CN101056673A - Hydrochloride of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile - Google Patents
Hydrochloride of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile Download PDFInfo
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Abstract
The present invention relates to a pharmaceutical composition comprising as active ingredient the hydrochloric acid salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl- phenyl]amino]-2-pyrimidinyl]amino]benzonitrile and to processes for their preparation.
Description
The present invention relates to comprise 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] Pharmaceutical composition and the preparation thereof of benzonitrile hydrochlorate.
WO 03/16306 openly suppresses the pyrimidine derivatives that HIV duplicates, comprising 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile and pharmaceutically acceptable salt thereof.The open 4-[[4-[[4-(2-cyano group vinyl)-2 of WO 04/0162581,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] preparation method of benzonitrile.
4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile, especially E-isomer, drug resistance strain and multidrug resistant strain (promptly medicine known in the art being produced the strain of resistance) to wild type HIV and HIV have the activity that good inhibition HIV duplicates.Therefore this chemical compound might become the good candidate chemical compound of exploitation HIV treatment of infection medicine.
Yet high pharmacologically active, good pharmacology's curve are not unique key elements that the decision chemical compound can become medicine.Good drug candidate preferably also should have stable chemistry and physical property; Should have acceptable toxicity curve; Should have acceptable bioavailability.
The bioavailability of chemical compound influences the dosage of administration required compound, so that reach this chemical compound in the intravital treatment valid density of patient.With respect to the higher chemical compound of bioavailability, the chemical compound that bioavailability is low need give higher dosage.Need the possible consequence of higher dosage to comprise: the risk of untoward reaction increases; The dosage form size increases; Administration frequency increases.These factors can influence the compliance of antiretroviral therapy.The treatment compliance is for influencing one of greatest factor of HIV therapeutic effect.Administration frequency increases and the increase of pill size can cause treating the compliance reduction, thereby reduces therapeutic effect.
Therefore, when the medicine of design HIV treatment, the reactive compound that preferably has acceptable bioavailability.
The bioavailability of predetermined oral administration chemical compound depends on the dissolubility of chemical compound in water, and the permeability of chemical compound (it is by the absorbed ability of goldbeater's skin).
Is biopharmaceutics categorizing system (Biopharmaceutics Classification System or BCS) based on medicine water solublity and intestinal permeability to the science criterion of classification of drug.According to BCS, classification of drug is as follows:
The 1st class: highly dissoluble-high osmosis
The 2nd class: low-solubility-high osmosis
The 3rd class: highly dissoluble-hypotonicity
The 4th class: low-solubility-hypotonicity
When the chemical compound per os with low-solubility or hypotonicity (the 2nd to 4 class) gave, its bioavailability was low.
Free alkali 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals]-amino] benzonitrile can be classified as BCS the 2nd compounds, so dissolubility is low in water.4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] not only to be presented in the water dissolubility low for benzonitrile, and dissolubility is also low in sour environment.So, during with conventional solid dosage forms oral administration, can expect that bioavailability is low.
When running into BCS the 2nd compounds that predetermined per os gives, the pharmaceutical technology personnel can turn to the probability of seeking to improve compound dissolution, for example by the suitable salt of preparation.4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile also follows this approach.Prepared salt shows in the water outlet in the dissolubility and HCl only there to be slightly dissolubility to be improved.Prepared salt still belongs to BCS the 2nd class.Therefore, can expect that also the bioavailability of prepared salt is low.
Be to have been found that 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl unexpectedly] amino]-the 2-pyrimidine radicals] amino] hydrochlorate, especially its E-isomer and the bioavailability in its free alkali is compared the body with remarkable improvement of benzonitrile.In fact, give salt of the present invention with solid dosage forms and have bioavailability in the body suitable with the bioavailability that gives free alkali with oral PEG 400 solution.Because bioavailability increases in the body, need not complicated preparation technique and just can prepare this hydrochlorate.
Also find hydrochlorate no hygroscopicity of the present invention, and under different humidity and temperature conditions chemistry and physically stable.
Accompanying drawing is described
Fig. 1 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the IR spectrum of polymorphic A of benzonitrile .HCl.
Fig. 2 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the X-ray powder diffraction of polymorphic A of benzonitrile .HCl.
Fig. 3 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the IR spectrum of polymorph b drying regime of benzonitrile .HCl.
Fig. 4 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the X-ray powder diffraction of polymorph b drying regime of benzonitrile .HCl.
Fig. 5 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the IR spectrum of polymorphic C of benzonitrile .HCl.
Fig. 6 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the X-ray powder diffraction of polymorphic C of benzonitrile .HCl.
Fig. 7 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the IR spectrum of pseudo-polymorphic D of benzonitrile .HCl.
Fig. 8 is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the X-ray powder diffraction of pseudo-polymorphic D of benzonitrile .HCl.
Detailed Description Of The Invention
The present invention relates to 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] hydrochloric acid (HCl) salt, its N-oxide or stereoisomer of benzonitrile.
Therefore, the invention particularly relates to formula (I) chemical compound, its N-oxide or stereoisomer
The N-oxide form of formula of the present invention (I) chemical compound will comprise formula (I) chemical compound that one of them or several tertiary N atom are oxidized to so-called N-oxide.
Above the term of Shi Yonging " stereoisomer " is defined as all possible stereoisomer that formula (I) chemical compound and N-oxide may have.Unless otherwise mentioned or the explanation, chemical name expression (I) chemical compound of chemical compound and all possible stereoisomer mixture of N-oxide thereof, and each individual isomer of essentially no other isomer.The stereoisomer of formula (I) chemical compound obviously comprises within the scope of the present invention.
Formula (I) chemical compound can exist 2 kinds of spatial configurations of the two keys of cyano group vinyl chain, i.e. E (Entgegen) configuration (E-isomer) and Z (Zusammen) configuration (Z isomer).Those skilled in the art know term E and Z.
The particular of formula (I) chemical compound is the E-isomer, i.e. formula (I-a) chemical compound:
Another particular of formula (I) chemical compound is the Z-isomer, i.e. formula (I-b) chemical compound:
No matter when mention the E-isomer herein, refer to pure E-isomer or the E-isomer of wherein E-isomer advantage existence and any isomer mixture of Z-isomer, promptly contain above 50% or especially above the 80%E-isomer, or more specifically surpass the isomer mixture of 90%E-isomer.The E-isomer of especially meaningfully essentially no Z-isomer.In this context basically aphalangia do not have or almost do not have the E-Z-mixture of Z-isomer, as contain especially 95% or even 98% or the isomer mixture of 99%E-isomer up to 90%.
No matter when mention the Z-isomer herein, refer to pure Z-isomer or the Z-isomer of wherein Z-isomer advantage existence and any isomer mixture of E-isomer, promptly contain above 50% or especially above the 80%Z-isomer, or more specifically surpass the isomer mixture of 90%Z-isomer.The Z-isomer of especially meaningfully essentially no E-isomer.In this context basically aphalangia do not have or almost do not have the E-Z-mixture of E-isomer, as contain nearly 90%, especially 95% or even 98% or the isomer mixture of 99%Z-isomer.
The polymorph of salt of the present invention also within the scope of the present invention.
The polymorph of medicinal compound may be important to the chemical compound that those relate in the dosage forms exploitation, because if this polymorph can not keep stable during clinical and stability study, accurate dosage then used or that measure may be inconsistent between a collection of and next group.In case medicinal compound preparation is used, determine the polymorph that each dosage form discharges, be important to guarantee that preparation process is used identical polymorph and is included in medication amount in each dosage identical.Therefore, must guarantee to provide some known combination of single polymorph or polymorph.In addition, some polymorph can show the thermodynamic stability of increase, may be more suitable for being included in the pharmaceutical preparation than other polymorph.As used herein, the polymorph of The compounds of this invention is identical chemical entities, but the crystal arrangement difference.
The solvent addition form (solvate) that salt of the present invention can form also within the scope of the present invention.The example of this type of form is as hydrate, alcoholates etc.Solvate is also referred to as pseudopolymorph herein.Be preferably anhydrous salt.
Particular of the present invention is i.e. (E) 4-[[4-[[4-(2-cyano group vinyl)-2 of formula (I-a) chemical compound, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] specific polymorph or the pseudopolymorph of benzonitrile .HCl.
First kind of specific polymorph of formula (I-a) chemical compound is referred to herein as crystal form A (seeing Fig. 1 and 2).
Second kind of specific crystal formation of formula (I-a) chemical compound is referred to herein as crystal form B.Crystal form B can exist by two states: dry state (polymorphic) and hygrometric state (pseudo-polymorphic).Only provide the feature (seeing Fig. 3 and 4) of dry state crystal form B.
The third specific polymorph of formula (I-a) chemical compound is referred to herein as crystal C (seeing Fig. 5 and 6).
The 4th kind of specific pseudopolymorph of formula (I-a) chemical compound is referred to herein as form D (seeing Fig. 7 and 8).
The preferred polymorph of formula (I-a) chemical compound is a crystal form A.
Hereinafter no matter when use, term " formula (I), (I-a) or (I-b) chemical compound " will also comprise N-oxide, stereoisomer and polymorph or pseudopolymorph.Particular importance be the pure form of spatial chemistry of formula (I) chemical compound.Preferred formula (I) chemical compound is formula (I-a) chemical compound.
Formula (I), (I-a) or (I-b) chemical compound can be by in the presence of suitable solvent such as suitable acid such as acetic acid are reacted corresponding free alkali and hydrochloric acid (HCl) and are prepared.
Formula (I), (I-a) or (I-b) chemical compound have the antiretroviral activity.They can suppress HIV, and especially HIV-1's duplicates.HIV (HIV (human immunodeficiency virus)) is the pathogenic factor of human acquired immune deficiency syndrome (AIDS) (AIDS).The preferential infected person T-4 cell of HIV virus, and destroy them or change their normal function, especially immune coordination function.As a result, the permanent minimizing of T-4 cell number appears in the patient of infection, and its behavior abnormality.Therefore, immune defense system can not be resisted and infect and tumor, and the HIV infected patient is usually because of opportunistic infection such as pneumonia or because of cancer mortality.Infect other relevant disease with HIV and comprise thrombocytopenia (thrombocytopaenia), Kaposi sarcoma (Kaposi ' s sarcoma) and be characterized as carrying out property demyelination, cause dementia and symptom central nervous system infection as carrying out property dysphonia, ataxia and disorientation.In addition, HIV infects also relevant with AIDS related syndromes (ARC) with peripheral neuropathy, carrying out property general lymphadenopathy (PGL).
