CN112409283A

CN112409283A - Parecoxib derivative and preparation method and application thereof

Info

Publication number: CN112409283A
Application number: CN202011334249.8A
Authority: CN
Inventors: 朱加望; 王泽根; 冯剑波; 姚瑶
Original assignee: Suzhou Puzheng Pharmaceutical Co ltd
Current assignee: Suzhou Puzheng Pharmaceutical Co ltd
Priority date: 2020-11-24
Filing date: 2020-11-24
Publication date: 2021-02-26
Also published as: CN112979572A; CN112979572B

Abstract

The invention relates to parecoxib derivatives shown as a formula I, racemates, stereoisomers, tautomers, isotopic markers, solvates, polymorphs, esters or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the parecoxib derivatives, a preparation method of the parecoxib derivatives, and medical and veterinary pharmaceutical applications of the parecoxib derivatives, wherein the structure of the formula I is as follows:

Description

Parecoxib derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical compounds, and particularly relates to a parecoxib derivative, a preparation method thereof and application of a medicament.

Background

Safe and effective analgesics remain an unmet market need, particularly for moderate to severe pain medications, which are currently dominated by opioids, narcotic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), but their widespread clinical use is limited by adverse effects of each of these various classes of drugs. While specific cyclooxygenase-2 (COX-2) inhibitors, such as Parecoxib (Parecoxib) described in patent US5932598, as prodrugs of Valdecoxib (Valdecoxib) for selective inhibition of cyclooxygenase-2, injections thereof have positive clinical application in acute moderate-severe pain, in particular perioperative or postoperative analgesia, the chemical structures of the Parecoxib and the Valdecoxib being as follows:

however, Parecoxib (Parecoxib) can only be clinically administered by deep muscle slow bolus injection, intravenous fast bolus injection or by existing intravenous routes, and Parecoxib can precipitate when mixed with other drugs in solution, and Parecoxib is strictly prohibited from being mixed with other drugs during dissolution or injection. In addition, there is a potential infection during the formulation and storage of parecoxib injection solutions, and patients must be injected twice a day by hospital professionals. The factors greatly reduce the clinical medication compliance of the parecoxib, and the change of the parecoxib administration form into oral administration can obviously improve the medication compliance of patients, and has good clinical significance.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a parecoxib derivative shown as a formula I, and a racemate, a stereoisomer, a tautomer, an isotopic marker, a solvate, a polymorph, an ester or a pharmaceutically acceptable salt thereof:

wherein R is selected from CH (R)¹)O-C(O)-R²、CH(R¹)O-C(O)-OR³、CH(R¹)-O-P(O)-(OR³)₂、CH(R¹)-O-SO₂-OR³(ii) a The R is¹Independently selected from hydrogen, halogen, and C1-C3 alkyl; r²Independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy; r³Independently selected from hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl; and said R is¹、R²、R³May be independently optionally substituted with halogen, hydroxy, amine, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, carboxy, cyano;

further, said R¹Selected from H, methyl, ethyl, propyl, isopropyl; the R is²Selected from the group consisting of hydroxymethyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropyl, cyclopropyl, CH₃OCH₂-、-CH₂F、N(CH₃)₂-CH₂-、NH(CH₃)-CH₂-、NH₂CH₂-; the R is³Selected from methyl, ethyl, isopropyl, -CH₂ CH₂Cl；

Further compounds are selected from formula II, formula III, formula IV:

wherein R2 is independently selected from C1-C5 alkyl, C3-C6 cycloalkyl; r3 is independently selected from C1-C5 alkyl, C3-C6 cycloalkyl; and said R2, R3 may be independently optionally substituted with halogen, hydroxy, amine, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, carboxy, cyano;

further compounds are selected from formula V:

wherein R is³Selected from C1-C3 alkyl, and R³May be optionally substituted with halogen, hydroxy, amino, C1-C3 dialkylamino, C1-C3 alkoxy;

according to an embodiment of the invention, said R³Selected from methyl, ethyl, propyl;

