CN101068597B - Fumarate of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile - Google Patents
Fumarate of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile Download PDFInfo
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Abstract
The present invention concerns methods and compositions of use for treatment of Alzheimer's Disease (AD). In certain embodiments, the methods concern preparation of phage-display single chain antibody libraries and screening against amyloid-beta (Abeta) protein or peptide. Anti-Abeta antibodies are selected and sequenced. In certain embodiments, synthetic Abeta binding peptides are designed and prepared, using portions of the anti-Abeta antibody sequences. The antibodies and peptides are of use for treatment of AD or for treatment of individuals at risk of developing AD. Compositions comprising anti-Abeta antibodies or Abeta binding peptides are also disclosed.
Description
The present invention relates to 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile fumarate, contain the Pharmaceutical composition of said fumarate; Relate to the preparation of this salt and this Pharmaceutical composition.
WO 03/16306 openly suppresses the pyrimidine derivatives that HIV duplicates, comprising 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile and pharmaceutically acceptable salt thereof.The method for preparing of WO 04/0162581 open 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile.
4-[[4-[[4-(2-cyanic acid 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 having been 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 ART.The treatment compliance is for influencing one of most important 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 HTV 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 through 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 following:
The 1st type: highly dissoluble-high osmosis
The 2nd type: low-solubility-high osmosis
The 3rd type: highly dissoluble-hypotonicity
The 4th type: low-solubility-hypotonicity
When the chemical compound per os with low-solubility or hypotonicity (the 2nd to 4 type) gave, its bioavailability was low.
Free alkali 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals]-amino] benzonitrile can be classified as BCS the 2nd compounds, and therefore dissolubility is low in water.It is low that 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile not only is presented in the water dissolubility, 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 property, for example through the suitable salt of preparation.4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile is also followed this approach.Prepared salt shows in the water outlet that dissolubility only has improvement slightly in the dissolubility and HCl.Prepared salt still belongs to the 2nd type of BCS.Therefore, can expect that also the bioavailability of prepared salt is low.
Be unexpectedly; Have been found that 4-[[4-[[4-(2-cyanic acid vinyl)-2 now; The 6-3,5-dimethylphenyl] amino]-the 2-pyrimidine radicals] amino] fumarate (trans CH (COOH)=CH (COOH)), especially its E-isomer of benzonitrile compared with its free alkali has bioavailability in the body that significantly improves.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 fumarate.
Also find fumarate no hygroscopicity of the present invention, and under different humidity and temperature conditions chemistry and physically stable.
Therefore, the present invention relates to formula (I) chemical compound, i.e. fumaric acid (trans CH (COOH)=CH (COOH)) salt, its N-oxide or stereoisomer of 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] 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.
The term that uses in the preceding text " stereoisomer " is defined as all possible stereoisomer that formula (I) chemical compound and N-oxide or quaternary amine possibly have.Only if mention in addition or explain, chemical name expression (I) chemical compound of chemical compound and all possible stereoisomer mixture of N-oxide, solvate or quaternary amine, and each individual isomer that has basically 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 cyanic acid 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 among this paper; 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.Especially meaningfully have basically no the E-isomer of Z-isomer.Among this paper 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 among this paper; 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.Especially meaningfully have basically no the Z-isomer of E-isomer.Among this paper 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 polymorphic of salt of the present invention also within the scope of the present invention.
The polymorphic of medicinal compound possibly be important to the chemical compound that those relate in the dosage forms exploitation; Because if this polymorphic can not keep stable during clinical and stability study, accurate dosage then used or that measure maybe be inconsistent between a collection of and next group.In case medicinal compound preparation is used, confirm the polymorph that each dosage form discharges, be important to guarantee that the 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, possibly be more suitable for being included in the pharmaceutical preparation than other polymorph.Use like this paper, the polymorph of The compounds of this invention is identical chemical entities, but crystal arrangement is different.
The solvent addition form (solvate) that salt of the present invention can form also within the scope of the present invention.The instance of this type of form is like hydrate, alcoholates etc.Solvate is also referred to as pseudopolymorph among this paper.Be preferably anhydrous salt.