The compounds of this invention also shows drug resistance and multidrug resistant HIV strain, especially drug resistance and multidrug resistant HIV-1 strain have activity, more especially, The compounds of this invention demonstrates for one or more non-nucleoside reverse transcriptase inhibitors known in the art are obtained drug-fast HIV strain, and especially the HIV-1 strain has activity.Non-nucleoside reverse transcriptase inhibitor known in the art is those non-nucleoside reverse transcriptase inhibitors except that The compounds of this invention, especially the non-nucleoside reverse transcriptase inhibitor for having gone on the market.
4-[[4-[[4-(2-cyano group vinyl)-2 has been described, the 6-3,5-dimethylphenyl among the WO 03/16306] amino]-the 2-pyrimidine radicals] amino] the inhibition HIV of the benzonitrile activity of duplicating, its by reference integral body be attached to herein.
Because the activity that antiretroviral character, especially their the anti-HIV character, particularly their inhibition HIV-1 of The compounds of this invention are duplicated, The compounds of this invention can be used for treating the HIV infected individuals and prevents these infection.Usually, The compounds of this invention can be used for treating the warm-blooded mammals of infective virus, the existence of virus by or depend on reverse transcriptase mediation.The disease of available The compounds of this invention prevention or treatment, especially relevant with other pathogenicity retrovirus with HIV disease comprises AIDS, AIDS related syndromes (ARC), carrying out property general lymphadenopathy (PGL) and the chronic central nervous system disease that is caused by retrovirus, as the dementia and the multiple sclerosis of HIV mediation.Therefore, formula (I), (I-a) or (I-b) chemical compound useful as drug.
Therefore, The compounds of this invention can be used as the medicine of anti-above-mentioned disease.Described purposes or Therapeutic Method as medicine comprise the patient who gives infected by HIV anti-and HIV and other pathogenicity retrovirus, and especially the HIV-1 associated conditions is effectively measured.Particularly, The compounds of this invention can be used for preparing medicine, and this medicine is used for the treatment of or prevents HIV to infect, and preferred therapeutic HIV infects.
In view of the effectiveness of The compounds of this invention, the mammal that also provides treatment infected by viral infection, particularly HIV comprises human method; Perhaps provide the prevention warm-blooded mammals to comprise the method that the mankind are infected by viral infection, particularly HIV.Described method comprises and giving that preferred per os comprises the salt of the present invention of human mammal effective dose.
Because compare with corresponding free alkali, The compounds of this invention has high bioavailability, therefore also can obtain to treat effective plasma levels after the Pharmaceutical composition administration, the saliniferous amount of described Pharmaceutical composition bag is than required the lacking of corresponding free alkali.So, can reduce the size of Pharmaceutical composition or can reduce administration frequency.
Therefore, the present invention also relates to Pharmaceutical composition, this Pharmaceutical composition contain the formula (I), (I-a) of acceptable carrier pharmaceutically and treatment effective dose or (I-b) chemical compound as active component.
The present invention also relates to comprise the formula (I), (I-a) of pharmaceutically acceptable carrier and treatment effective dose or (I-b) chemical compound is as the Pharmaceutical composition of active component, condition is that said composition does not contain emtricitabine (emtricitabine) and fumaric acid tenofovir ester (tenofovir diisoproxylfumarate).
Particularly, the present invention also relates to Pharmaceutical composition, said composition contains the formula (I), (I-a) of acceptable carrier pharmaceutically and treatment effective dose or (I-b) chemical compound is as active component, and condition is that said composition does not contain one or more efabirenzs and/or one or more ucleotides reverse transcriptase inhibitors.
Be the administration purpose, can with formula of the present invention (I), (I-a) or (I-b) chemical compound be mixed with various Pharmaceutical compositions.As citable suitable groups compound, all compositionss are generally used for the whole body administration.In order to prepare Pharmaceutical composition of the present invention, as the effective dose formula (I) of active component, (I-a) or (I-b) chemical compound fully mix with pharmaceutically acceptable carrier, according to the form of the required preparation of administration, carrier can adopt various ways.These Pharmaceutical compositions are ideal for being particularly useful for the unit dosage forms that per os gives.For example, when the compositions of preparation peroral dosage form, can adopt any drug media commonly used,, can adopt as water, glycols, oils, alcohols etc. as situation at oral liquid such as suspensoid, syrup, elixir, Emulsion and solution; Perhaps, can adopt solid carrier such as starch, sugar, Kaolin, diluent, lubricant, binding agent, disintegrating agent etc. in the situation of powder, pill, capsule and tablet.Because convenient drug administration, tablet and capsule are represented best oral unit dosage form, obviously can adopt the solid medicinal carrier in this case.For the intestines and stomach topical composition, although carrier can comprise other compositions such as cosolvent, comprise sterilized water usually, most of at least sterilized water.For example, can prepare injection solution, wherein carrier comprises the mixture of saline solution, glucose solution or saline and glucose solution.Also the injection suspensoid can be prepared, suitable liquid-carrier, suspending agent etc. can be adopted in this case.Also comprise the solid form preparation that is used to face with before being transformed into liquid form preparation.In being applicable to the compositions of percutaneous dosing, optional penetrating agent and/or the suitable wetting agent of comprising of carrier, optional suitable additives combination with than any character of small scale, this additive can not bring great illeffects to skin.Described additive can promote percutaneous drug delivery, and/or can help to prepare desired composition.These compositionss can give in every way, as with transdermal patch, in fixed point mode (spot-on), give with ointment.Salt of the present invention can be the method and formulation that adopts through this mode administration by this area also, gives through sucking or being blown into.Therefore, common salt of the present invention can solution, the form of suspension or dry powder gives lung.Go into or be blown into any system that discharges solution, suspension or dry powder and develop for per os or snuffing, all be applicable to the administration of The compounds of this invention.
The compounds of this invention also can drop form topical, especially eye drop.Described eye drop can be solution or suspensoid form.In order to discharge and any system that develops all is applicable to the administration of The compounds of this invention as the solution of eye drop or suspension.
WO 2004/069812 is attached to herein by reference, pyrimidine derivatives 4-[[4-[[4-(2-cyano group vinyl)-2 has wherein been described, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile and pharmaceutically acceptable salt thereof, prevention sexual intercourse or relevant intimate contact and ability of infected by HIV through between the companion.Therefore, the present invention also relates to Pharmaceutical composition, said composition is to be fit to be applied to the form that the position of related intimate contact maybe can take place at the sexual intercourse position, described position is just like genitals, rectum, mouth, hands, lower abdomen, thigh, especially vagina and mouthful, and comprise the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound as active component.Particularly, the present invention relates to Pharmaceutical composition, said composition is to be fit to be applied to the form that the position of related intimate contact maybe can take place at the sexual intercourse position, described position is just like genitals, rectum, mouth, hands, lower abdomen, thigh, especially vagina and mouthful, and comprise the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound is as active component, condition is that said composition does not contain emtricitabine and fumaric acid tenofovir ester.More especially, the present invention also relates to Pharmaceutical composition, said composition is to be fit to be applied to the form that the position of related intimate contact maybe can take place at the sexual intercourse position, described position is just like genitals, rectum, mouth, hands, lower abdomen, thigh, especially vagina and mouthful, and comprise the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound is as active component, condition is that said composition does not contain one or more nucleoside reverse transcriptase inhibitor and/or one or more nucleotide reverse transcriptase inhibitors.Can quote specially suitable compositions as one sees fit, all compositionss are generally used for being applied to vagina, rectum, mouth and skin, as gel, jelly, ointment, ointment, membrane, sponge, foam, intravaginal rings, diaphragm, rectum or vaginal suppository, vagina or rectum or mouthful cheek tablet, collutory.In order to prepare these Pharmaceutical compositions, effective amount of actives is fully mixed with pharmaceutically acceptable carrier, described carrier can adopt various ways according to the form of administration.In order to increase the time of staying of these Pharmaceutical compositions, in compositions, can preferably comprise bioadhesive polymer, especially bioadhesive polymer at medicine-feeding part.Bioadhesive polymer may be defined as and adheres to the living organism surface as the material on mucosa or the skin histology.
Therefore, the present invention also relates to contain the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound it is characterized in that as the Pharmaceutical composition of active component the Pharmaceutical composition bioadhesion is to site of administration.Site of administration is preferably vagina, rectum, mouth or skin, most preferably is vagina.Particularly, the present invention also relates to contain the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound as the Pharmaceutical composition of active component, it is characterized in that this Pharmaceutical composition bioadhesion to site of administration, condition is that said composition does not contain emtricitabine and fumaric acid tenofovir ester.More especially, the present invention also relates to contain the formula (I), (I-a) of pharmaceutically acceptable carrier and effective dose or (I-b) chemical compound as the Pharmaceutical composition of active component, it is characterized in that this Pharmaceutical composition bioadhesion to site of administration, condition is that said composition does not contain one or more nucleoside reverse transcriptase inhibitor and/or one or more nucleotide reverse transcriptase inhibitors.
Easy and dosage is even for administration, it is especially favourable that above-mentioned Pharmaceutical composition is mixed with unit dosage forms.Unit dosage forms used herein refers to be suitable as the physics discrete unit of unit dose, and constituent parts comprises the active component that calculates the scheduled volume that produces required therapeutic effect, and required pharmaceutical carrier.The example of these unit dosage forms is tablet (comprising scored tablet or coated tablet), capsule, pill, powder bag (powder packets), wafer, suppository, injection solution agent or suspensoid etc., and isolating multiple dose form (multiples).
Those skilled in the art know, and accurate dose and administration frequency depend on the concrete disease of being treated; The sanatory order of severity; Concrete patient's age, body weight, sex, disease degree and general physical condition and the individual other drug that may take.In addition, according to treatment patient's response and/or according to the assessment of physician's prescription The compounds of this invention, obviously described effective daily dose can reduce or increase.
Pharmaceutical composition of the present invention can give in being independent of a day of patient feed any time.Preferably, after patient's feed, give the present composition.
The object of the invention embodiment relates to composition for oral liquid, promptly is applicable to the Pharmaceutical composition of oral administration, described compositions comprise the formula (I), (I-a) of pharmaceutically acceptable carrier and treatment effective dose or (I-b) chemical compound as active component; Particularly, the present invention relates to composition for oral liquid, promptly be applicable to the Pharmaceutical composition of oral administration, described compositions comprises the formula (I) of pharmaceutically acceptable carrier and treatment effective dose, (I-a) or (I-b) chemical compound is as active component, condition is that said composition does not contain emtricitabine and fumaric acid tenofovir ester, more especially relate to the Pharmaceutical composition that is applicable to oral administration, described compositions comprises the formula (I) of pharmaceutically acceptable carrier and treatment effective dose, (I-a) or (I-b) chemical compound is as active component, and condition is that said composition does not contain one or more nucleoside reverse transcriptase inhibitor and/or one or more nucleotide reverse transcriptase inhibitors.