according to an embodiment of the present invention, non-limiting specific examples of the compounds represented by formulas I, II, III, IV and V, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters thereof, or pharmaceutically acceptable salts thereof are as follows:

the invention also provides a preparation method of the compound shown in the formula I and racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, ester or pharmaceutically acceptable salt thereof, but not limited to the methods described below. All starting materials are prepared or purchased directly according to the general rules of the target molecule and by protocols in these routes, methods well known to those of ordinary skill in the art of organic chemistry. The compounds of the invention can be synthesized by combining the methods described below with synthetic methods known in the art of synthetic organic chemistry or variations thereon as recognized by those skilled in the art. One skilled in the art will recognize that depending on the particular target structure, one or more of the following schemes may optionally be combined, or any of one or more of the schemes may be combined to provide a synthetic scheme.

Compounds of formula I according to the invention, wherein R is as defined for formula I, and wherein X represents Cl, Br, I, -OTf, -OMs, -OTs, etc., can be prepared according to scheme 1 by reacting parecoxib with R-X under appropriate conditions, optionally with K₂CO₃、CsCO₃CsF, DIPEA, DBU, LiHMDS, Py and other bases:

compounds of formula II may be prepared according to scheme 2, wherein R²As defined in formula II, wherein X represents Cl, Br, I, -OTf, -OMs, -OTs and the like, and parecoxib is reacted with R under appropriate conditions²-C(O)-O-CH₂-X reaction, optionally K₂CO₃、CsCO₃CsF, DIPEA, DBU, LiHMDS, Py and other bases:

compounds of formula III may be prepared according to scheme 3, R³As defined in formula III, wherein X represents Cl, Br, I, -OTf, -OMs, -OTs, etc., and parecoxib is reacted with X-CH under appropriate conditions₂-O-P(O)-(OR³)₂Reaction, the reaction can select K₂CO₃CsCO3, CsF, DIPEA, DBU, LiHMDS, Py and other bases:

compounds of formula IV may be prepared according to scheme 4, R³As defined in formula IV, wherein X represents Cl, Br, I, -OTf, -OMs, -OTs and the like, and parecoxib is reacted with X-CH under proper conditions₂-O-SO₂-OR³Reaction, the reaction can select K₂CO₃CsCO3, CsF, DIPEA, DBU, LiHMDS, Py and other bases:

compounds of formula V may be prepared according to scheme 5, wherein R³As defined in formula III, wherein X represents Cl, Br, I, -OTf, -OMs, -OTs and the like, and parecoxib is reacted with R under appropriate conditions³O-C(O)-O-CH₂-X reaction, optionally K₂CO₃CsCO3, CsF, DIPEA, DBU, LiHMDS, Py and other bases:

the invention further provides a pharmaceutical composition, which comprises the compound of formula I, racemate, stereoisomer, tautomer, isotopic marker, solvate, polymorph, ester or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials and carriers.

The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with (and preferably capable of stabilizing) the active ingredient of the composition and is not deleterious to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients for the delivery of the active compound.

The invention further provides the use of the compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters or pharmaceutically acceptable salts thereof or the pharmaceutical composition thereof in the manufacture of a medicament for the treatment of inflammation or pain.

According to an embodiment of the invention, the pain is selected from inflammatory pain, dental pain, scapulohumeral periarthritis pain, osteoarthritis pain, gynaecological pain, muscular pain, trauma pain, cancer induced pain, surgical pain and other acute moderate severe pain.

According to an embodiment of the invention, said co-administration comprises a regimen of administration in a sequential manner which will provide the beneficial effects of said combination of drugs, and also comprises co-administration in a substantially simultaneous manner, e.g. in the same formulation comprising a fixed ratio of these active substances or in a plurality of separate formulations comprising each drug. The pharmaceutical compositions of the present invention may be used in conjunction or in conjunction with other therapeutic agents.

The other therapeutic agent may be selected from codeine, dihydrocodeine, hydromorphone, oxycodone, methadone, morphine, fentanyl, meperidine (dolantin), or other opioid analgesics, which may be co-administered to increase drug efficacy and reduce the dosage of opioid analgesics, resulting in fewer side effects or potential risks of treatment.

