CN108690078A - A kind of benzo plug piperazine phosphate derivative, preparation method and its application in medicine - Google Patents

A kind of benzo plug piperazine phosphate derivative, preparation method and its application in medicine Download PDF

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Publication number
CN108690078A
CN108690078A CN201810265480.2A CN201810265480A CN108690078A CN 108690078 A CN108690078 A CN 108690078A CN 201810265480 A CN201810265480 A CN 201810265480A CN 108690078 A CN108690078 A CN 108690078A
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Prior art keywords
general formula
alkyl
mixtures
compounds represented
pharmaceutical salt
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Inventor
黄建
祝令建
姜威
朱林桂
何社彬
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention relates to a kind of benzo plug piperazine phosphate derivative, preparation method and its applications in medicine.Specifically, the present invention relates to such as general formula I compounds represented and preparation method thereof, such compound has stronger analgesia and anti-inflammatory effect.

Description

A kind of benzo plug piperazine phosphate derivative, preparation method and its in medicine Using
Technical field
The present invention relates to medicinal chemistry arts, and in particular to benzo plug piperazine analog derivative, the compound have stronger town Pain and anti-inflammatory effect.
Background technology
Many benzo plug piperazine analogs are known, are widely present in various natural products and clinical medicine, are had wide General pharmacological activity.Such as Meloxicam, chemistry entitled 4- hydroxy-2-methyls-N- (5- methyl -2- thiazolyls) -2H-1,2- Benzo plug piperazine -3- formamide -1,1- dioxide, has the following structure:
It has selective depression II cyclooxygenase (COX-2) effect, is mainly used for treating rheumatoid arthritis and bone Arthritis, it can also be used to antipyretic-antalgic.
Known prodrug is often as it with systemic effect and with being absorbed through gastrointestinal tract and rapidly transform into parent medicine Object is to ensure that parent drug reaches the organized ability of institute and is selected.The application provides the prodrug of benzo plug piperazine analog, i.e., Benzo plug piperazine phosphate compounds.
Invention content
The present invention provides or mixtures thereof general formula I compounds represented form or its pharmaceutical salt:
Wherein:
R1Selected from hydrogen, amino, halogenated alkyl, hydroxyl, nitro, alkyl, naphthenic base and heterocycle, aryl or heteroaryl, institute Alkyl, halogenated alkyl, naphthenic base or heterocycle are stated optionally by one or more selected from aryl, heteroaryl, halogen, alkyl, cycloalkanes Base, halogenated alkyl substituent group replaced;
R2And R3It is each independently selected from hydrogen, amino, halogen, halogenated alkyl, hydroxyl, nitro, cyano, alkyl, naphthenic base, miscellaneous Ring group, aryl or heteroaryl;
R4And R5It is each independently selected from hydrogen, alkali metal, alkaline-earth metal, alkyl, naphthenic base, heterocycle, aryl or heteroaryl, The alkyl, halogenated alkyl, naphthenic base or heterocycle are optionally by one or more selected from aryl, heteroaryl, halogen, alkyl, ring Alkyl, halogenated alkyl, oxo ,-OR6,-NR6R7,-C(O)NR6R7Substituent group replaced;
R6,R7Separate is hydrogen, halogen, amino, alkyl, naphthenic base, heterocycle, wherein the alkyl, heterocycle are appointed Choosing is further replaced by one or more substituent groups selected from halogen, oxo, cyano, hydroxyl, nitro;
M=0,1,2,3 or 4;
N=1,2,3,4,5 or 6;
When there are multiple R in general formula I2Or R4Functional group, R2Or R4It can be identical or different.
In some embodiments, or mixtures thereof general formula I compounds represented form or its pharmaceutical salt, have Such as lower structure:
Wherein, R1,R2,R3,R4,R5, m is as described in general formula I.
In some embodiments, or mixtures thereof general formula I compounds represented form or its pharmaceutical salt, have Such as lower structure:
Wherein, R1,R2,R3,R4,R5, m is as described in general formula I.
In some embodiments, or mixtures thereof general formula I compounds represented form or its pharmaceutical salt, have Such as lower structure:
Wherein, R1,R2,R3,R4, n, m be as described in general formula I.
In some embodiments, or mixtures thereof general formula I compounds represented form or its pharmaceutical salt, have Such as lower structure:
Wherein, R1,R2,R3,R4, m is as described in general formula I.