Particularly composition for oral liquid is the Peroral solid dosage form Pharmaceutical composition, more especially is tablet or capsule, even more especially is tablet.Tablet of the present invention can be mixed with tablet once a day.
Pharmaceutical composition of the present invention preferably comprise formula (I), (I-a) or (I-b) those amounts of chemical compound be equivalent to about 5 to about 500mg corresponding free alkali 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile, its E or Z isomer, more preferably be equivalent to about 10mg to the corresponding free alkali of about 250mg, also more preferably be equivalent to about 20mg to the corresponding free alkali of about 200mg.Preferred Pharmaceutical composition of the present invention comprise formula (I), (I-a) or (I-b) those amounts of chemical compound be equivalent to the corresponding free alkali of 25mg, 50mg, 75mg, 100mg or 150mg (alkali equivalent).
Above or hereinafter the term " about " of using relates to the implication of numerical value x, as x ± 10%.
Formula (I), (I-a) or (I-b) granularity of chemical compound be more preferably less than 25 μ m preferably less than 50 μ m, also be more preferably less than 20 μ m.The further preferred about 15 μ m or littler of granularity, or about 12 μ m or littler, or about 10 μ m or littler, or about 5 μ m or littler.Most preferably particle size range is between about 0.2 to about 15 μ m, or between about 0.2 to about 10 μ m.
Pharmaceutical composition of the present invention preferably comprises wetting agent.As for the wetting agent in the present composition, can use any wetting agent that tolerates on the physiology that is adapted at using in the Pharmaceutical composition.
Well known wetting agent is an amphiphilic compound; It comprises polar hydrophilic part and nonpolar hydrophobic parts.
Term " hydrophilic " or " hydrophobicity " are relative terms.
The relative hydrophilic of wetting agent or hydrophobicity can be represented by its hydrophile-lipophile balance value (HLB value).The wetting agent of low HLB value is classified as " hydrophobicity " wetting agent, and the wetting agent of high HLB value is classified as " hydrophilic " wetting agent.As empirical law, it is generally acknowledged that the HLB value is the hydrophilic wetting agent greater than about 10 wetting agent; It is generally acknowledged that the HLB value is the hydrophobicity wetting agent less than about 10 wetting agent.
The present composition preferably comprises the hydrophilic wetting agent.The HLB value that should understand wetting agent is only probably indicated the hydrophilic/hydrophobic of wetting agent.The HLB value of concrete wetting agent can change according to measuring the used method of HLB value; Can change according to its commercial source; Batch and batch between also change.Those skilled in the art can easily debate the hydrophilic wetting agent that is not applicable to Pharmaceutical composition of the present invention.
Wetting agent of the present invention can be anion, cation, amphion or nonionic wetting agent, the preferred latter.Wetting agent of the present invention also can be the mixture of two or more wetting agent.
The suitable wetting agent that uses in the present composition is listed below.Should emphasize listed wetting agent only for illustrate, representational, be not limit.Therefore the invention is not restricted to the following wetting agent of enumerating.In the present composition, also can use the mixture of wetting agent.
Can be used for suitable wetting agent of the present invention comprises:
A) polyethylene glycol fatty acid monoesters, comprise lauric acid, oleic acid, stearic acid, castor oil acid (ricinoic acid) etc. and PEG 6,7,8,9,10,12,15,20,25,30,32,40,45,50,55,100,200,300,400, the ester of 600 grades, for example PEG-6 laurate or stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or stearate, PEG-10 laurate or oleate or stearate, PEG-12 laurate or oleate or stearate or ricinoleate ester, PEG-15 stearate or oleate, PEG-20 laurate or oleate or stearate, the PEG-25 stearate, PEG-32 laurate or oleate or stearate, the PEG-30 stearate, PEG-40 laurate or oleate or stearate, the PEG-45 stearate, the PEG-50 stearate, the PEG-55 stearate, PEG-100 oleate or stearate, the PEG-200 oleate, the PEG-400 oleate, the PEG-600 oleate; (wetting agent that belongs to such is as being called Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emul gante, Nikkol, Myrj, Crodet, Albunol, Lactomul);
B) polyethylene glycol fatty acid diester, comprise lauric acid, stearic acid, Palmic acid, oleic acid etc. and PEG-8,10,12,20,32,400 etc. diester, for example PEG-8 dilaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate or dioleate, PEG-20 dilaurate or distearate or dioleate, PEG-32 dilaurate or distearate or dioleate, PEG-400 dioleate or distearate; (wetting agent that belongs to such is as being called Mapeg, Polyalso, Kessco, Cithrol);
C) polyethylene glycol fatty acid monoesters and two ester admixtures are as PEG 4-150 monolaurate and dilaurate, PEG 4-150 monoleate and dioleate, PEG 4-150 monostearate and distearate etc.; (wetting agent that belongs to such is as being called Kessco);
D) polyethylene glycol glycerol fatty acid ester is as PEG-20 glycerol monolaurate or glyceryl stearate or glyceryl oleate, PEG-30 glycerol monolaurate or glyceryl oleate, PEG-15 glycerol monolaurate, PEG-40 glycerol monolaurate etc.; (wetting agent that belongs to such is as being called Tagat, Glycerox L, Capmul);
E) alcohol-grease exchange product comprises alcohol or polyhydric alcohol such as glycerol, propylene glycol, ethylene glycol, Polyethylene Glycol, sorbitol, tetramethylolmethane etc. and natural oil and/or hydrogenated oil and fat or fat soluble vitamin such as Oleum Ricini, castor oil hydrogenated, vitamin A, vitamin D, vitamin E, vitamin K; Edible vegetable oil such as Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, palm-kernel oil, almond oil, the ester of almond oil etc., for example PEG-20 Oleum Ricini or castor oil hydrogenated or Semen Maydis oil glyceride or almond oil glyceride, the PEG-23 Oleum Ricini, PEG-25 castor oil hydrogenated or trioleate, the PEG-35 Oleum Ricini, PEG-30 Oleum Ricini or castor oil hydrogenated, the PEG-38 Oleum Ricini, PEG-40 Oleum Ricini or castor oil hydrogenated or palm-kernel oil, the PEG-45 castor oil hydrogenated, PEG-50 Oleum Ricini or castor oil hydrogenated, the PEG-56 Oleum Ricini, PEG-60 Oleum Ricini or castor oil hydrogenated or Semen Maydis oil glyceride or almond oil glyceride, the PEG-80 castor oil hydrogenated, PEG-100 Oleum Ricini or castor oil hydrogenated, the PEG-200 Oleum Ricini, PEG-8 caprylic/capric glyceride, PEG-6 caprylic/capric glyceride, lauroyl Polyethylene Glycol-32 glyceride, stearoyl PEG glyceride, tocopherol PEG-1000 succinate (TPGS); (wetting agent that belongs to such is as being called Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS);
F) polyglyceryl fatty acid ester comprises polyglyceryl fatty acid ester such as polyglycereol-10 laurates or oleate or stearate, polyglycereol-10 monoleate and dioleate, polyglycereol polyricinoleic acid ester etc.; (wetting agent that belongs to such is as being called Nikkol Decaglyn, Caprol or Polymuls);
G) sterol derivative comprises the polyethyleneglycol derivative of sterol, as PEG-24 cholesterol ethers, PEG-30 Dihydrocholesterol, PEG-25 plant sterol, PEG-30 soyasterol etc.; (wetting agent that belongs to such is as being called Solulan
TMOr Nikkol BPSH);
H) Polyethylene Glycol fatty acid esters of sorbitan is as the PEG-10 sorbitan laurate, PEG-20 Arlacel-20 or Arlacel-65 or Arlacel-80 or sorbitan trioleate or anhydro sorbitol list isostearate or Arlacel-40 or Arlacel-60, the PEG-4 Arlacel-20, the PEG-5 Arlacel-80, PEG-6 Arlacel-80 or Arlacel-20 or Arlacel-60, the PEG-8 Arlacel-60, PEG-30 anhydro sorbitol four oleates, PEG-40 sorbitan oleate or anhydro sorbitol four oleates, PEG-60 anhydro sorbitol tetrastearate, the PEG-80 Arlacel-20, PEG sorbitol six oleates (Atlas G-1086) etc.; (wetting agent that belongs to such is as being called Liposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas);
I) polyethylene glycol alkyl ether is as PEG-10 oleyl ether or cetyl ether or stearyl ether, PEG-20 oleyl ether or cetyl ether or stearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether (laureth-23), PEG-100 stearyl ether etc.; (wetting agent that belongs to such is as being called Volpo, Brij);
J) sugar ester is as sucrose distearate/monostearate, sucrose monostearate or monopalmitate or monolaurate etc.; (wetting agent that belongs to such is as being called Sucro ester, Crodesta, sucrose monolaurate);
K) polyalkylene glycol alkyl phenol is as PEG-10-100 nonyl phenol (Triton X series), PEG-15-100 octyl phenol ether (Triton N series) etc.;
1) polyox-yethylene-polyoxypropylene block copolymer (poloxamer) is as poloxamer 108, poloxamer 188, poloxamer 237, poloxamer 288 etc.; (wetting agent that belongs to such is as being called Synperonic PE, Pluronic, Emkalyx, Lutrol
TM, Supronic, Monolan, Pluracare, Plurodac);
M) ion wetting agent, comprise cation, anion and zwitterionic surfactant, soap for example is as enuatrol, sodium lauryl sulphate, sarcosyl, dioctyl sodium sulphosuccinate, Sodium myristate, sodium palmitate, sodium state, sodium ricinoleate etc.; Bile salts for example is as sodium cholate, sodium taurocholate, NaGC etc.; Phospholipid for example is as Ovum Gallus domesticus Flavus lecithin/soybean lecithin, hydroxylated lecithin, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Phosphatidylserine etc.; Phosphate ester for example is as the esterification products of polyoxyethylene-10 oleyl ether di(2-ethylhexyl)phosphate ethanol ammonium, aliphatic alcohol or ethoxylized fatty alcohol and phosphoric acid or anhydride; Carboxylate (salt) for example is as succinyl group monoglyceride, stearyl (stearyl) fumaric acid sodium, stearyl propylene glycol monomester succinate (stearoyl propylene glycol hydrogen succinate), the tartaric list of list/diacetylization-and the list of two glyceride, citric acid-and two glyceride, fatty acid glycerine lactate, fatty acid lactate, stearyl-2-calcium lactate/sodium, stearyl calcium lactate/sodium, alginate, propylene glycol alginate, ether carboxylate (salt) etc.; For example sulfuric ester (salt) and sulphonic acid ester (salt) are as ethoxylated alkyl sulfuric ester (salt), alkylbenzene sulfuric ester (salt), alpha-olefin sulphonic acid ester (salt), acyl group isethionic acid ester (salt), acyl taurate (salt), alkyl glycerylether sulphonic acid ester (salt), octyl group disodium sulfosuccinate, endecatylene amide groups-MEA-disodium sulfosuccinate etc.; Cation wetting agent for example is as bromination cetyl three ammoniums, NSC 9951, cetab, chlorination dodecyl ammonium, alkyl benzyl dimethyl ammonium salt, diisobutyl benzene oxygen ethyoxyl dimethyl benzyl ammonium salt, alkyl pyridine salt, betanin (empgen BB), ethoxylated amine (polyoxyethylene-15 coconut amine) etc.