No matter when hereinafter uses, and 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 through in the presence of suitable solvent such as suitable acid such as acetic acid are reacted corresponding free alkali and fumaric acid 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) is the pathogenic factor of human 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 is unusual.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 like 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; Be 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.
The activity that the inhibition HIV of 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile duplicates has been described among the WO 03/16306, its by reference integral body be attached among this paper.
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, like 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.Said purposes as medicine or Therapeutic Method comprises 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 treatment or prevention of HIV infects, 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.Said 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 after the Pharmaceutical composition administration, also can obtain to treat effective plasma levels, the saliniferous amount of said 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.
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 compositions does not contain one or more efabirenzs and/or one or more ucleotides RTIs.
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 like water, glycols, oils, alcohols etc. like 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, in this situation, suitable liquid-carrier, suspending agent etc. can be adopted.Also comprise and be used to face solid form preparation 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.Said additive can promote percutaneous drug delivery, and/or can help to prepare desired compsn.These compositionss can give in every way, as with transdermal patch, with 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 through 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 transmits solution, suspension or dry powder and develop for per os or snuffing, all be applicable to give The compounds of this invention.
The compounds of this invention also can drop form topical, especially eye drop.Said eye drop can be solution or suspensoid form.In order to discharge as the solution of eye drop or suspension and any system that develops all be applicable to and give The compounds of this invention.
WO 2004/069812 is attached among this paper by reference; Pyrimidine derivatives 4-[[4-[[4-(2-cyanic acid 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; Said 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 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; Said 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 compositions does not comprise one or more NRTIs 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, like gel, jelly, ointment, ointment, membrane, sponginum, 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, said 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 like 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.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 the Pharmaceutical composition bioadhesion to site of administration, condition is that said composition does not contain one or more NRTIs and/or one or more nucleotide reverse transcriptase inhibitors.Site of administration is preferably vagina, rectum, mouth or skin, most preferably is vagina.
Easy and dosage is even for administration, it is especially favourable that above-mentioned Pharmaceutical composition is mixed with unit dosage forms.The unit dosage forms that this paper uses refers to be suitable as the physics discrete unit of UD, and constituent parts comprises the active component that calculates the scheduled volume that produces required therapeutic effect, and required pharmaceutical carrier.The instance 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 possibly 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 said 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, said compositions comprise pharmaceutically acceptable carrier and the formula (I), (I-a) of treatment effective dose or (I-b) chemical compound as active component; Relate in particular to and be fit to the Pharmaceutical composition that per os gives; Said compositions comprises pharmaceutically acceptable carrier, and chemical compound is as active component with the formula (I), (I-a) of treatment effective dose or (I-b), and condition is that said composition does not comprise one or more NRTIs and/or one or more nucleotide reverse transcriptase inhibitors.
Particularly composition for oral liquid is the Peroral solid dosage form Pharmaceutical composition, is more especially to be tablet or capsule, even is more especially and 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-cyanic acid 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).
Preceding text or the term " about " of hereinafter using relate to the mode of numerical value x, like 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 in the present composition, uses is listed below.Should stress listed wetting agent be merely illustrate, representational, be not exhaustive.