The other therapeutic agent may be selected from narcotic analgesic drugs or narcotics.

The individual dosage forms of the invention may be adapted for oral or topical administration.

Pharmaceutical compositions and dosage forms typically include one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and examples of suitable excipients provided herein are not limited thereto. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form will depend on a variety of factors well known in the art, including, but not limited to, the route by which the dosage form is to be administered to a patient, and the like. For example, oral dosage forms such as tablets may contain excipients that are not suitable for parenteral administration. Because of their ease of administration, tablets and capsules are the most commonly used oral dosage forms in which solid excipients are used. Tablets may be coated, if desired, by standard techniques and may be prepared by any of the methods of pharmacy.

Representative oral dosage forms of the invention are prepared by intimately mixing the active ingredient with at least one excipient according to conventional pharmaceutical compounding techniques. The excipients may be in a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in liquid oral dosage forms or aerosols include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, solubilizing agents, stabilizers, lubricants, binders, and disintegrating agents.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to: talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention typically comprises about 50% to 99% by weight of the pharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are not limited to: commercial products sold as AVICEL-PH-101, AVICEL-PH-103AVICEL RC-581, AVICEL-PH-105 (from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103Tm and Starch 1500 LM.

The disintegrant used in the compositions of the present invention can disintegrate the tablet when exposed to an aqueous environment, and a sufficient amount of the disintegrant should be used to prepare the solid oral dosage form of the present invention.

The lactose-free compositions of the invention may comprise various excipients well known in the art, as well as excipients listed, for example, in the United States Pharmacopeia (USP) SP (XXI)/NF (XVI). Lactose-free compositions generally comprise an active ingredient, a pharmaceutically compatible and pharmaceutically acceptable amount of binder/filler and a lubricant, with a preferred lactose-free dosage form comprising the active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The invention further includes anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, see Jens t. carstensen, Drug Stability: principles & Practice, version 2, Marcel Dekker, new york, 1995, pages 379-80. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing components and in a low moisture or low humidity environment. Anhydrous pharmaceutical compositions should be prepared and stored so as to retain their anhydrous nature. Accordingly, it is preferred that anhydrous compositions be packaged using materials known to be water resistant, so that they can be packaged in a suitable kit. Examples of suitable packages include, but are not limited to, sealed foils, plastics, single dose containers (e.g., vials), blister packs, and folio packs.

The invention further includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. These compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The amount and dosage regimen of therapeutically active compound for treating a disease using a compound or composition of the invention depends on a variety of factors including the age, weight, sex and health of the patient, the severity of the inflammation or disease-related inflammation, the route and frequency of administration and the particular compound used, and the like. Prodrug compositions should contain similar dosages as the parent compound. The pharmaceutical composition may contain from about 0.1 to about 1000mg, preferably from about 1 to about 300mg, most preferably from about 20 to about 200mg of the active ingredient. A daily dosage of about 0.01-100mg/kg body weight, preferably about 0.05-20mg/kg body weight, most preferably about 0.1-10mg/kg body weight is suitable. The daily dose can be administered in one or more divided doses per day.

In some cases, it may be desirable to use active ingredients in amounts outside the dosage ranges disclosed herein. After combining the individual patient's responses, the clinician or attending physician will know how and when to discontinue, adjust or terminate therapy.

The compounds of the invention are also useful in veterinary therapy of companion (companion) animals including mammals, rodents, and the like, wild animals, and farm animals. More preferred animal subjects include horses, pigs, cattle, rabbits, dogs, and cats.

It is generally preferred that the active ingredients of the present invention are not administered to the patient at the same time or by the same route. Accordingly, the present invention further provides a kit which, when used by a clinician, simplifies the administration of appropriate amounts of active ingredients to a patient.

The kit comprises a compound of formula I and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters thereof, or pharmaceutically acceptable unit dosage forms thereof, and unit dosage forms of the other therapeutic agents.

Interpretation of terms:

unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. The definitions of the groups and the structures of the compounds in such combinations and after the combination should fall within the scope of the present specification.