In above-mentioned suitable wetting agent list, listed different probabilities, for example PEG-20 oleyl ether or cetyl ether or stearyl ether, this will represent PEG-20 oleyl ether and PEG-20 cetyl ether and PEG-20 stearyl ether.Therefore, for example PEG-20 Oleum Ricini or castor oil hydrogenated or Semen Maydis oil glyceride or almond core glyceride must be read as PEG-20 Oleum Ricini and PEG-20 castor oil hydrogenated and PEG-20 corn glyceride and PEG-20 almond core glyceride.
Preferred wetting agent is sodium lauryl sulphate, dioctyl sodium sulphosuccinate in the present composition, or belongs to the wetting agent of Polyethylene Glycol fatty acid esters of sorbitan class, for example is called the wetting agent of tween, as polysorbas20,60,80.Wetting agent most preferably is polysorbas20.
In the present composition, the concentration that wetting agent exists is about 0.01% to about 5% weight with respect to composition total weight preferably, is preferably about 0.1% to about 3% weight, and more preferably about 0.1% to about 1% weight.The amount that wetting agent uses in the present composition can be depending on compositions Chinese style (I), (I-a) or (I-b) amount of chemical compound or formula (I), (I-a) or (I-b) granularity of chemical compound.Measure many more or granularity is more little, may need many more wetting agent.
In the situation of Peroral solid dosage form Pharmaceutical composition of the present invention, as tablet or capsule, compositions also can further include organic polymer.
Organic polymer can be used as binding agent during preparation of compositions.
The organic polymer that uses in the present composition can be synthetic, the semi-synthetic or non-synthetic organic polymer of any water solublity that can tolerate on the physiology.
Therefore, for example polymer can be natural polymer such as polysaccharide or polypeptide or derivatives thereof, or is synthetic polymer such as polyalkylene oxide (as PEG), polyacrylate, polyvinylpyrrolidone etc.Certainly also can use blended polymer, as block copolymer and glycopeptide.
The molecular weight that polymer suits is between 500D-2MD, and when 20 ℃ of 2% aqueous solution, suitable apparent viscosity is 1-15,000mPa.s.For example water-soluble polymer can be selected from:
-alkylcellulose is as methylcellulose;
-hydroxy alkyl cellulose is as hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose;
-hydroxyalkyl alkylcellulose, as hydroxyethylmethyl-cellulose and hydroxypropyl emthylcellulose (as HPMC 2910 15mPa.s; HPMC 2910 5mPa.s);
-carboxyl alkyl cellulose is as carboxymethyl cellulose;
-carboxyl alkyl cellulose alkali metal salt is as sodium carboxymethyl cellulose;
-carboxyalkyl alkylcellulose is as carboxymethylethylcellulose;
-carboxyl alkyl cellulose ester;
-starch is as starch 1551;
-pectin is as carboxymethyl amylopectin sodium;
-chitin derivative is as chitosan;
-heparin and heparinoid;
-polysaccharide is as alginic acid, its alkali metal and ammonium salt, carrageenin, galactomannan, tragacanth, agar, arabic gum, guar gum and xanthan gum;
-polyacrylic acid and salt thereof;
Acid of-polyisobutylene and salt thereof, methacrylate ester copolymer;
-polyvinyl alcohol;
The copolymer of-polyvinylpyrrolidone, polyvinylpyrrolidone and vinyl acetate;
-polyalkylene oxide, as the copolymer of poly(ethylene oxide) and poly(propylene oxide) and oxirane and expoxy propane, the husky amine (poloxamines) of poloxamer and pool Lip river for example.
Pharmaceutically acceptable and have the polymer of not enumerating as the appropriate physicochemical properties of preamble definition, be suitable for preparing the present composition equally.
Organic polymer is preferably starch, polyvinylpyrrolidone or cellulose ether, as PVPK29-32, PVP K90, methylcellulose, hydroxypropyl cellulose, hydroxyethylmethyl-cellulose or hydroxypropyl emthylcellulose (HPMC).
Described HPMC contains enough hydroxypropyls and methoxyl group, so that it has water solublity.HPMC with hydroxypropyl molar substitution of about 0.8 to about 2.5 methoxyl group substitution value and about 0.05 to about 3.0 generally is water miscible.The methoxyl group substitution value refers to the average number of the methyl ether base that every anhydroglucose unit exists in the cellulosic molecule.The hydroxypropyl molar substitution refer to cellulosic molecule in the average mol of expoxy propane of each anhydroglucose unit reaction.Preferred HPMC is hypromellose 291015mPa.s or hypromellose 29105mPa.s, especially preferred hypromellose 291015mPa.s.To be hypromellose include title in the title (United States Adopted Name) (seeing Martindale, TheExtra Pharmacopoeia, the 29th edition, the 1435th page) in the U.S. to hydroxypropyl emthylcellulose.In 4-digit number " 2910 ", the front two digits is represented about percentage ratio of methoxyl group, and third and fourth bit digital is represented the general percentage ratio composition of hydroxyl propoxyl group; 15mPa.s or 5mPa.s is for representing that 2% aqueous solution is in 20 ℃ apparent viscosity value.
In the present composition, the amount that organic polymer be fit to exist can be up to about 10% weight, and preferred about 0.1% to about 5%, and more preferably from about 0.5% to about 3% weight (with respect to the gross weight of compositions).
In the situation of Peroral solid dosage form Pharmaceutical composition of the present invention, as tablet or capsule, said composition also can further comprise diluent and/or fluidizer.
Pharmaceutically acceptable diluent comprise calcium carbonate, calcium hydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, calcium sulfate, the microcrystalline Cellulose that comprises silicified microcrystalline cellulose, Powderd cellulose, dextrates (dextrates), dextrin, dextrose excipient, fructose, Kaolin, lactose, Lactis Anhydrous, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized Starch, sodium chloride, sucrose, compressible sugar, flour sand sugar, can Microcelac
The spray-drying mixt of lactose monohydrate of having bought and microcrystalline Cellulose (75: 25), can Prosolv
The spray-drying mixt of microcrystalline Cellulose of having bought and silica sol (98: 2) coprocessing.Preferred lactose monohydrate, microcrystalline Cellulose or silicified microcrystalline cellulose.
Pharmaceutically acceptable fluidizer comprises Pulvis Talci, silica sol, starch, magnesium stearate.Preferred silica sol.
In the situation of tablet, compositions also can further comprise disintegrating agent and lubricant.
Pharmaceutically acceptable disintegrating agent comprises that starch, ion exchange resin such as amberlite (Amberlite), crospolyvinylpyrrolidone, modified cellulose gum such as cross-linking sodium carboxymethyl cellulose are (as Ac-di-Sol
), primojel, sodium carboxymethyl cellulose, sodium lauryl sulphate, modified corn starch, microcrystalline Cellulose, aluminium-magnesium silicate, alginic acid, alginate, Powderd cellulose.
Pharmaceutically acceptable lubricant comprises magnesium stearate, calcium stearate, stearic acid, Pulvis Talci, Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG.
In addition, tablet of the present invention can comprise the excipient that other are optional, as correctives, sweeting agent and coloring agent.
Based on the gross weight meter of compositions, solid pharmaceutical composition of the present invention can comprise (% weight):
(a) 5-50% formula (I), (I-a) or (I-b) chemical compound;
(b) 0.01-5% wetting agent;
(c) 40-92% diluent;
(d) 0.1-5% fluidizer.
Based on the gross weight meter of label, tablet of the present invention can comprise (% weight):
(a) 5-50% formula (I), (I-a) or (I-b) chemical compound;
(b) 0.01-5% wetting agent;
(c) 40-92% diluent;
(d) 0-10% polymer;
(e) 2-10% disintegrating agent;
(f) 0.1-5% fluidizer;
(g) 0.1-1.5% lubricant.
Can be optional with tablet bag film-coat of the present invention by coating method known in the art.The Film coated tablets ratio is easier the swallowing of label of coating not; easier and the difference of other tablets-especially when film-coat comprises dyestuff or pigment; can reduce viscosity, can improve stability (extending the expiration date) in addition, for example because coating can protect active component to avoid the influence of light.Film-coat is preferably the coating of promptly releasing.Film-coat can comprise film forming polymer, and optional plasticizer or the pigment of comprising.Suitable film forming polymer example is a hydroxypropyl emthylcellulose, and the suitable manufacturing methods example is Polyethylene Glycol such as Macrogol 3000 or 6000 or glycerol triacetate.Those skilled in the art know the suitable coating material that available medicinal tablet is used.Film-coat is preferably opaque film-coat.Suitable coating material example is Opadry
, Opadry especially
II white coating powder.Can pass through direct compression or wet granulation tablet of the present invention.
Therefore, the present invention also relates to preparation and contain formula (I), (I-a) or (I-b) method of the tablet of chemical compound, this method may further comprise the steps:
(i) do active component, disintegrating agent and optional fluidizer mixed with diluent;
(ii) choose wantonly gained mixture in lubricant and the step (i) is mixed;
(iii), step (i) or (ii) middle gained mixture are compressed into tablet in drying regime; With
(iv) optional with the (iii) middle gained tablet bag film-coat of step.
The present invention also relates to preparation and contain formula (I), (I-a) or (I-b) method of the tablet of chemical compound, this method may further comprise the steps:
(i) do active component and part diluent mixed;
(ii) binding agent and wetting agent are dissolved in the binder solution solvent preparation binder solution;
(iii) the (ii) middle gained binder solution of step is sprayed on the middle gained mixture of step (i);
(iv) the (iii) middle gained wet powder of drying steps sieves and optional the mixing then;
(v) remaining diluent part, disintegrating agent and optional fluidizer are sneaked in the (iv) middle gained mixture of step;
(vi) (v) choose wantonly in the gained mixture and add lubricant to step;
(vii) (vi) the gained mixture is compressed into tablet with step;
(viii) optional with step (vii) gained tablet bag film-coat.