In one embodiment of the invention, or mixtures thereof general formula I compounds represented form or its is pharmaceutical Salt has the following structure:
Wherein, R4,R5Respectively hydrogen, alkali metal, alkaline-earth metal, benzyl or
In another embodiment of the present invention, or mixtures thereof general formula I compounds represented form or its is pharmaceutically acceptable Salt, have the following structure:
Wherein, R4It is identical or different, be hydrogen, alkali metal, alkaline-earth metal, benzyl or
The typical compound of the present invention includes, but are not limited to:
Wherein, R4For
Or mixtures thereof general formula I compounds represented as described above form is prepared the present invention also provides a kind of or it can medicine The method of salt, this method include:Formula X compound and phosphorus oxychloride reaction, then carry out the step of corresponding alcoholysis/or hydrolysis Suddenly,
Wherein, R1,R2,R3,R4,R5, m, n be as described in general formula I.
Further, the alcoholysis reaction agents useful for same is selected from R4OH,R5At least one of OH.
In embodiments, or mixtures thereof general formula I compounds represented form or the method for its pharmaceutical salt, should Method includes:Formula X compound and phosphorus oxychloride reaction, then be hydrolyzed, alcoholysis reaction the step of, alcoholysis reaction examination used Agent is R4OH,
Wherein, R1,R2,R3,R4, m, n be as described in general formula I.
There is no limit for hydrolysis or alcoholysis reaction object sequence in preparation method of the present invention.
Hydrolysis agents useful for same is selected from water, basic solvent in preparation method of the present invention, and the basic solvent is this Field technology personnel are known or it is believed that selected from but not limited to alkali metal hydroxide, alkaline earth metal hydroxide, alkali gold Belong to carbonated etc..
Or mixtures thereof general formula I compounds represented as described above form is prepared the present invention also provides a kind of or it can medicine The method of salt, this method include:The step of Formula X compound is reacted with Formula XI compound,
Wherein, R1,R2,R3,R4,R5, m, n be as described in general formula I.
Or mixtures thereof general formula I compounds represented as described above form is prepared the present invention also provides a kind of or it can medicine The method of salt, this method include:Formula X compound is reacted with -1 compound of Formula XI, then be hydrolyzed/or alcoholysis reaction step Suddenly, the alcoholysis reaction agents useful for same is R4OH,
Wherein, R1,R2,R3,R5, m, n as previously mentioned, LG be leaving group, the leaving group be those skilled in the art It is known or it is believed that selected from but not limited to p-methyl benzenesulfonic acid (OTs), methanesulfonic acid (OMs), methoxyl group, aryl etc..
The present invention also provides Formula VII compounds, have the following structure:
Wherein, R1,R2,R3, m is as described in general formula I.
The present invention also provides Formula VII compounds, have the following structure:
Wherein, R1,R2,R3,R5, n, m be as described in general formula I.
The present invention also provides the method using Formula VII or -1 preparation of compounds of formula I of Formula VII, this method includes:Formula VII or VII-1 carries out the step of water hydrolysis/or alcoholysis reaction.
Further, Formula X compound of the present invention can refer to"Central-South pharmacy"Described in the 2nd phase of volume 4 in April, 2006 Prepared by reaction condition, and document content is introduced into specification, and reaction equation is substantially as follows:
Wherein, R1,R2,R3, m is as described in general formula I.
Further, the present invention also provides a kind of pharmaceutical compositions, containing treatment effective dose as shown in general formula I Or mixtures thereof compound form or its pharmaceutical salt and pharmaceutical carrier, diluent or excipient, the pharmaceutical composition With in treatment rheumatoid arthritis, osteoarthritis or the purposes in relieving pain.
Pharmaceutical composition of the present invention can be made into common pharmaceutical formulation, such as tablet, capsule, pulvis, syrup, liquid The pharmaceutic adjuvants such as fragrance, sweetener, liquid or solid filler or diluent can be added in agent, suspending agent, injection.
Dosage used in the compound of the present invention clinic is 0.01mg~1000mg/ days, can also according to the weight of the state of an illness or The difference of dosage form deviates this range.
The present invention also provides general formula I compounds represented, such compound or pharmaceutically acceptable salt thereof or contain active drug agent The pharmaceutical composition of amount is being prepared in treatment rheumatoid arthritis, osteoarthritis or the purposes in relieving pain (analgesia) drug
The present invention also provides general formula I compounds represented, such compound or pharmaceutically acceptable salt thereof or contain active drug agent Purposes of the pharmaceutical composition of amount in preparing selective depression II cyclooxygenase (COX-2) drug.