The optional substitution with a substituent described herein covers the absence of substitution as well as substitution with one or more substituents.

The term "halogen" refers to F, Cl, Br and I.

The number of carbon atoms of the term "alkyl" is preferably 1 to 12, and may also be 1 to 6, or 1 to 5, and further preferably ranges from 1 to 3, and specifically, the following groups may be included but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl;

the term "cycloalkyl" preferably has a carbon number of 3 to 8, more preferably in the range of 3 to 6, and may be selected, for example, from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to effect the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosage regimen to be followed, whether to administer it in combination with other compounds, the timing of administration, the tissue to be administered and the physical delivery system carried.

The term "pharmaceutically acceptable salt" can be any conventional acid addition salt or base addition salt, as long as it is pharmaceutically acceptable. Suitable inorganic acids may be selected from hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclylcarboxylic and sulfonic classes of organic acids. Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metal or organic salts. More preferred metal salts include, but are not limited to, suitable alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiologically tolerable metal salts. Such salts can be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts may be prepared from tertiary and quaternary amine salts, including, in part, trometamine, diethylamine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared by conventional methods by reacting a compound of the present invention with a suitable acid or base.

The term "solvate" is those forms of the compounds of the present invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which the coordination is with water. In the present invention, the preferred solvate is a hydrate. Further, pharmaceutically acceptable solvates (hydrates) of the compounds of general formula I according to the invention refer to co-crystals and clathrates of compound I with one or more molecules of water or other solvents in stoichiometric amounts. Solvents that may be used for the solvate include, but are not limited to: water, methanol, ethanol, ethylene glycol and acetic acid.

Advantageous effects

The invention provides a parecoxib derivative which is convenient and highly compliant, and can be selected from an analgesic (pain killer) which is orally or externally applied. The drug has quick response in acute pain treatment, particularly acute moderate-severe pain relief, pain caused by trauma, pain relieving in operation and the like, and has the beneficial effects of more stable blood concentration and longer drug half-life compared with injection administration of parecoxib. Compared with parecoxib administered by injection, the parecoxib derivative provided by the invention can be selected to be orally administered, has basically equivalent medicinal effect, and has better patient compliance and operation safety (shown in figure I).

Drawings

FIG. 1 is a graph showing the monitoring of plasma concentrations (ng/mL) of Valdecoxib (Valdecoxib) in male ICR mice for Parecoxib (Parecoxib) (1mg/kg, i.v.);

FIG. 2 is a graph showing the monitoring of plasma concentrations (ng/mL) of prototype Parecoxib (Parecoxib) (1mg/kg, i.v.) in male ICR mice;

FIG. 3 is a graph showing that Compound 1(1mg/kg, i.v.) is monitored for plasma concentration (ng/mL) of Valdecoxib (Valdecoxib) in male ICR mice;

FIG. 4 is a graph showing that Compound 1(1mg/kg, i.v.) was monitored for plasma concentration (ng/mL) of Parecoxib (Parecoxib) in male ICR mice;

figure 5 is a schematic of compound 1(1mg/kg, i.v.) monitoring plasma concentration (ng/mL) (not detected) of compound 1 in male ICR mice;

FIG. 6 is a graph showing that Compound 1(10mg/kg, p.o.) is monitored for Valdecoxib (Valdecoxib) plasma concentration (ng/mL) in male ICR mice;

FIG. 7 is a graph depicting Compound 1(10mg/kg, p.o.) monitoring plasma concentrations (ng/mL) of Parecoxib (Parecoxib) in male ICR mice;

figure 8 shows that compound 1(10mg/kg, p.o.) was monitored in male ICR mice for plasma concentration (ng/mL) (not detected) of compound 1;

FIG. 9 is a graph showing that Compound 2(1mg/kg, i.v.) is monitored for plasma concentration (ng/mL) of Valdecoxib (Valdecoxib) in male ICR mice;

FIG. 10 is a graph showing that Compound 2(1mg/kg, i.v.) was monitored for plasma concentration (ng/mL) of Parecoxib (Parecoxib) in male ICR mice;

figure 11 is a schematic of compound 2(1mg/kg, i.v.) monitoring plasma concentrations (ng/mL) of compound 2 in male ICR mice (not detected);