Those skilled in the art will appreciate that the optimum equipment that is used for said method.Those skilled in the art can improve the universal method of above-mentioned preparation tablet of the present invention, and for example other steps beyond above-mentioned given step add some component.
Formula of the present invention (I), (I-a) or (I-b) chemical compound can use separately or with the other treatment medicine, unite use as antiviral agents, antibiotic, immunomodulator or vaccine, with the treatment viral infection.They also can use separately or unite use with other prophylactic agents, with prophylaxis of viral infections.The compounds of this invention can be used for vaccine and prevents in the method for individual infective virus in long-term.Chemical compound can be independent, or be used from these vaccines with mode and other antiviral drugs one consistent with the conventional use of reverse transcriptase inhibitors in the vaccine.Therefore, The compounds of this invention can make up with the pharmaceutically acceptable auxiliary agent that routine in the vaccine adopts, and gives with the prevention effective dose, protects individuality to avoid the HIV infection between the extended period.
Antiretroviral chemical compound and formula (I), (I-a) or (I-b) also useful as drug of combination of compounds.Therefore, the present invention also relates to product, this product comprises (a) formula (I), (I-a) or (I-b) chemical compound and (b) one or more other antiretroviral chemical compounds, as the combination formulations of while, difference or sequential use in anti-HIV treatment.Different medicines can be combined into unitary agent with pharmaceutically acceptable carrier.Therefore, the present invention also relates to Pharmaceutical composition, said composition contains pharmaceutically acceptable carrier, (a) formula (I), (I-a) or (I-b) chemical compound and (b) one or more other antiretroviral drugs of treatment effective dose.Particularly, the present invention also relates to product, this product comprises (a) formula (I), (I-a) or (I-b) chemical compound, (b) one or more other antiretroviral chemical compounds, as the combination formulations of while, difference or sequential use in anti-HIV treatment, condition is that said composition does not contain emtricitabine and fumaric acid tenofovir ester.More especially, the present invention also relates to product, this product comprises (a) formula (I), (I-a) or (I-b) chemical compound, (b) one or more other antiretroviral chemical compounds, as the combination formulations of while, difference or sequential use in anti-HIV treatment, condition is that one or more other antiretroviral chemical compounds are different from nucleoside reverse transcriptase inhibitor and/or nucleotide reverse transcriptase inhibitors.Different medicines can be combined into unitary agent with pharmaceutically acceptable carrier.Therefore, the present invention also relates to Pharmaceutical composition, said composition contains pharmaceutically acceptable carrier, (a) formula (I), (I-a) or (I-b) chemical compound and (b) one or more other antiretroviral drugs of treatment effective dose.Particularly, the present invention relates to Pharmaceutical composition, said composition comprises pharmaceutically acceptable carrier, (a) formula (I), (I-a) or (I-b) chemical compound and (b) one or more other antiretroviral drugs of treatment effective dose, condition is that said composition does not contain emtricitabine and fumaric acid tenofovir ester.The present invention also relates to Pharmaceutical composition, said composition comprises pharmaceutically acceptable carrier, (a) formula (I), (I-a) or (I-b) chemical compound and (b) one or more other antiretroviral drugs of treatment effective dose, condition is that described one or more other antiretroviral chemical compounds are different from nucleoside reverse transcriptase inhibitor and/or nucleotide reverse transcriptase inhibitors.
Described other antiretroviral chemical compounds are known antiretroviral chemical compound, as suramin, pentamidine, Thymopentin, castanospermine, dextran (sulphuric acid dextran), foscarnet sodium (phosphonoformic acid trisodium); Nucleoside reverse transcriptase inhibitor, as zidovudine (3 '-azido-3 '-deoxyribosylthymine, AZT), didanosine (2 ', 3 '-didanosine; DdI), zalcitabine (zalcitabine, ddC) or lamivudine (2 ', 3 '-dideoxy-3 '-thiocytidine, 3TC), stavudine (2 ', 3 '-two dehydrogenations-3 '-deoxyribosylthymine, d4T), Abacavir, abacavir sulfate, emtricitabine ((-) FTC), raceme FTC etc.; Non-nucleoside reverse transcriptase inhibitor, as nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] [1,4] diaza -6-ketone), efavirenz, Delavirdine, TMC-120, TMC-125 etc.; TIBO (tetrahydrochysene-imidazo [4,5,1-jk] [1,4]-benzodiazepines-2 (1H)-ketone and thioketone)-compounds, as (S)-8-chloro-4,5,6,7-tetrahydrochysene-5-methyl-6-(3-methyl-2-butene base) imidazo [4,5,1-jk] [1,4] benzodiazepine-2 (H)-thioketone; α-APA (α-phenyl amino phenyl yl acetamide) compounds is as α-[(2-nitrobenzophenone) amino]-2,6-dichloro-benzenes-acetamide etc.; Trans-the activator protein inhibitor, TAT-inhibitor for example is as RO-5-3335 or REV inhibitor etc.; Protease inhibitor such as indinavir, ritonavir, Saquinavir, Lopinavir (ABT-378), viracept see nelfinaivr, An Punaiwei, TMC-114, BMS-232632, VX-175 etc.; Melt protein inhibitor, as T-20, T-1249 etc.; The CXCR4 receptor antagonist is as AMD-3100 etc.; The viral integrase enzyme inhibitor; Nucleotide-sample reverse transcriptase inhibitors is as tenofovir, diphosphonic acid tenofovir, fumaric acid tenofovir ester (tenofovir disoproxil fumarate) etc.; The ribonucleotide reductase inhibitor is as hydroxyurea etc.; The CCR5 antagonist is as ancriviroc, hydrochloric acid aplaviroc, vicriviroc.
Other antiviral drugs by different event in targeting virus life cycle gives The compounds of this invention, can strengthen the therapeutical effect of these chemical compounds.Aforesaid therapeutic alliance suppress HIV duplicate aspect the performance cooperative effect because each composition of combination medicine acts on the different loci that HIV duplicates.Compare with the monotherapy drug administration, the use of these combination medicines can reduce the dosage that ideal treatment or the required conventional antiretroviral drugs of preventive effect are given.These combination medicines can reduce or eliminate the side effect of conventional single antiretroviral therapy, can not disturb the antiviral activity of each medicine simultaneously.These combination medicines reduce treats drug-fast probability to single medicine, simultaneously with any xicity related minimum that drops to.These combination medicines also can increase the effect of conventional medicine, and can not increase xicity related.
The compounds of this invention also can with following immunoregulation medicament administering drug combinations: as levamisole, bropirimine, Anti-Human's interferon-alpha antibody, interferon-ALPHA, interleukin-22, met-enkephalin, aminodithioformic acid diethylester, tumor necrosis factor, naltrexone etc.; Antibiotic is as pentamidine isethionate (pentamidine isethiorate) etc.; Cholinomimetic is as bright, the donepezil of tacrine, Li Fansi, galantamine etc.; NMDA channel blocker such as memantine are to prevent or anti-infection and disease or the disease symptoms relevant with ARC as AIDS with the HIV infection, as dementia.
Although the present invention concentrates on the purposes of The compounds of this invention prevention or treatment HIV infection, The compounds of this invention also can be used as other viral inhibitor, and these viruses rely on the similar reverse transcriptase of necessary incident in their life cycle.
Experimental section
A. formula (I-a) chemical compound is synthetic
A) with 10.99kg (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile and 57 liters of acetic acid (2L/mol) are in preparation vessel in heating to 90 ℃.Solution in 95 ℃ of filtrations, and is washed with 3L acetic acid (0.21L/mol).Add 2.973 liters of hydrochloric acid (1.1 moles/mole) in 80 ℃.Slowly add 60 premium on currency (2L/ mole) in 85 ℃.Mixture slowly is cooled to 25 ℃, with 5.4 premium on currency washed twice, in 50 ℃ of dryings.Pulverize products therefrom.Obtain: formula (I-a) chemical compound crystal form A.
B) will about 150mg formula (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile .HCl chemical compound and 500ml acetone is heated to backflow in beaker.Under room temperature, make the gained partially crystallizable.Evaporating solvent under air flow is until obtaining desciccate.Obtain: formula (I-a) chemical compound crystal form B.
C) with 73.29kg (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile and 300 liters of acetic acid (2L/ mole) are in preparation vessel in heating to 104 ℃.With solution in 100 ℃ of filtrations.Add 19.8 liters of hydrochloric acid (1.1 moles/mole) in 91.4 ℃.In 70 ℃, slowly add 150 premium on currency (2L/ mole).Mixture is slowly cooled to 20 ℃, with 75 premium on currency washed twice, and in 75 ℃ of dryings.Pulverize products therefrom.Obtain: formula (I-a) chemical compound crystal C.
D) with 10.99kg (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile and 57 liters of acetic acid (2L/ mole) are in preparation vessel in heating to 93 ℃.Solution in 100 ℃ of filtrations, is washed with 3L acetic acid (0.21L/mol).Add 2.973 liters of hydrochloric acid (1.1 moles/mole) in 85 ℃.Between 85 ℃-65 ℃, slowly add 60 premium on currency (2L/ mole).Mixture is slowly cooled to 19.5 ℃, with 5.4 premium on currency washed twice, and in 50 ℃ of dryings.Pulverize products therefrom.This product of 230mg is mixed with 1ml water, and under room temperature, pulled an oar 1 day.Obtain: formula (I-a) compound form D.
B. the feature of formula (I-a) chemical compound
Listed the result of infrared spectrum and X-ray powder diffraction (XRPD) feature analysis of crystal form A, crystal form B, crystal C and form D below.Also listed differential scanning calorimetry (DSC) analysis result of crystal form A.
Infrared spectrum: KBr dispersion
Chemical compound to be analyzed is mixed tablet forming (Ph.Eur.) with alkali halide.
Instrument: Nicolet Magna 560 FTIR spectrophotometers
Scanning times: 32
Resolution: 1cm
-1
Wave-length coverage: 4000-400cm
-1
Baseline correction: be
Detector: DTGS, band KBr window
Beam splitter: Ge is on KBr
Alkali halide: KBr (potassium bromide)
Powder X-ray RD
On the PW3050/60 type Philips X ' PertPRO MPD diffractometer of band PW3040 type generator, carry out X-ray powder diffraction (XRPD) analysis.These instrument and equipment have PW3373/00 type Cu LFF X-ray tube.
Chemical compound to be analyzed is layered on the zero background specimen holder.