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; The ester that comprises lauric acid, oleic acid, stearic acid, castor oil acid (ricinoic acid) etc. and PEG 6,7,8,9,10,12,15,20,25,30,32,40,45,50,55,100,200,300,400,600 etc., 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, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30 stearate, PEG-40 laurate or oleate or stearate, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate; (wetting agent that belongs to such is as being called Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, 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 like 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 like 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; The ester of edible vegetable oil such as Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, palm-kernel oil, almond oil, almond oil etc., for example PEG-20 Oleum Ricini or castor oil hydrogenated or Semen Maydis oil glyceride or almond oil glyceride, PEG-23 Oleum Ricini, PEG-25 castor oil hydrogenated or trioleate, PEG-35 Oleum Ricini, PEG-30 Oleum Ricini or castor oil hydrogenated, PEG-38 Oleum Ricini, PEG-40 Oleum Ricini or castor oil hydrogenated or palm-kernel oil, PEG-45 castor oil hydrogenated, PEG-50 Oleum Ricini or castor oil hydrogenated, PEG-56 Oleum Ricini, PEG-60 Oleum Ricini or castor oil hydrogenated or Semen Maydis oil glyceride or almond oil glyceride, PEG-80 castor oil hydrogenated, PEG-100 Oleum Ricini or castor oil hydrogenated, 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, like 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 like 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, PEG-4 Arlacel-20, PEG-5 Arlacel-80, PEG-6 Arlacel-80 or Arlacel-20 or Arlacel-60, PEG-8 Arlacel-60, PEG-30 anhydro sorbitol four oleates, PEG-40 sorbitan oleate or anhydro sorbitol four oleates, PEG-60 anhydro sorbitol tetrastearate, 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 like 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 like 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 like PEG-10-100 nonyl phenol (Triton X series), PEG-15-100 octyl phenol ether (Triton N series) etc.;
L) polyox-yethylene-polyoxypropylene block copolymer (poloxamer) is like 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 like enuatrol, sodium lauryl sulphate, sarcosyl, dioctyl sodium sulphosuccinate, Sodium myristate, sodium palmitate, sodium state, sodium ricinoleate etc.; Bile salts for example is like sodium cholate, sodium taurocholate, NaGC etc.; Phospholipid for example is like Ovum Gallus domesticus Flavus lecithin/soybean lecithin, hydroxylated lecithin, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, Phosphatidylserine etc.; Phosphate ester for example is like 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 like 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 like 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 like 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, like 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 or formula (I), (I-a) or (I-b) granularity of chemical compound of chemical compound.Measure more or granularity is more little, possibly need many more wetting agent.
In the situation of Peroral solid dosage form Pharmaceutical composition of the present invention, like 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 (like PEG), polyacrylate, polyvinylpyrrolidone etc.Certainly also can use blended polymer, like 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 such as methylcellulose;
-hydroxy alkyl cellulose such as hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose;
-hydroxyalkyl alkylcellulose such as hydroxyethylmethyl-cellulose and hydroxypropyl emthylcellulose;
-carboxyl alkyl cellulose such as carboxymethyl cellulose;
-carboxyl alkyl cellulose alkali metal salt such as sodium carboxymethyl cellulose;
-carboxyalkyl alkylcellulose such as carboxymethylethylcellulose;
-carboxyl alkyl cellulose ester;
-starch;
-pectin such as carboxymethyl amylopectin sodium;
-chitin derivative such as chitosan;
-heparin and heparinoid;
-polysaccharide such as alginic acid, alkali metal and ammonium salt thereof, 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;
The copolymer of-polyalkylene oxide such as PEO and PPOX and oxirane and expoxy propane, for example poloxamer and the husky amine (poloxamines) in pool Lip river.
Pharmaceutically acceptable and have the polymer of not enumerating like the appropriate physicochemical properties of preamble definition, be suitable for preparing the present composition equally.
Organic polymer is preferably starch, polyvinylpyrrolidone or cellulose ether, like PVP K29-32, PVP K90, methylcellulose, hydroxypropyl cellulose, hydroxyethylmethyl-cellulose or hydroxypropyl emthylcellulose (HPMC).
Said 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 2910 15mPa.s or hypromellose 2910 5mPa.s, especially preferred hypromellose 2910 15mPa.s.Hydroxypropyl emthylcellulose is that hypromellose is included the title in the title (United States Adopted Name) (seeing Martindale, The Extra Pharmacopoeia, the 29th edition, the 1435th page) in the U.S..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, like tablet or capsule, said composition also can further comprise diluent and/or fluidizer.
Pharmaceutically acceptable diluent comprises 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; The lactose monohydrate of can
having bought and the spray-drying mixt of microcrystalline Cellulose (75: 25); The microcrystalline Cellulose of can
having bought and the spray-drying mixt of 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 starch; Ion exchange resin such as amberlite (Amberlite); Crospolyvinylpyrrolidone; Modified cellulose gum such as cross-linking sodium carboxymethyl cellulose (like
); 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, like 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 not label of coating more is prone to swallow; More be prone to distinguish with 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 instance is a hydroxypropyl emthylcellulose, and the suitable manufacturing methods instance 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.Examples of suitable coating materials
especially
II white powder coated.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 like 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 in long-term, prevents in the method for individual infective virus.Chemical compound can be independent, or with vaccine in RTI is conventional uses consistent mode to be used for these vaccines with other antiviral drugs.Therefore, The compounds of this invention can with the conventional pharmaceutically acceptable auxiliary agent combination of adopting in the vaccine, give with the prevention effective dose between the extended period, avoid the HIV infection to protect individuality.