FIG. 12 is a graph showing that Compound 2(10mg/kg, p.o.) is monitored for Valdecoxib (Valdecoxib) plasma concentration (ng/mL) in male ICR mice;

FIG. 13 is a graph showing that Compound 2(10mg/kg, p.o.) monitors Parecoxib (Parecoxib) plasma concentrations (ng/mL) in male ICR mice;

figure 14 shows that compound 2(10mg/kg, p.o.) was monitored in male ICR mice for plasma concentration (ng/mL) (not detected) of compound 2.

FIG. 15 is a graph showing Parecoxib (2mg/kg, i.v.) monitoring plasma concentration (ng/mL) of Valdecoxib (Valdecoxib) in male cynomolgus monkeys;

FIG. 16 is a graph showing the monitoring of plasma concentrations (ng/mL) of Parecoxib (Parecoxib) in male cynomolgus monkeys (2mg/kg, i.v.);

FIG. 17 is a graph showing that Compound 2(15mg/kg, p.o.) is monitored for plasma concentration (ng/mL) of Valdecoxib (Valdecoxib) in male cynomolgus monkeys;

FIG. 18 is a graph showing that Compound 2(15mg/kg, p.o.) monitors Parecoxib (Parecoxib) plasma concentrations (ng/mL) in male cynomolgus monkeys;

figure 19 is a schematic showing that compound 2(15mg/kg, p.o.) was monitored in male cynomolgus monkeys for plasma miniconcentrations (ng/mL) of compound 2.

Note: i.v. for "intravenous" administration and p.o. for "oral" administration

Detailed Description

The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1 was synthesized.

Separately, K was added to a mixture of Parecoxib Parecoxib (200mg, 0.54mmol, 1.0eq) dissolved in DMF (2mL)₂CO₃(375mg, 2.7mmol, 5.0eq), methyl chloroacetate (1.16g, 10.8mmol, 20eq), and the reaction was stirred at room temperature for 18 hours. By H₂The reaction mixture was diluted with O (20mL) and extracted with EtOAc (20mL x 2). The combined organic phases were washed with saturated brine (15mL)Over Na₂SO₄After drying, filtration and concentration in vacuo. The crude residue obtained was purified by TLC (PE/EA. RTM.1.7: 1) to yield 50mg of crude product which was purified by prep-HPLC (0.1% HCOOH/H in ACN)₂O) was further purified to give compound 1 as a white solid (16.65mg, 6% yield).

LCMS:(M+H)+:443.1

¹H-NMR(400MHz,CDCl3)δ＝8.00(m,2H),7.38(m,7H),5.91(s,2H),2.61(q,J＝7.2Hz,2H),2.52(s,3H),2.08(s,3H),1.10(t,J＝7.2Hz,3H).

Example 2 was synthesized.

K was added to a mixture of Parecoxib Parecoxib (200mg, 0.541mmol, 1.0eq) dissolved in DMF (5mL) separately₂CO₃(746mg, 5.41mmol, 1.54eq), chloromethyl isopropyl carbonate (4mL), at room temperature stirring reaction for 18 hours. By H₂The reaction mixture was diluted with O (30mL) and extracted with EtOAc (40 mL. times.3). The combined organic phases were washed with saturated brine (30 mL. times.3) and Na₂SO₄Dry filtration and concentration gave a crude residue which was purified by TLC (EtOAc: PE ═ 1:2) to give example 2 as a white solid (104.4mg, 33.73% yield). LCMS (M + H) +:487.2

¹H-NMR(400MHz,DMSO-d6)δ＝8.01-7.94(m,2H),7.50-7.39(m,5H),7.35-7.30(m,2H),5.91(s,2H),4.87-4.71(m,1H),2.65(dd,J＝7.1Hz,2H),2.49(s,3H),1.23(d,J＝6.2Hz,6H),0.92(t,J＝7.2Hz,3H).

Synthesis example 3.