Device parameter
Generator voltage: 45kV
Generator current intensity: 40mA
Diffraction geometry: Bragg-Brentano
Object stage (stage): rotatable stage (spinner stage)
Condition determination
Scan pattern: continuously
Sweep limits: 3-50 ° of 2 θ
Step-length: 0.01675 °/step
Gate time: 29.845 seconds/step
Rotator rotational time: 1 second
Radiation type: CuK α
Beam wavelength: 1.54056
Diffracted beam path, incident beam path
The long anti-scatter shielding of program divergent slit: 15mm :+
Soller slit: 0.04rad Soller slit: 0.04rad
Light beam mask 15mm Ni light filter :+
(beam mask)
Anti-scatter slit: 1 ° of detector: X ' Celerator
Light beam cutter (beam knife)+
Differential scanning calorimetry
About 3mg chemical compound to be analyzed is transferred in the standard aluminum TA-Instrument specimen disc.With suitable lid specimen disc is sealed, be equipped with record DSC curve on the TA-Instruments Q1000 MTDSC of RCS cooling unit.Use following parameter:
Initial temperature: 20 ℃
Firing rate: 10 ℃/min
Final temperature: 350 ℃
Nitrogen flow rate: 50ml/min
The result
Crystal form A-IR
Crystal form A is characterised in that about 2217,1652,1497,1435,1338,1199 and 550cm
-1The FTIR spectrum that the typical absorption band is arranged.
1631,1596,1537,1504,1249,1214,1179,1152 and 1070cm
-1Can be observed other absorption band.(see figure 1).
Crystal form A-XRPD
Crystal form A is characterised in that the typical diffraction maximum of 9.7 ° ± 0.2 °, 13.5 ° ± 0.2 ° of 2-θ position and 15.0 ° ± 0.2 °.The feature of crystal form A also is in 2-θ position the X-ray powder diffraction peak of 9.1 ° ± 0.2 °, 11.0 ° ± 0.2 °, 14.6 ° ± 0.2 °, 22.0 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.3 ° ± 0.2 ° and 26.7 ° ± 0.2 °.(see figure 2) (intensity can be because of influencing the processing of intensity, the most important thing is the sample treatment process and occur changing)
Crystal form A-DSC
Decompose during the crystal form A fusing.The fusing initial temperature of following decomposition is about 250 ℃, in about 286 ℃ of beginning fusions.
Crystal form B
Crystal form B can exist by two states: dry state and hygrometric state.Only provide the feature of dry state crystal form B.
Crystal form B-IR
Crystal form B is characterised in that about 2227,2220,1599,1500,1440,1341,1209,549 and 544cm
-1The FTIR spectrum that the typical absorption band is arranged.
About 1656,1538,1518,1270,1179,1152 and 1070cm
-1Can be observed other absorption band.(see figure 3).
Crystal form B-XRPD
Crystal form B is characterised in that the typical diffraction maximum of 4.5 ° ± 0.2 °, 8.8 ° ± 0.2 ° of 2-θ position and 12.5 ° ± 0.2 °.The feature of crystal form B also is in 2-θ position the X-ray powder diffraction peak (see figure 4) of 10.3 ° ± 0.2 °, 14.7 ° ± 0.2 °, 20.6 ° ± 0.2 °, 22.2 ° ± 0.2 ° and 26.1 ° ± 0.2 °.(intensity can be because of influencing the processing of intensity, the most important thing is the sample treatment process and occur changing).
Crystal C-IR
Crystal C is characterised in that about 2221,1654,1502,1239,1193 and 546cm
-1The FTIR spectrum that the typical absorption band is arranged.
About 1627,1580,1537,1492,1216,1173,1157 and 1084cm
-1Can be observed other absorption band.(see figure 5).
Crystal C-XRPD
Crystal C is characterised in that the typical diffraction maximum of 11.9 ° ± 0.2 °, 14.3 ° ± 0.2 ° of 2-θ position and 22.3 ° ± 0.2 °.The feature of crystal C also is in 2-θ position the X-ray powder diffraction peak (see figure 6) of 12.8 ° ± 0.2 °, 18.5 ° ± 0.2 °, 21.2 ° ± 0.2 °, 24.3 ° ± 0.2 ° and 26.0 ° ± 0.2 °.(intensity can be because of influencing the processing of intensity, the most important thing is the sample treatment process and occur changing).
Form D-IR
Form D is characterised in that about 2218,1657,1506,1448,1357,1220 and 547cm
-1The FTIR spectrum that the typical absorption band is arranged.
About 1620,1597,1565,1247,1214,1179,1152 and 1073cm
-1Can be observed other absorption band.(see figure 7).
Form D-XRPD
Form D is characterised in that the typical diffraction maximum of 6.6 ° ± 0.2 °, 11.6 ° ± 0.2 ° of 2-θ position and 17.1 ° ± 0.2 °.The feature of form D also is in 2-θ position the X-ray powder diffraction peak (see figure 8) of 15.0 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.5 ° ± 0.2 °, 21.6 ° ± 0.2 ° and 29.8 ° ± 0.2 °.(intensity can be because of influencing the processing of intensity, the most important thing is the sample treatment process and occur changing).
C. dissolubility data
Table 1 has been listed free alkali (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] dissolubility data of benzonitrile and formula (I-a) chemical compound.
Table 1:
| Chemical compound | Concentration (mg/ml) | ||
| Water | 0.01N HCl | PEG 400 | |
| Free alkali (E isomer) | 0.00002 | 0.019 | 40 |
| Formula (I-a) chemical compound (crystal form A) | 0.0012 | 0.043 | |
Free alkali and HCl salt are poorly soluble in water and 0.01N HCl.Free alkali and HCl salt can be classified as BCS the 2nd compounds.The dissolubility of free alkali in PEG 400 significantly increases.
D. stability data
A) chemical stability
Formula (I-a) chemical compound (crystal form A) is stored under different humidity and temperature conditions.After the storage, analyze the impurity percentage rate of salt with high performance liquid chromatography (HPLC).
Collection in the following Table 2.Deducibility goes out on the compound chemistry stable.
Table 2:
| Storage requirement | Total impurities % (%, w/w) | ||
| 1 week | 4 | 8 weeks | |
| Contrast | 0.43 | - | - |
| 40℃/75％RH | - | 0.42 | 0.44 |
| 50 ℃/air | - | 0.41 | 0.41 |
| RT/＜5％RH | - | 0.44 | 043 |
| RT/56％RH | - | 0.44 | 0.41 |
| RT/75％RH | - | 0.43 | 0.41 |
Illustrate:-=not test
The RT=room temperature
The RH=relative humidity
Find that also this chemical compound is non-hygroscopic.
B) physical stability
Studied after storing for 6 weeks under different humidity and the temperature conditions stability of formula (I-a) chemical compound (crystal form A) crystal structure.Adopt the same terms of describing in the table 2.
After the storage, use the infrared spectrum analysis chemical compound.
Observe crystal structure and do not change, show that this compound crystal is stable.
Also studied formula (I-a) chemical compound (crystal form A) in 5 ℃ and the stability of the following storage of 25 ℃/80%RH after 1 year.Find that this compound physical is stable.
E. tablet
Illustrating tablet composition of the present invention has:
Compositions 1a
Label:
Formula (I-a) chemical compound 27.5mg (being 25mg alkali equivalent)
Lactose monohydrate 242.0mg
Hypromellose 2910 15mPa.s 5.6mg
Polysorbate20 1.4mg
Microcrystalline Cellulose 52.5mg
Cross-linking sodium carboxymethyl cellulose 17.5mg
Silica sol 1.05mg
Magnesium stearate 2.45mg
The sheet film-coat
Opadry
II white coating powder 14mg
Purified water
*80 μ l
Compositions 1b
Label:
Formula (I-a) chemical compound 27.5mg (being 25mg alkali equivalent)
Lactose monohydrate 52.25mg
Hypromellose 2910 5mPa.s 1.40mg
Polysorbate20 0.35mg
Microcrystalline Cellulose 13.125mg
Cross-linking sodium carboxymethyl cellulose 4.375mg
Magnesium stearate 1.00mg
The sheet film-coat
Opadry
II white coating powder 4mg
Purified water
*In right amount
Compositions 1c
Label:
Formula (I-a) chemical compound 27.5mg (being 25mg alkali equivalent)
Lactose monohydrate 56.97mg
Hypromellose 2910 5mPa.s 1.75mg
Polysorbate20 0.35mg
Silicified microcrystalline cellulose 16.83mg
Cross-linking sodium carboxymethyl cellulose 5.5mg
Magnesium stearate 1.10mg
The sheet film-coat
Opadry
II white coating powder 4.4mg
Purified water
*In right amount
Compositions 1d
Label:
Formula (I-a) chemical compound 27.5mg (being 25mg alkali equivalent)
Lactose monohydrate 55.145mg
Polyvinylpyrrolidone 3.25mg
Polysorbate20 0.35mg
Silicified microcrystalline cellulose 16.605mg
Cross-linking sodium carboxymethyl cellulose 6.05mg
Magnesium stearate 1.10mg
The sheet film-coat
Opadry
II white coating powder 4.4mg
Purified water
*In right amount
Compositions 2a
Label:
Formula (I-a) chemical compound 110mg (being 100mg alkali equivalent)
Lactose monohydrate 159.5mg
Hypromellose 2910 15mPa.s 5.6mg
Polysorbate20 1.4mg
Microcrystalline Cellulose 52.5mg
Cross-linking sodium carboxymethyl cellulose 17.5mg
Silica sol 1.05mg
Magnesium stearate 2.45mg
The sheet film-coat
Opadry
II white coating powder 14mg
Purified water
*80 μ l
Compositions 2b
Label:
Formula (I-a) chemical compound 110mg (being 100mg alkali equivalent)
Lactose monohydrate 209.00mg
Hypromellose 2910 5mPa.s 5.6mg
Polysorbate20 1.4mg
Microcrystalline Cellulose 52.5mg
Cross-linking sodium carboxymethyl cellulose 17.5mg
Magnesium stearate 4.00mg
The sheet film-coat
Opadry
II white coating powder 16mg
Purified water
*In right amount
Compositions 2c
Label:
Formula (I-a) chemical compound 110mg (being 100mg alkali equivalent)
Lactose monohydrate 227.88mg
Hypromellose 2910 5mPa.s 7.00mg
Polysorbate20 1.4mg
Silicified microcrystalline cellulose 67.32mg
Cross-linking sodium carboxymethyl cellulose 22.00mg
Magnesium stearate 4.40mg
The sheet film-coat
Opadry
II white coating powder 17.6mg
Purified water
*In right amount
Compositions 2d
Label:
Formula (I-a) chemical compound 110mg (being 100mg alkali equivalent)
Lactose monohydrate 220.58mg
Polyvinylpyrrolidone 13.00mg
Polysorbate20 1.4mg
Silicified microcrystalline cellulose 66.42mg
Cross-linking sodium carboxymethyl cellulose 24.2mg
Magnesium stearate 4.40mg
The sheet film-coat
Opadry
II white coating powder 17.6mg
Purified water
*In right amount
Compositions 3a
Label:
Formula (I-a) chemical compound 55mg (being 50mg alkali equivalent)
Lactose monohydrate 214.5mg
Hypromellose 2910 15mPa.s 5.6mg
Polysorbate20 1.4mg