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.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 one or more other antiretroviral chemical compounds are different from NRTI and/or nucleotide reverse transcriptase inhibitors.Different drug can be combined into single preparation 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.
Said other antiretroviral chemical compounds are known antiretroviral chemical compound, like suramin, pentamidine, Thymopentin, castanospermine, dextran (sulphuric acid dextran), foscarnet sodium (phosphonoformic acid trisodium); NRTI, as zidovudine (3 '-azido-3 '-AZT, AZT), didanosine (2 ', 3 '-didanosine; DdI), zalcitabine (zalcitabine; DdC) or lamivudine (2 '; 3 '-dideoxy-3 '-thiocytidine; 3TC), stavudine (2 ', 3 '-two dehydrogenations-3 '-AZT, d4T), Abacavir, abacavir sulfate, emtricitabine (emtricitabine) ((-) FTC), raceme FTC etc.; Non-nucleoside reverse transcriptase inhibitor; Like 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]-benzodiazepine
-2 (1H)-ketone and thioketone)-compounds, like (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 (1H)-thioketone; α-APA (α-phenyl amino phenyl yl acetamide) compounds is like α-[(2-nitrobenzophenone) amino]-2,6-dichloro-benzenes-acetamide etc.; Trans-the activator protein inhibitor, TAT-inhibitor for example is like 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, like T-20, T-1249 etc.; The CXCR4 receptor antagonist is like AMD-3100 etc.; The viral integrase enzyme inhibitor; Nucleotide-appearance RTI is like tenofovir, diphosphonic acid tenofovir, fumaric acid tenofovir ester (tenofovir disoproxil fumarate) etc.; The ribonucleotide reductase inhibitor is like hydroxyurea etc.; The CCR5 antagonist is like ancriviroc, hydrochloric acid aplaviroc, vicriviroc.
Other antiviral drugs through 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: like levamisole, bropirimine, Anti-Human's IFN-antibody, interferon-ALPHA, interleukin-22, MEK, aminodithioformic acid diethylester, tumor necrosis factor, naltrexone etc.; Antibiotic is like pentamidine isethionate (pentamidine isethiorate) etc.; Cholinomimetic is like 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 like AIDS with the HIV infection, like 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
1 mole of (E) 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile free alkali is dissolved in the acetic acid (2L/mol, 80-100 ℃).Add the 1.2mol fumaric acid.In 60-70 ℃, add entry (2L/mol) in batches.With this mixture in stirred overnight at room temperature.Filtering-depositing, the water washed twice, and, obtain 90% formula (I-a) chemical compound in 50 ℃ of vacuum dryings.
B. dissolubility data
Table 1 has been listed the dissolubility data of free alkali (E) 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile and formula (I-a) chemical compound.
Table 1:
Free alkali and fumarate be poor solubility in water and 0.01N HCl.Free alkali and fumarate can be classified as BCS the 2nd compounds.The dissolubility of free alkali in PEG 400 significantly increases.
C. stability data
A) chemical stability
Chemical compound (I-a) is stored under different humidity and temperature conditions.After the storage, analyze the impurity percentage rate of this salt with HPLC (HPLC).With collection in the following Table 2.Deducibility goes out on formula (I-a) compound chemistry stable.
Table 2:
Explanation:-=do not test
The RT=room temperature
The RH=relative humidity
Also discoverable type (I-a) chemical compound is non-hygroscopic.
B) physical stability
Studied after storing for 6 weeks under different humidity and the temperature conditions formula (I-a) compound crystal stability of structure.Adopted 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 on this compound crystal stable.