To an acetonitrile (2mL) mixture containing Parecoxib Parecoxib (200mg, 0.540mmol, 1.0eq) dissolved therein were added DIPEA (174mg, 1.35mmol, 2.5eq), chloromethyl carbonate (134.4mg, 1.08mmol, 2.0eq), respectively, and the reaction was stirred at room temperature for 18 hours. After spin-drying, using H₂O (3mL) Dilute reactionThe mixture was extracted with EtOAc (3 mL. times.3). The combined organic phases were washed with saturated brine (3 mL. times.3) and Na₂SO₄Dry filtration and concentration gave a crude residue which was purified by TLC (EtOAc: PE ═ 1:2) to give example 2 as a white solid (178.2mg, 72.1% yield).

LCMS:(M+H)+:459.1

¹H NMR(400MHz,MeOD)δ8.09–7.92(m,2H),7.51–7.26(m,7H),5.96(s,2H),3.77(s,3H),2.65(q,J＝7.2Hz,2H),2.51(s,3H),1.02(t,J＝7.2Hz,3H).

Example 4 was synthesized.

To a mixture of Parecoxib (200mg, 0.540mmol, 1.0eq) dissolved in acetonitrile (2mL), DIPEA (174.4mg, 1.35mmol, 2.5eq), chloromethyl ethyl carbonate (149.6mg, 1.08mmol, 2.0eq) were added, respectively, and the reaction was stirred at room temperature for 18 hours. After spin-drying, using H₂The reaction mixture was diluted O (3mL) and extracted with EtOAc (3 mL. times.3). The combined organic phases were washed with saturated brine (3 mL. times.3) and Na₂SO₄Dry filtration and concentration gave a crude residue which was purified by TLC (EtOAc: PE ═ 1:2) to give example 2(194.1mg, 76% yield) as a white solid.

LCMS:(M+H)+:473.1

Synthesis example 5.

The following compounds 5 to 28 were synthesized with reference to example 1

Detailed description of the preferred embodiments

Also included within the scope of the present invention are pharmaceutical compositions comprising the active compounds in admixture with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (hereinafter collectively referred to as "carrier" materials), and if desired other pharmaceutically active ingredients. The active compounds according to the invention can be administered by the oral route or in a form for external administration, preferably in a pharmaceutical combination adapted to the route of administration and orally in a therapeutically effective dose.

Example 6 Pharmacokinetic (PK) experiments

6.1 Pharmacokinetic (PK) study in ICR mice

Experimental materials and methods:

intravenous group: administration dose: 1 mg/kg; solvent: 5% DMSO + 10% Solutol + 85% Saline; number of animals: ICR male mice were dosed 12 hours after fasting and continued 4 hours after dosing. Sample collection time point: 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24 h;

the concentration of the compound in the sample was determined by LC-MS/MS after preparation of the standard curve and QC samples.

Oral administration group: the administration dose is 10 mg/kg; solvent: 5% DMSO + 10% Solutol + 85% Saline; number of animals: ICR male mice were dosed 12 hours after fasting and continued 4 hours after dosing. Sample collection time point: 15min, 30min, 1h, 2h, 4h, 8h and 24 h;

And (3) testing results:

experiments prove that the compound, particularly the compound of the embodiment, can be quickly converted into Parecoxib (Parecoxib) and Valdecoxib (Valdecoxib) serving as a medicinal active ingredient in vivo after being orally taken, the blood concentration is basically matched with the blood concentration converted into the Valdecoxib (Valdecoxib) serving as a medicinal active ingredient in vivo after being taken by Parecoxib injection, the effect is quick, and the compound shows more stable blood concentration and longer medicinal action time (t) compared with the Parecoxib injection_1/2Prolonged), i.e. has better drug effect and action time. Meanwhile, the prototype compound 1 or the prototype compound 2 in blood is not detected in animal experiments, which shows that the compound 1 or the compound 2 can be quickly converted into the parecoxib or the valdecoxib serving as the active ingredient after oral administration, has similar effect with the parecoxib injection administration, and is more stable and better in patient compliance. See in particular the results of the tests for compound 1 and compound 2 shown in figures 3-14.