Microcrystalline Cellulose 52.5mg
Cross-linking sodium carboxymethyl cellulose 17.5mg
Silica sol 1.05mg
Magnesium stearate 2.45mg
The sheet film-coat
Opadry
II white coating powder 14mg
Purified water
*80 μ l
Compositions 3b
Label:
Formula (I-a) chemical compound 55mg (being 50mg alkali equivalent)
Lactose monohydrate 104.50mg
Hypromellose 2910 5mPa.s 2.80mg
Polysorbate20 0.70mg
Microcrystalline Cellulose 26.25mg
Cross-linking sodium carboxymethyl cellulose 8.75mg
Magnesium stearate 2.00mg
The sheet film-coat
Opadry
II white coating powder 8.00mg
Purified water
*In right amount
Compositions 3c
Label:
Formula (I-a) chemical compound 55mg (being 50mg alkali equivalent)
Lactose monohydrate 113.94mg
Hypromellose 2910 5mPa.s 3.50mg
Polysorbate20 0.70mg
Silicified microcrystalline cellulose 33.66mg
Cross-linking sodium carboxymethyl cellulose 11.0mg
Magnesium stearate 2.20mg
The sheet film-coat
Opadry
II white coating powder 8.80mg
Purified water
*In right amount
Compositions 3d
Label:
Formula (I-a) chemical compound 55mg (being 50mg alkali equivalent)
Lactose monohydrate 110.29mg
Polyvinylpyrrolidone 6.50mg
Polysorbate20 0.70mg
Silicified microcrystalline cellulose 33.21mg
Cross-linking sodium carboxymethyl cellulose 12.1mg
Magnesium stearate 2.20mg
The sheet film-coat
Opadry
II white coating powder 8.80mg
Purified water
*In right amount
Compositions 4
Label:
Formula (I-a) chemical compound 82.5mg (being 75mg alkali equivalent)
Lactose monohydrate 165.435mg
Polyvinylpyrrolidone 9.75mg
Polysorbate20 1.05mg
Silicified microcrystalline cellulose 49.815mg
Cross-linking sodium carboxymethyl cellulose 18.15mg
Magnesium stearate 3.30mg
The sheet film-coat
Opadry
II white coating powder 13.2mg
Purified water
*In right amount
Compositions 5a
Label:
Formula (I-a) chemical compound 165mg (being 150mg alkali equivalent)
Lactose monohydrate 330.87mg
Polyvinylpyrrolidone 19.5mg
Polysorbate20 2.1mg
Silicified microcrystalline cellulose 99.63mg
Cross-linking sodium carboxymethyl cellulose 36.30mg
Magnesium stearate 6.6mg
The sheet film-coat
Opadry
II white coating powder 19.80mg
Purified water
*In right amount
Compositions 5b
Label:
Formula (I-a) chemical compound 165mg (being 150mg alkali equivalent)
Lactose monohydrate 341.82mg
Hypromellose 2910 5mPa.s 10.5mg
Polysorbate20 2.1mg
Silicified microcrystalline cellulose 100.98mg
Cross-linking sodium carboxymethyl cellulose 33.00mg
Magnesium stearate 6.6mg
The sheet film-coat
Opadry
II white coating powder 19.80mg
Purified water
*In right amount
*In final tablet, do not exist.
Above-mentioned tablet prepares through following method: hypromellose or polyvinylpyrrolidone and polysorbate20 are dissolved in the purified water (in right amount), then described solution are sprayed on the fluidized powder of being made up of the mixture of crystal form A and lactose monohydrate.Dry gained granule sieves and mixes with microcrystalline Cellulose or silicified microcrystalline cellulose, cross-linking sodium carboxymethyl cellulose and optional silica sol.After adding magnesium stearate, mixture of powders is pressed into tablet, uses Opadry then
The suspension of II white coating powder in purified water is with tablet bag film-coat.
In above-mentioned composition, microcrystalline Cellulose is preferably Avicel
PH101, cross-linking sodium carboxymethyl cellulose is preferably Ac-Di-Sol
Silicified microcrystalline cellulose is preferably Prosolv
HD90; Polyvinylpyrrolidone is preferably PVP K29-32.
F. bioavailability study in the body
A) for bioavailability in the body of research formula (I-a) chemical compound, in male beagle (beagle dogs), study.
Bioavailability behind formula (I-a) the chemical compound oral administration and the bioavailability behind the free alkali intravenous administration are compared.
The preparation that is used for intravenous administration is (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] 75%PEG 400/25% aseptic aqueous solution of benzonitrile free alkali, dosage is 1.25mg/kg.
The preparation that is used for oral administration is:
-(E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] PEG 400 solution (group I) of benzonitrile free alkali;
-contain 7.67% (w/w) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] capsule (No. 0 of benzonitrile (E) free alkali, 0.18% (w/w) sodium lauryl sulphate, 0.18% (w/w) silicon dioxide, the granular lactose monohydrate of 91.97% (w/w); Red capsule medicated cap-red utricule) (group II);
-contain the capsule (No. 0 of 8.36% (w/w) formula (I-a) chemical compound, 0.18% (w/w) sodium lauryl sulphate, 0.18% (w/w) silicon dioxide, the granular lactose monohydrate of 91.28% (w/w); Red capsule medicated cap-red utricule) (group III).
(%w/w is based on capsular content)
Different preparations are with the dosage level oral administration of 5mg alkali equivalent/Kg.The weight of animals based on prior mensuration prepares preparation.Use the preceding body weight of administration, and calculate the accurate dosage of every kind of preparation by average 5mg alkali equivalent/Kg.
0 (=predose), 0.5,1,2,4,6,8,24,32,48 and 72 hour after administration are from jugular vein blood-sample withdrawal (4ml is on EDTA).After the sampling, immediately blood sample is placed in the ice-melt and lucifuge.Under 5 ℃,, make separating plasma with blood sample centrifugal 10 minutes with about 1900xg.The separated plasma sample is transferred in second pipe in 2 hours behind blood sample collection, and uses until analyzing in≤-18 ℃ of preservations.In institute is free, with the blood sample lucifuge, and place in the ice-melt or≤-18 ℃ under.
By fixed LC-MS/MS research method, measure 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] plasma concentration of benzonitrile (E).With the API-3000MS/MS (Applied Biosystems) of HPLC-pump (Agilent) and automatic sampler (Interscience) coupling on carry out LC-MS/MS and analyze.
Calculate average (n=2) plasma concentration and each sample time of each preparation.Measure peak plasma concentration (C
Max), corresponding peak time (T
Max) and AUC
0-t(wherein t is corresponding to the time point that finally can survey concentration more than the quantitative limit).With AUC
0-tBe extrapolated to infinite area under curve (AUC with calculating
0-inf), wherein β be elimination rate constant Ct/ β by latter stage plasma concentration-time data log-linear regression determine.Calculate average (n=2) PK parameter of all preparations.With oral administration post dose-normalized average A UC
0-infValue is divided by intravenous administration post dose-normalized average A UC
0-infValue obtains 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] absolute bioavailability (F of benzonitrile (E)
Abs) estimated value, this is used for all oral formulations.
The result that above-mentioned research obtains is summarised in the table 3.
Table 3
| Preparation | IV | Oral group of I | Oral group of II | Oral group of III |
| Dosage | 1.25mg/kg | 5mg/kg | 5mg/kg | 5mg/kg |
| Time (hour) | Mean concentration (ng/ml) (n=2) | Mean concentration (ng/ml) (n=2) | Mean concentration (ng/ml) (n=2) | Mean concentration (ng/ml) (n=2) |
| 0 | ||||
| 0.13 | 644 | |||
| 0.25 | 696 | |||
| 0.5 | 582 | 102 | ＜1.00 | 57.2 |
| 1 | 482 | 206 | 5.19 | 367 |
| 2 | 426 | 277 | 18.9 | 542 |
| 4 | 315 | 288 | 21.2 | 407 |
| 6 | 241 | 265 | 16.2 | 387 |
| 8 | 129 | 257 | 13.4 | 333 |
| 24 | 114 | 131 | 6.68 | 126 |
| 32 | 70.3 | 92.7 | 5.75 | 136 |
| 48 | 55.5 | 63.3 | 2.87 | 66.1 |
| 72 | 29.5 | 44.7 | ＜1.00 | 36.6 |
| C maxng/ml | 341 | 21 | 542 | |
| T maxh | 4 | 4 | 2 | |
| AUC 0-72h ng.h/ml | 7330 | 8359 | 308(n＝1) | 10231 |
| AUC 0-INF ng.h/ml | 8661 | 10854 | 464 | 11770 |
| F abs | 31％ | 1.34％ | 34.0％ |
Can reach a conclusion from above result: when giving with solid dosage forms, with corresponding free alkali 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile (E) compares, and formula (I-a) chemical compound has significantly better bioavailability.The bioavailability and the free alkali of formula (I-a) chemical compound are suitable with the bioavailability of oral PEG 400 solution administrations.
B) also studied formula (I-a) chemical compound at the intravital oral administration biaavailability of people.
The health volunteer accepts 2 kinds of treatments.
Treatment A:25mg/ml free alkali (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] 100%PEG 400 solution of benzonitrile.
Treatment B: the tablet of above-described compositions 2a.
In one group of 12 experimenter, each experimenter accepts three single doses, and each single dose is equivalent to 100mg free alkali (E) 4-[[4-[[4-(2-cyano group vinyl)-2,6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile.Give each dosage the 1st day of each treatment cycle.
During three kinds of treatments, experimenter (n=12) accepts at random: the treatment B of single dose under the treatment B of the treatment A of single dose, fasting stage single dose and the feed condition under the feed condition, each treatment is the intermission (wash-out) at least 2 weeks at interval.Per os gives single dose 100mg (E)-4-[[4-[[4-(2-cyano group vinyl)-2 during each treatment, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] behind benzonitrile alkali or the equivalent, measure (E) 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] the 216 hour pharmacokinetic curves of benzonitrile in blood plasma.In order to measure blood plasma (E)-4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile concentration, before administration and study blood drawing (every each administration of experimenter adds up to 19 samples) in 0.5,1,2,3,4,6,8,12,16,24,32,48,72,96,120,144,168 and 216 hour behind the medicine.