Well-known to those skilled in the art, the dosage of drug depends on many factors, including but and it is non-limiting with Lower factor:The activity of specific compound used, the age of patient, the weight of patient, the health status of patient, patient row by, The combination etc. of the diet, administration time, administering mode, the rate of excretion, drug of patient;In addition, best therapeutic modality is such as controlled The type of the pattern for the treatment of, the consumption per day of general formula compound I or pharmaceutical salt can be verified according to traditional therapeutic scheme.
Detailed description of the invention
Unless stated to the contrary, otherwise following that there are following meanings with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise 1 To the alkyl of 10 carbon atoms, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting embodiment include methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propylenes Base, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl-pentens Base, 3,3- dimethyl amyl groups, 2- ethylpentyls, 3- ethylpentyls, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethyls Hexyl, 4- ethylhexyls, 2- methyl -2- ethylpentyls, 2- methyl -3- ethylpentyls, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its it is each Kind branched isomer etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be any workable It is substituted on tie point, preferably one or more following groups, independently selected from aryl, heteroaryl, halogen, alkyl, cycloalkanes Base, halogenated alkyl.
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 A carbon atom.The non-limiting embodiment of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, Cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.Polycyclic naphthene base Include the naphthenic base of loop coil, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, the polycyclic moiety of a carbon atom (claiming spiro-atom) is shared between monocycle, these can To contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably It is 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group bases according to the number for sharing spiro-atom between ring and ring Or more spiro cycloalkyl groups, preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl groups.The non-limiting embodiment of spiro cycloalkyl group includes
" cycloalkyl " refers to 5 to 20 yuan, and each ring in system and shared a pair of of the carbon adjoined of other rings in system are former The full carbon polycyclic moiety of son, wherein one or more rings can contain one or more double bonds, but neither one ring has completely The pi-electron system of conjugation.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to a group cyclic number can be divided into it is bicyclic, three Ring, Fourth Ring or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic alkyl.Condensed ring The non-limiting embodiment of alkyl includes
" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic group of two carbon atoms being not directly connected Group, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 Member, more preferably 7 to 10 yuan.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, preferably For bicyclic, tricyclic or Fourth Ring, it is more selected as bicyclic or tricyclic.The non-limiting embodiment of bridge ring alkyl includes
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocyclic ring, wherein being connected to one with precursor structure The ring risen is naphthenic base, and non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..Naphthenic base can be Optionally substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from virtue Base, heteroaryl, halogen, alkyl, naphthenic base, halogenated alkyl.
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 annular atoms, Wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)qThe hetero atom of (wherein q is 0 to 2 integer), but do not include-O- The loop section of O- ,-O-S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is miscellaneous original Son, more preferable heterocyclic ring include 3 to 10 annular atoms, and more preferable heterocyclic ring includes 5 to 6 annular atoms.Monocyclic heterocycles base Non-limiting embodiment include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base, pyranose, Tetrahydrofuran base etc..Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.
" spiro heterocyclic radical " refers to 5 to 20 yuan, and the polycyclic heterocyclic group of an atom (claiming spiro-atom) is shared between monocycle, wherein One or more annular atoms are selected from nitrogen, oxygen or S (O)qThe hetero atom of (wherein q is integer 0 to 2), remaining annular atom are carbon.These One or more double bonds can be contained, but neither one ring has the pi-electron system of total conjugated.It is preferably 6 to 14 yuan, more excellent It is selected as 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring Or more spiro heterocyclic radicals, preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 Member/5 yuan or 5 yuan/6 yuan single spiro heterocyclic radicals.The non-limiting embodiment of spiro heterocyclic radical includes
" condensed hetero ring base " refers to 5 to 20 yuan, each ring in system and shared a pair of of the atom adjoined of other rings in system Polycyclic heterocyclic group, one or more rings can contain one or more double bonds, but neither one ring has the π of total conjugated Electronic system, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining ring Atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.It can be divided into bicyclic, tricyclic, Fourth Ring according to a group cyclic number Or polycyclic condensed hetero ring base, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases.Condensed hetero ring base Non-limiting embodiment include
" bridge heterocycle " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more Annular atom is selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom are carbon.Preferably 6 to 14 yuan, More preferably 7 to 10 yuan.It can be divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge heterocycle according to a group cyclic number, it is preferably double Bicyclic or tricyclic is more selected as at ring, tricyclic or Fourth Ring.The non-limiting embodiment of bridge heterocycle includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocycle, and non-limiting embodiment includes:
Deng.