D. tablet
Illustrating tablet composition of the present invention has:
Compositions 1a
Label:
The sheet film-coat
Purified water * 80 μ l
Compositions 1b
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 1c
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 1d
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 2a
Label:
The sheet film-coat
Purified water * 80 μ l
Compositions 2b
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 2c
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 2d
Label:
The sheet film-coat
II white coating powder 17.6mg
Purified water * is an amount of
Compositions 3a
Label:
The sheet film-coat
Purified water * 80 μ l
Compositions 3b
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 3c
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 3d
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 4
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 5a
Label:
The sheet film-coat
Purified water * is an amount of
Compositions 5b
Label:
The sheet film-coat
Purified water * is an amount of
* 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 said 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 the suspension of
II white coating powder in purified water then tablet bag film-coat.
In above-mentioned composition; Microcrystalline Cellulose is preferably
PH101, and cross-linking sodium carboxymethyl cellulose is preferably
silicified microcrystalline cellulose and is preferably
HD90; Polyvinylpyrrolidone is preferably PVP K29-32.
E. bioavailability study in the body
In male beagle (beagle dog), studied bioavailability in the body of formula (I-a) chemical compound.
The preparation that oral administration uses has:
-(E) PEG 400 solution (25mg/ml) of 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile free alkali (group I);
-contain by 32.9mg formula (I) chemical compound (being 25mg alkali equivalent); 300mg lactose DC (directly compression); 0.59mg silicon dioxide; 0.59mg the capsule of the mixture that sodium lauryl sulphate is formed (No. 0; Red capsule medicated cap-red utricule) (group II);
The dosage level of group II preparation oral administration is 5mg alkali equivalent/Kg.The weight of animals based on prior mensuration prepares preparation.Use the preceding body weight of administration, and calculate accurate dosage by average 5mg alkali equivalent/Kg.
Press the day volume of 0.2ml/kg body weight, use stomach tube through gavage, per os contrasts PEG400 preparation (group I).With every dog 2ml PEG400 flushing stomach tube, on stomach tube, place the syringe that is full of the 10ml air then.Pause 10-15 take-off pipe after second.
According to cross-over design, contrast PEG400 solution (group I) and formula (I-a) chemical compound (group II).2 dogs of first group give 5mg eq./kg (0.2ml/kg) group I control formulation, and 2 dogs of second group give 5mg alkali equivalent/kg (2 capsules/dog) group II fumarate preparation.After 14 days removing phase (washout-period), first group of dog gives fumarate preparation (group II), and second group of dog gives control formulation (group I).
0 (=predose) after the 0th day and administration in the 14th day, 0.5,1,2,4,6,8,24,32,48,72 and 96 hour are from jugular vein blood sampling (3ml is on EDTA).Behind the blood sample collection, immediately with the blood sample lucifuge.At room temperature, with blood sample centrifugal about 10 minutes, make separating plasma with 1900xg.Isolate blood plasma, be transferred in second pipe, freezing in blood sample collection 2 hours.
Through the LC-MS/MS method of having verified, (E)-4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] the amino]-2-pyrimidine radicals] amino] benzonitrile in the difference analysed for plasma sample.With the API-3000 system (Applied Biosystems) of HPLC-system (Agilent) coupling on carry out LC-MS/MS and analyze.
Use WinNonlin software (WinNonlin Release 4.0.1a Enterprise; Pharsight Corporation, Mountain View, California; U.S.A.), individual PC-time graph is carried out non-compartment model pharmacokinetic analysis.Calculate peak PC (C
Max) and corresponding peak time (T
Max).Use linear rise/logarithm downward modulation trapezoidal rule (linear up/log down trapezoidal rule), calculate area (AUC under PC-time graph
0- t).With AUC
0-96hWith calculate AUC
0-∞, C9
6h/ β and elimination rate constant β are confirmed by the log-linear regression of PC-time data in latter stage.Calculate the mean plasma concentration and average pharmacokinetic parameter of every kind of preparation.
The mean plasma concentration of group I and group II provides in table 3 with basic pharmacokinetic parameter.
Table 3: after per os gives 5mg alkali equivalent/kg group I and organizes the II preparation; Average (± S.D) PC and some basic pharmacokinetic parameters of (E)-4-in male beagle [[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile.
