cervix to shorten and expand. In a normal pregnancy, salamander usually begins two weeks before the expected date of delivery. Once a diagnosis of full-term delivery is made, the benefits of restraining delivery and allowing it to occur are measured. The risk of inhibiting childbirth is mainly due to the side effects of birth-inhibiting drugs. Once H-dan has diagnosed full-term delivery and determined that the age of pregnancy is suitable for childbirth suppression, it is necessary to decide on contraindications to full-term delivery, such as eclampsia, preeclampsia, placental rupture , Fetal death or abnormality, fetal depression or chorioamnionitis, and then select a specific convenient anti-birth agent (toclytic agent) ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ------- ---- (Please read the precautions on the back before filling out this page} * 11 The anti-birth agents with different pharmacological properties have been tried to control the delivery before term. The most commonly used anti-birth agents include norepinephrine receptor Stimulants, such as epinephrine or its synthetic analogs and derivatives, salbutamol, terbutaline, isoxsuprine, ritododrine, and Fenoterol 'magnesium sulfate, prostaglandin inhibitors such as aspirin, indomethacin and naproxen, ethanol, and choke-blocking agents such as nipidifene ( nipedifine) or Nicardi (Nicardipine). -5- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X29 * 7 male thin) 577739 A7 B7 Patent Application No. 87118094 amendment page of Chinese specification (October 89) 5. Description of the invention ( 4) (Please read the precautions on the back before filling out this page) Prostaglandins have been shown to be used for the closure of the last three catheters in the pregnancy. US Patents 5,380,738; 5,344,991; 5,393,790; 5,434,178; 5,474,995; 5,510,368 And WO 96/06840 'W0 96/03388' WO 96/03 3 87, WO 96/25405, WO 95 / 15316'WO 94/15932 'WO 94/27980, WO 95/0050 and WO 94/13635, WO 94 / 20480, and WO 94/2673 1 describe compounds that selectively inhibit cyclooxygenase-2. It has been described that [pyrazole-1 -yl] besysulfame is a cyclooxygenase-2 inhibitor, which can be used For the treatment of inflammation, arthritis, and pain, pre-clinical and clinical trials have shown few side effects. US Patent No. 5,466,823 states that it can be used to treat inflammation. However, no one has previously stated that it can be used to treat and prevent full-term delivery. The invention uses these for oxygenation -2 compounds having selective inhibition treatment and prevention of birth before term, while maintaining the flow of each cycle of the fetal ductus arteriosus blood. Detailed description of the present invention: Consumption cooperation of employees of the Central Standards Bureau of the Ministry of Economic Affairs. The present invention provides a pharmaceutical composition for treating or preventing fetal arterial catheter circulation before full-term delivery, which is used for patients in need of such treatment or prevention. Wherein the composition includes a therapeutically effective amount of a compound of formula I

This paper size applies to China National Standard (Cns) 8-4 specification (210X297 male thin) 577739 Patent Application No. wm〇94 Chinese Manual Revised Page (10/89) (° ¾ i \ B {y

5. Description of the invention (7) The ICw of 4 ^ Λ is less than about 0.2 μM, and inhibition of cyclooxygenase · 2 is better than inhibition of cycloaddition. The ratio of enzyme-1 ^ is at least 50, more preferably at least 100. compound of. It is particularly preferred that the cyclooxygenase IC50 of these compounds is greater than about 1 μM, and more preferably greater than 10 μM. This month provides a medicine for treating or preventing fetal artery circulation during preterm delivery. A composition for use in a patient in need of such treatment or prevention. This composition can be administered to a pregnant woman who has experienced childbirth before full term. The composition consists essentially of a compound of formula I alone or in combination with other medicaments for delivery. The amount given can be effectively Suppress or suppress Lu Lu. These anti-birth agents include dot-adrenergic receptor stimulants, such as epinephrine or its synthetic analogs and derivatives salbutamol, terbutaline, and isoxsuprine. Heptodine, and fenothol, magnesium sulfate, ethanol, activin antagonists, cardiac anti-heart rate hairless agents such as lidocaine or ecaine neide ( 〇cainide), nitric oxide supply agents such as S-nitroso-N-ethenyl penicillamine, nitric oxide nucleophiles and adducts, nitroglycerin, hydroxylamine, sodium azide, diethylamine oxidation Nitrogen and the like, and nitric oxide precursors such as L-arginine, and calcium channel blockers such as nipedifine or nicardipine. Derivatives include any compound that can be structurally related to a cyclooxygenase_2 inhibitor or a compound that is substantially equivalent to the biological activity of a cyclooxygenase_2 inhibitor. By way of example, 1 ' such inhibitors may include, but are not limited to, their prodrugs. Preferred compounds that inhibit cyclooxygenase-2 include compounds of formula I, in which A is selected from the group consisting of yinyl, isosteyl, p-phenenyl, dihydroanyl, aranan, pyrrolyl, pyridine Azolyl, thiazolyl, imidazolyl, isoprazolyl, cyclopentene-10- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 cm) (Please read the precautions on the back first) Fill out this page} \ Printed by Chinese Consumers' Cooperative of the Central Procurement Bureau of the Ministry of Economic Affairs, 577739 No. 87118094, Chinese Application for Correction of the Patent Application (October 89) A7 B7 fV ι〇η Revised, V. Description of Invention (11) 4- [2-methyl_4-phenyl-5-humazolyl] benzenesulfonamide; and 4- [5- (3 · fluoro-4-methoxyphenyl-2-trifluoromethyl) -4 -Spityl] benzoic acid amine. There is a class of highly interesting compounds represented by formula II once in formula I: R6 V. R5 -N [, R4

Η N

II (Please read the notes on the back before filling this page) where R4 is selected from hydrogen ion, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkyl Aminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkyloxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyano Base and base groups; where R5 is selected from the group consisting of hydrogen ions, alkyl groups, cyano groups, hydroxyalkyl groups, cycloalkyl groups, alkynyl groups, and halogens; and employees of the Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives where R6 is selected from arylalkenyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; where R4 is optionally substituted at one or more groups selected from the following groups Substituted, hydrogen, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, alkynyl, meridyl, fluorenyl, ethynyl, alkyl, cycloalkyl, alkyl Amine group, dialkylamino group, alkoxycarbonyl group, aminecarbonyl group, alkoxy group, alkoxy group, sulfamoyl group, heterocyclic group and amine group; or medically Acceptable salt or derivative thereof. A particularly interesting group of compounds of the formula II is the formula -14-This paper is in accordance with China National Standard (CNS) A4 (210 × 297)

Claims (1)

577739 A B c D Patent Application No. 087118094 Chinese Application for Patent Scope Replacement (December 1992) 6. Scope of Patent Application 1. A method for maintaining fetal arterial duct circulation during the treatment or prevention of full-term delivery in patients in need A pharmaceutical composition comprising a therapeutically effective amount of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1Η-pyrazol-1-yl] benzoxamine (Hillard葆; celecoxib) or a pharmaceutically acceptable salt or derivative thereof. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)