Heterocycle can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, naphthenic base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" aryl " refers to 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle (is namely shared and adjoined The ring of carbon atom pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene, most preferably phenyl.The aryl rings can be thick Together on heteroaryl, heterocycle or cycloalkyl ring, also known as benzheterocycle base, wherein being with the ring that precursor structure links together Aryl rings, non-limiting embodiment include:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkanes Base, heterocycle, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogenated alkyl, Hydroxyalkyl, carboxyl, carboxylate.
" heteroaryl " refers to 1 to 4 hetero atom as annular atom, remaining annular atom is 5 to 14 yuan of aryl of carbon, Middle hetero atom includes oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.Heteroaryl be preferably be 5 yuan or 6 yuan, such as furyl, thienyl, Pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can condense In on aryl, heterocycle or cycloalkyl ring, and benzo heteroaryl is can be described as, wherein being miscellaneous with the ring that precursor structure links together Aryl rings, non-limiting embodiment include:
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl is as defined above.Non- limit Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy Deng.
" halogenated alkyl " refers to alkyl and is replaced by one or more halogens, and wherein alkyl is as defined above.
" oxo base " refers to=O.
" carboxylate " refers to-C (O) O (alkyl) or (naphthenic base), and wherein alkyl, naphthenic base is as defined above.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technology personnel, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.For example, amino or hydroxyl with free hydrogen may be unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.
" pharmaceutical composition " indicate containing one or more compounds described herein or its physiologically pharmaceutical salt or The mixture and the pharmaceutical carrier of other components such as physiology and excipient of pro-drug and other chemical constituents.Medicine The purpose of compositions is the administration promoted to organism, and bioactivity is played in turn conducive to the absorption of active constituent.
The known starting material of the present invention may be used or be synthesized according to methods known in the art, or can purchase certainly Method obtains in the companies such as Acros Organics or Aldrich Chemical Company or bibliography CN102775401A It takes.
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-6 (ppm) unit provides.The measurement of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometers, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS);The measurement of ESI-MS is used FINNIGANLCQAd (ESI) mass spectrograph (manufacturer:Thermo, model:FinniganLCQadvantageMAX), LCMS is used High performance liquid chromatography (manufacturer:Agilent, model:1200) gradient elution is carried out, is scanned with positive ion mode, mass scanning Ranging from 100~1500.
Specific implementation mode
The present invention is further described with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment 1
It is under -40 DEG C of cryostats, dichloromethane (30mL) suspension of compound X-1 (8.43g) and pyridine (3.83g) is slow Slowly it is added in pyridine (6.78g) and dichloromethane (40mL) solution of phosphorus oxychloride (4.44g), after reacting 3 hours, with 15% Reaction is quenched in sodium hydrate aqueous solution (135mL), and organic phase and water phase are carried out liquid separation, discard organic phase, water phase uses dichloro again Methane wash (80mL × 3), water phase filter to obtain product 4.24g, yield 40%, purity 96% after being cooled to 0-5 DEG C of standing.
1HNMR(400MHz,DMSO-d6):δ 8.01-7.99 (m, 2H), 7.97-7.88 (m, 6H), 7.32 (d, J= 1.6Hz, 2H), 2.95 (s, 6H), 2.42ppm (d, J=1.6Hz, 6H);
13CNMR(100MHz,DMSO-d6):δ 160.9 (d, J=3.4Hz), 155.2 (d, J=2.4Hz), 147.8, (147.7,136.2,134.1,133.2,133.0,127.3 d, J=3.6Hz), 126.1,123.0,118.3 (d, J= 3.6Hz),118.26,36.9,11.4ppm;
31PNMR(162MHz,DMSO-d6):δ–14.26ppm;ESI-MS(m/z):826.62(M-18),413.79, 430.76。
Embodiment 2
It is under -40 DEG C of cryostats, dichloromethane (30mL) suspension of compound X-1 (8.43g) and pyridine (3.83g) is slow Slowly it is added in pyridine (6.78g) and dichloromethane (40mL) solution of phosphorus oxychloride (4.44g), after reacting 3 hours, uses benzylalcohol Reaction is quenched in (6g), adds aqueous solution 100ml, and organic phase and water phase are carried out liquid separation, discard water phase, organic phase is washed with water It washs (80mL × 3).Organic phase is dried over anhydrous sodium sulfate, and filtering, after concentration, gained residue crosses column purification and obtains product 4.84g, yield 33%, purity 96%.