6.2 cynomolgus Pharmacokinetic (PK) study:

experimental materials and methods:

oral administration group:

administration dose: 15mg/kg, vehicle: 5% DMA + 10% solutol + 85% sulfobutylcyclodextrin; number of animals: 3 male cynomolgus monkeys; administration was carried out 12 hours after fasting and fasting was continued for 4 hours after administration. Sample collection time point: 15min, 30min, 1h, 2h, 3h, 5hr, 8h, 12h and 24 h.

Injectable administration of Parecoxib (Parecoxib):

administration dose: 2mg/kg, vehicle: 5% DMSO + 10% Solutol + 85% Saline; number of animals: 3 male cynomolgus monkeys; administration was carried out 12 hours after fasting and fasting was continued for 4 hours after administration. Sample collection time point: 5min, 15min, 30min, 1h, 2h, 3h, 5h, 8h, 12h and 24 h.

And (3) testing results:

experiments prove that particularly after the compound (such as the compound 2) of the embodiment is orally taken, the Parecoxib and the vardenib (Valdecoxib) serving as a medicinal active ingredient thereof are quickly converted in vivo, and the blood concentration is basically matched with the blood concentration of the vardenib (Valdecoxib) serving as the medicinal active ingredient converted in vivo after injection administration of the Parecoxib, the effect is quick, and the stable blood concentration and the longer medicament action time (t) compared with the injection administration of the Parecoxib are shown (t is_1/2Prolonged), i.e. has better drug effect and action time. It was also found that only minute amounts of the prototype compound 2 were found in the animal blood concentration test. This indicates that compound 2 is capable of converting to parecoxib or its active ingredient, valdecoxib, in time after oral administration. The oral administration of compound 2 has similar effect to that of parecoxib injection, and is more stable and better in patient compliance, and is quickly converted into parecoxib and valdecoxib. See in particular the results of the test for compound 2 shown in figures 15-19.

Claims

1. A compound of formula I, and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, or pharmaceutically acceptable salts thereof:

wherein R is selected from CH (R)¹)O-C(O)-R²、CH(R¹)O-C(O)-OR³、CH(R¹)-O-P(O)-(OR³)₂、CH(R¹)-O-SO₂-OR³；

The R is¹Independently selected from hydrogen, halogen, and C1-C3 alkyl; r²Independently selected from C1-C12 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy; r³Independently selected from hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl; and said R is¹、R²、R³May be independently optionally substituted by halogen, hydroxyl, amine, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, carboxyl, cyano.

2. The compound of formula I according to claim 1, wherein formula I is selected from formula II, formula III, formula IV:

wherein R2 is independently selected from C1-C5 alkyl, C3-C6 cycloalkyl; r3 is independently selected from C1-C5 alkyl, C3-C6 cycloalkyl; and the R2 and R3 can be independently and optionally substituted by halogen, hydroxyl, amino, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxy, carboxyl and cyano.

3. A compound of formula I according to claim 1, wherein formula I is selected from formula V:

wherein R is³Selected from C1-C3 alkyl, and R³May be optionally substituted with halogen, hydroxy, amino, C1-C3 dialkylamino, C1-C3 alkoxy.

4. A compound of formula I according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters, or pharmaceutically acceptable salts thereof:

。

5. the process according to any one of claims 1 to 4, wherein the compound of formula I is prepared by synthesis using parecoxib and R-X, wherein R is as defined in formula I and X is halogen, and wherein the process is selected from the following schemes 1 to 5:

。

6. a pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4 and racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, esters thereof or pharmaceutically acceptable salts thereof, compositions thereof and a pharmaceutically acceptable carrier.

7. Use of the pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment of acute pain, in particular moderate to severe pain such as surgical pain, toothache, trauma pain, osteoarthritis pain, scapulohumeral periarthritis pain, myalgia, gynecological pain, cancer-induced pain, and the like.

8. Use of a pharmaceutical composition according to claim 7 for the manufacture of a medicament for veterinary use in the treatment of acute pain in an animal, in particular veterinary use such as surgical pain.