Based on the AUC-value, the fumarate capsule with (E)-the contrast PEG400 solution of 4-[[4-[[4-(2-cyanic acid vinyl)-2,6-3,5-dimethylphenyl] amino]-2-pyrimidine radicals] amino] benzonitrile seems bioequivalence.
Claims (8)
1. be applicable to the solid pharmaceutical composition of oral administration, it comprises pharmaceutically acceptable year
Body and as formula (I-a) chemical compound of the treatment effective dose of active component.
2. the Pharmaceutical composition of claim 1, said compositions also comprises wetting agent.
3. the Pharmaceutical composition of claim 2, wherein said wetting agent is a tween.
4. the Pharmaceutical composition of claim 1, said compositions is a tablet form.
5. the Pharmaceutical composition of claim 4, said compositions is the bag film-coat.
6. the Pharmaceutical composition of claim 4, wherein based on the gross weight meter of label, said tablet 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%.
7. the Pharmaceutical composition of claim 1, it is as medicine.
8. the Pharmaceutical composition of claim 1 is in the purposes of preparation in the medicine, and wherein said medicine is used for treatment or prevention of HIV infects.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MYPI20043578A MY169670A (en) | 2003-09-03 | 2004-09-02 | Combinations of a pyrimidine containing nnrti with rt inhibitors |
| MYPI20043578 | 2004-09-02 | ||
| PCT/EP2004/052028 WO2005021001A1 (en) | 2003-09-03 | 2004-09-03 | Combinations of a pyrimidine containing nnrti with rt inhibitors |
| EPPCT/EP2004/052028 | 2004-09-03 | ||
| EP05101447 | 2005-02-25 | ||
| EP05101447.0 | 2005-02-25 | ||
| PCT/EP2005/054341 WO2006024667A1 (en) | 2004-09-02 | 2005-09-02 | Furamate of 4-( (4-( (4- (2-cyanoethenyl) -2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101068597A CN101068597A (en) | 2007-11-07 |
| CN101068597B true CN101068597B (en) | 2012-04-18 |
Family
ID=38137294
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
| 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
Country Status (6)
| Country | Link |
|---|---|
| CN (2) | CN101068597B (en) |
| AP (1) | AP2296A (en) |
| CR (1) | CR9031A (en) |
| SG (1) | SG155885A1 (en) |
| UA (2) | UA92469C2 (en) |
| ZA (1) | ZA200701826B (en) |
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| 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 |
| 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 |
| RS65159B1 (en) * | 2016-10-24 | 2024-02-29 | Janssen Sciences Ireland Unlimited Co | Dispersible compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003016306A1 (en) * | 2001-08-13 | 2003-02-27 | Janssen Pharmaceutica N.V. | Hiv inhibiting pyrimidines derivatives |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY169670A (en) * | 2003-09-03 | 2019-05-08 | Tibotec Pharm Ltd | Combinations of a pyrimidine containing nnrti with rt inhibitors |
-
2005
- 2005-09-02 CN CN2005800380936A patent/CN101068597B/en active Active
- 2005-09-02 SG SG200905799-3A patent/SG155885A1/en unknown
- 2005-09-02 CN CNA200580038025XA patent/CN101056673A/en active Pending
- 2005-09-02 AP AP2007003934A patent/AP2296A/en active
- 2005-09-02 UA UAA200702178A patent/UA92469C2/en unknown
- 2005-09-02 UA UAA200701971A patent/UA92467C2/en unknown
-
2007
- 2007-03-01 ZA ZA200701826A patent/ZA200701826B/en unknown
- 2007-03-30 CR CR9031A patent/CR9031A/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003016306A1 (en) * | 2001-08-13 | 2003-02-27 | Janssen Pharmaceutica N.V. | Hiv inhibiting pyrimidines derivatives |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| UA92469C2 (en) | 2010-11-10 |
| CR9031A (en) | 2009-01-16 |
| CN101056673A (en) | 2007-10-17 |
| SG155885A1 (en) | 2009-10-29 |
| ZA200701826B (en) | 2008-07-30 |
| AP2296A (en) | 2011-10-31 |
| AP2007003934A0 (en) | 2007-04-30 |
| CN101068597A (en) | 2007-11-07 |
| UA92467C2 (en) | 2010-11-10 |
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