1HNMR(400MHz,DMSO-d6):δ12.8(s,1H),7.94-7.81(m,4H),7.32-7.26(m,7H), 7.17-7.15(m,4H),5.06-5.01(m,2H),4.97-4.92(m,2H),3.05(s,3H),2.37(s,3H),
31PNMR(400MHz,DMSO-d6):δ4.35;LCMS(ESI)(m/z):[M+H]+611.85,[M+Na]+= 633.73。
Embodiment 3
Into methanol (600ml), THF (200ml), sodium carbonate (17.38g), XII (50g), palladium carbon (10g), hydrogenation is added After reacting 20h, through filtering, it is concentrated to give product 40.87g, yield 92%, purity 93%.
LCMS(ESI):[M+H]+=521.80.
Compound XIII (21.33g) is dissolved in acetonitrile (600ml), is cooled to 0 DEG C, TMSBr (30g) is slowly added dropwise.0 After DEG C reaction 2 hours, reaction solution is concentrated, acetonitrile (500ml) is added and dissolves, after concentration is dry again, acetonitrile (600ml) is added, It is slowly added into water (100ml), concentration is dry again.Then dichloromethane (600ml) and normal heptane (600ml) mashing, filtering is added After obtain 12g products, yield 71%, purity 90%.
1HNMR(400MHz,DMSO-d6):δ7.93-7.91(m,1H),7.88-7.84(m,2H),7.78-7.74(m, 1H), 7.21 (d, J=1.2Hz, 1H), 2.96 (s, 3H), 2.38 (d, J=1.2Hz, 3H);LCMS(ESI)(m/z):[M+H]+ =431.75.

Claims (15)

1. or mixtures thereof general formula I compounds represented form or its pharmaceutical salt:
Wherein:
R1Selected from hydrogen, amino, halogenated alkyl, hydroxyl, nitro, alkyl, naphthenic base and heterocycle, aryl or heteroaryl, the alkane Base, halogenated alkyl, naphthenic base or heterocycle are optionally by one or more selected from aryl, heteroaryl, halogen, alkyl, naphthenic base, halogen The substituent group of substituted alkyl is replaced;
R2And R3Be each independently selected from hydrogen, amino, halogen, halogenated alkyl, hydroxyl, nitro, cyano, alkyl, naphthenic base, heterocycle, Aryl or heteroaryl;
R4And R5It is miscellaneous to be each independently selected from hydrogen, alkali metal, alkaline-earth metal, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, benzo Ring group, benzo heteroaryl orThe alkyl, halogenated alkyl, naphthenic base, heterocycle, Benzheterocycle base or benzo heteroaryl are optionally by one or more selected from aryl, heteroaryl, halogen, alkyl, naphthenic base, alkyl halide Base, oxo ,-OR6,-NR6R7,-C(O)NR6R7Substituent group replaced;
R6,R7It is separate for hydrogen, halogen, amino, alkyl, naphthenic base, heterocycle, wherein the alkyl, heterocycle optionally into One step is replaced by one or more substituent groups selected from halogen, oxo, cyano, hydroxyl, nitro;
M=0,1,2,3 or 4,
N=1,2,3,4,5 or 6.
2. or mixtures thereof general formula I compounds represented according to claim 1 form or its pharmaceutical salt, special Sign is that general formula I has the following structure:
Wherein, R1,R2,R3,R4,R5, m as described in the appended claim 1.
3. or mixtures thereof general formula I compounds represented according to claim 1 form or its pharmaceutical salt, special Sign is that general formula I has the following structure:
Wherein, R1,R2,R3,R4,R5, m it is as described in claim 1.
4. or mixtures thereof general formula I compounds represented according to claim 1 form or its pharmaceutical salt, special Sign is that general formula I has the following structure:
Wherein, R1,R2,R3,R4, n, m it is as described in claim 1.
5. or mixtures thereof general formula I compounds represented according to claim 1 or 2 form or its pharmaceutical salt, It is characterized in that general formula I has the following structure:
Wherein, R4,R5Respectively hydrogen, alkali metal, alkaline-earth metal, benzyl or
6. or mixtures thereof the general formula I compounds represented according to claim 1,3 or 4 form or its pharmaceutical salt, It is characterized in that general formula I has the following structure:
Wherein, R1,R2,R3,R4, m it is as described in claim 1.