When under the condition on the feed during the research pharmacokinetics, under the feed condition, give two in three dosage of each experimenter, i.e. standardized breakfast of feed in 10 minutes before treating A or treatment B.For ' fasting ' condition, before studying medicine, the necessary fasting of experimenter at least 10 hours.When research under fasted conditions is studied medicine after 4.5 hours during pharmacokinetics, the experimenter accepts their food first (have only treatment B like this) when lunch.
Particularly,, allow the experimenter to enter research institution (testing facility), except allowed the water inlet experimenter's overnight fasting at least 10 hours in preceding 2 hours up to ingestion of drugs at the 1st day.For the experimenter of receive treatment at random under the condition on the feed A or treatment B, in research institution, eat up standardization and give trial drug in early 10 minutes after the meal.For the experimenter of the B that under fasting state, receives treatment at random, at overnight fasting after at least 10 hours, take trial drug and do not take food.
Standardization breakfast is made up of four bread, two Petasos or the coffee of cheese, butter, fruit jam and two cups of decaffeination or with milk and/or sugared tea.Under test nurse or researcher's supervision, in 20 minutes, eat up this standard meal.
For all experimenters, between 9a.m.-11a.m, trial drug gives with the water of about 200mL.After the administration 2 hours, allow all experimenters' water inlets.Provided lunch in 4.5 hours after the administration, dinner was provided after the administration in 10 hours.After the dinner, allow the experimenter to recover their diet.The 2nd day, behind 24 hours the pharmacokinetics sample, the experimenter came out from research institution, gets back to mechanism after 8 hours after gathering administration, and repeated aforementioned process to do further assessment in the 3rd, 4,5,6,7,8 and 10 day.More particularly, in order to measure blood plasma (E)-4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] benzonitrile concentration, before administration and study blood drawing (every each administration of experimenter adds up to 19 samples) in 0.5,1,2,3,4,6,8,12,16,24,32,48,72,96,120,144,168 and 216 hour behind the medicine.For every experimenter's individuality, the interval at least 2 weeks is arranged between each time administration.
By the LC-MS/MS method of checking, carry out (E)-4-[[4-[[4-in the human plasma (2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] bioanalysis of benzonitrile.
Table 4 has gathered the result of research in the human body.
Table 4:
| (E)-and 4-[[4-[[4-(2-cyano group vinyl)-2, the 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] pharmacokinetics (mean value SD) of benzonitrile | Treatment A feed | Treatment B | |
| Feed | Fasting | ||
| N C max(ng/ml) AUC last(ng.h/ml) AUC ∞(ng.h/ml) | 12 372(37) 12448(2688) 12945(2988) | 12 316(59) 10455(2525) 10905(2754) | 12 210(119) 7421(2939) 7804(3101) |
Claims (17)
1. Pharmaceutical composition, described compositions comprise formula (I) chemical compound, its N-oxide or the stereoisomer of pharmaceutically acceptable carrier and treatment effective dose as active component
2. the Pharmaceutical composition of claim 1, its Chinese style (I) chemical compound is formula (I-a) chemical compound
3. the Pharmaceutical composition of claim 2, its Chinese style (I-a) chemical compound is polymorphic A, it is characterized in that the X-ray powder diffraction peak of 9.7 ° ± 0.2 °, 13.5 ° ± 0.2 ° of 2-θ position and 15.0 ° ± 0.2 °.
4. the Pharmaceutical composition of claim 3, the feature of wherein said polymorphic A also are the X-ray powder diffraction peak of 9.1 ° ± 0.2 °, 11.0 ° ± 0.2 °, 14.6 ° ± 0.2 °, 22.0 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.3 ° ± 0.2 ° of 2-θ position and 26.7 ° ± 0.2 °.
5. each Pharmaceutical composition in the aforementioned claim, described compositions is applicable to oral administration.
6. each Pharmaceutical composition in the aforementioned claim, described compositions is a solid composite.
7. each Pharmaceutical composition in the aforementioned claim, described compositions also comprises wetting agent.
8. the Pharmaceutical composition of claim 7, wherein said wetting agent is a tween.
9. each Pharmaceutical composition in the aforementioned claim, described compositions is a tablet form.
10. the Pharmaceutical composition of claim 9, described compositions bag film-coat.
11. each Pharmaceutical composition in the aforementioned claim, described compositions has following composition:
(a) active component of 5-50%;
(b) wetting agent of 0.01-5%;
(c) diluent of 40-92%;
(d) polymer of 0-10%;
(e) disintegrating agent of 2-10%;
(f) fluidizer of 0.1-5%;
(g) lubricant of 0.1-1.5%.
12. being described compositionss, each Pharmaceutical composition in the aforementioned claim, condition do not contain emtricitabine and fumaric acid tenofovir ester.
13. being described compositionss, each Pharmaceutical composition among the claim 1-11, condition do not contain one or more nucleoside reverse transcriptase inhibitor and/or one or more nucleotide reverse transcriptase inhibitors.
14. a method for preparing each Pharmaceutical composition in the aforementioned claim said method comprising the steps of:
(i) do active component and part diluent mixed;
(ii) binding agent and wetting agent are dissolved in the binder solution solvent preparation binder solution;
(iii) the (ii) middle gained binder solution of step is sprayed on the middle gained mixture of step (i);
(iv) the (iii) middle gained wet powder of drying steps sieves and optional the mixing then;
(v) remaining diluent part, disintegrating agent and optional fluidizer are sneaked in the (iv) middle gained mixture of step;
(vi) (v) choose wantonly in the gained mixture and add lubricant to step;
(vii) (vi) the gained mixture is compressed into tablet with step;
(viii) optional with step (vii) gained tablet bag film-coat.
15. formula (I-a) chemical compound of formula (I) chemical compound of definition or claim 2 definition purposes in each the compositions in preparation claim 1-13 in the claim 1, wherein said compositions are used for the treatment of or prevents the HIV infection.
16. the method for formula (I) chemical compound of definition is characterized in that making corresponding free alkali and hydrochloric acid reaction in the presence of suitable acid in the preparation claim 1.
17. the method for claim 16, wherein said suitable acid is acetic acid.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MYPI20043578 | 2004-09-02 | ||
| MYPI20043578A MY169670A (en) | 2003-09-03 | 2004-09-02 | Combinations of a pyrimidine containing nnrti with rt inhibitors |
| EPPCT/EP2004/052028 | 2004-09-03 | ||
| EP05101467.8 | 2005-02-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510012919.7A Division CN104586850A (en) | 2004-09-02 | 2005-09-02 | Fumarate of 4- [[4- [[4- (2-cyanoethenyl) -2,6-dimethylphenyl)amino] -2-pyrimidinyl]amino]benzonitrile |
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| CN101056673A true CN101056673A (en) | 2007-10-17 |
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|---|---|---|---|
| CNA200580038025XA Pending CN101056673A (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile |
| CN2005800380936A Active CN101068597B (en) | 2004-09-02 | 2005-09-02 | Fumarate of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile |
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| CN2005800380936A Active CN101068597B (en) | 2004-09-02 | 2005-09-02 | Fumarate of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile |
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| Country | Link |
|---|---|
| CN (2) | CN101056673A (en) |
| AP (1) | AP2296A (en) |
| CR (1) | CR9031A (en) |
| SG (1) | SG155885A1 (en) |
| UA (2) | UA92467C2 (en) |
| ZA (1) | ZA200701826B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013170421A1 (en) * | 2012-05-14 | 2013-11-21 | 上海迪赛诺药业有限公司 | Rilpivirine hydrochloride alcoholate polymorph and preparation method thereof |
| CN103420920A (en) * | 2012-05-14 | 2013-12-04 | 上海迪赛诺药业有限公司 | Rilpivrine hydrochloride alcoholate polymorphs and preparation methods thereof |
| CN110191704A (en) * | 2016-10-24 | 2019-08-30 | 爱尔兰詹森科学公司 | Dispersible composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO3429B1 (en) * | 2001-08-13 | 2019-10-20 | Janssen Pharmaceutica Nv | Hiv inhibiting pyrimidines derivatives |
| MY169670A (en) * | 2003-09-03 | 2019-05-08 | Tibotec Pharm Ltd | Combinations of a pyrimidine containing nnrti with rt inhibitors |
| WO2004016581A1 (en) * | 2002-08-09 | 2004-02-26 | Janssen Pharmaceutica N.V. | Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile |
-
2005
- 2005-09-02 AP AP2007003934A patent/AP2296A/en active
- 2005-09-02 UA UAA200701971A patent/UA92467C2/en unknown
- 2005-09-02 CN CNA200580038025XA patent/CN101056673A/en active Pending
- 2005-09-02 CN CN2005800380936A patent/CN101068597B/en active Active
- 2005-09-02 UA UAA200702178A patent/UA92469C2/en unknown
- 2005-09-02 SG SG200905799-3A patent/SG155885A1/en unknown
-
2007
- 2007-03-01 ZA ZA200701826A patent/ZA200701826B/en unknown
- 2007-03-30 CR CR9031A patent/CR9031A/en not_active Application Discontinuation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013170421A1 (en) * | 2012-05-14 | 2013-11-21 | 上海迪赛诺药业有限公司 | Rilpivirine hydrochloride alcoholate polymorph and preparation method thereof |
| CN103420920A (en) * | 2012-05-14 | 2013-12-04 | 上海迪赛诺药业有限公司 | Rilpivrine hydrochloride alcoholate polymorphs and preparation methods thereof |
| CN103420920B (en) * | 2012-05-14 | 2016-04-27 | 上海迪赛诺药业有限公司 | Rilpivrine hydrochloride alcoholate polymorphic form and preparation method thereof |
| CN110191704A (en) * | 2016-10-24 | 2019-08-30 | 爱尔兰詹森科学公司 | Dispersible composition |
| TWI821163B (en) * | 2016-10-24 | 2023-11-11 | 愛爾蘭商健生科學愛爾蘭無限公司 | Dispersible compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| UA92467C2 (en) | 2010-11-10 |
| ZA200701826B (en) | 2008-07-30 |
| CN101068597B (en) | 2012-04-18 |
| CR9031A (en) | 2009-01-16 |
| AP2296A (en) | 2011-10-31 |
| CN101068597A (en) | 2007-11-07 |
| AP2007003934A0 (en) | 2007-04-30 |
| SG155885A1 (en) | 2009-10-29 |
| UA92469C2 (en) | 2010-11-10 |
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