7. or mixtures thereof general formula I compounds represented form or its pharmaceutical salt according to claim 1 or 5, It is characterized in that general formula I has the following structure:
Wherein, R4It is identical or different, be hydrogen, alkali metal, alkaline-earth metal, benzyl or
8. or mixtures thereof compound as follows form or its pharmaceutical salt:
Wherein, R4For
9. it is a kind of prepare as or mixtures thereof claim 1-8 any one of them general formula I compounds represented form or its can The method of medicinal salt, this method include:Formula X compound is reacted with phosphorus oxychloride, then carries out corresponding alcoholysis/or hydrolysis instead The step of answering, the preferably described alcoholysis reaction agents useful for same are selected from R4OH,R5At least one of OH,
Wherein, R1,R2,R3,R4,R5, m, n it is as described in claim 1.
10. it is a kind of prepare as or mixtures thereof claim 1-8 any one of them general formula I compounds represented form or its The method of pharmaceutical salt, this method include:The step of Formula X compound is reacted with Formula XI compound,
Wherein, R1,R2,R3,R4,R5, m, n it is as described in claim 1.
11. it is a kind of prepare as or mixtures thereof claim 1-8 any one of them general formula I compounds represented form or its The method of pharmaceutical salt, this method include:Formula X compound is reacted with -1 compound of Formula XI, then be hydrolyzed/or alcoholysis reaction The step of,
Wherein, R1,R2,R3,R5, m, n it is as described in claim 1, LG is leaving group.
12. Formula VII compound, has the following structure:
Wherein, R1,R2,R3, m it is as described in claim 1.
13. a kind of pharmaceutical composition, described pharmaceutical composition contains claim 1-8 any one of them of therapeutically effective amount Close or mixtures thereof object form or its pharmaceutical salt and pharmaceutically acceptable carrier, diluent or excipient.
14. or mixtures thereof claim 1-8 any one of them compounds form or its pharmaceutical salt, or according to right It is required that purposes of the pharmaceutical composition in preparing selective depression II cyclooxygenase (COX-2) drug described in 13.
15. or mixtures thereof claim 1-8 any one of them compounds form or its pharmaceutical salt, or according to right It is required that pharmaceutical composition described in 13 is in treatment rheumatoid arthritis, osteoarthritis or the purposes in relieving pain drug.
CN201810265480.2A 2017-03-29 2018-03-28 A kind of benzo plug piperazine phosphate derivative, preparation method and its application in medicine Pending CN108690078A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111635433A (en) * 2019-03-02 2020-09-08 陕西合成药业股份有限公司 Novel enol non-steroid compound and preparation method and application thereof
WO2022229576A1 (en) * 2021-04-30 2022-11-03 Atlanthéra Hydroxybisphosphonic derivatives of meloxicam for the treatment of inflammatory joint diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4233299A (en) * 1977-12-16 1980-11-11 Boehringer Ingelheim Gmbh 4-Hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides and salts thereof
US4474955A (en) * 1981-06-17 1984-10-02 Vincenzo Iannella Process for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxide, and its phosphoric ester
CN1688315A (en) * 2001-04-05 2005-10-26 瑞蔻达蒂股份有限公司 Use of selective COX-2 inhibitors for the treatment of urinary incontinence

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4233299A (en) * 1977-12-16 1980-11-11 Boehringer Ingelheim Gmbh 4-Hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides and salts thereof
US4474955A (en) * 1981-06-17 1984-10-02 Vincenzo Iannella Process for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxide, and its phosphoric ester
CN1688315A (en) * 2001-04-05 2005-10-26 瑞蔻达蒂股份有限公司 Use of selective COX-2 inhibitors for the treatment of urinary incontinence

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111635433A (en) * 2019-03-02 2020-09-08 陕西合成药业股份有限公司 Novel enol non-steroid compound and preparation method and application thereof
WO2022229576A1 (en) * 2021-04-30 2022-11-03 Atlanthéra Hydroxybisphosphonic derivatives of meloxicam for the treatment of inflammatory joint diseases
FR3122427A1 (en) * 2021-04-30 2022-11-04 Atlanthéra HYDROXYBISPHOSPHONIC DERIVATIVES OF MELOXICAM FOR THE TREATMENT OF INFLAMMATORY OSTEOARTICULAR DISEASES

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