WO2006024667A1 - Furamate de 4- ( (4- ( (4- (2-cyanoethenyl) -2, 6-dimethylphenyl) amino) -2-pyrimidinyl) amino) benzonitrile - Google Patents

Furamate de 4- ( (4- ( (4- (2-cyanoethenyl) -2, 6-dimethylphenyl) amino) -2-pyrimidinyl) amino) benzonitrile Download PDF

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Publication number
WO2006024667A1
WO2006024667A1 PCT/EP2005/054341 EP2005054341W WO2006024667A1 WO 2006024667 A1 WO2006024667 A1 WO 2006024667A1 EP 2005054341 W EP2005054341 W EP 2005054341W WO 2006024667 A1 WO2006024667 A1 WO 2006024667A1
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WO
WIPO (PCT)
Prior art keywords
compound
peg
pharmaceutical composition
formula
amino
Prior art date
Application number
PCT/EP2005/054341
Other languages
English (en)
Inventor
Paul Theodoor Agnes Stevens
Jozef Peeters
Roger Petrus Gerebern Vandecruys
Alfred Elisabeth Stappers
Alex Herman Copmans
Original Assignee
Janssen Pharmaceutica N.V.
Tibotec Pharmaceuticals Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from MYPI20043578A external-priority patent/MY169670A/en
Priority to SI200531539T priority Critical patent/SI1789139T1/sl
Priority to KR1020077006376A priority patent/KR101276571B1/ko
Priority to JP2007528885A priority patent/JP4922937B2/ja
Priority to AU2005279157A priority patent/AU2005279157B2/en
Priority to BRPI0514861-8A priority patent/BRPI0514861A/pt
Priority to EP05779369A priority patent/EP1789139B1/fr
Priority to NZ553322A priority patent/NZ553322A/en
Priority to AP2007003933A priority patent/AP2487A/xx
Priority to CN2005800380936A priority patent/CN101068597B/zh
Application filed by Janssen Pharmaceutica N.V., Tibotec Pharmaceuticals Ltd. filed Critical Janssen Pharmaceutica N.V.
Priority to CA2577273A priority patent/CA2577273C/fr
Priority to DK05779369.7T priority patent/DK1789139T3/da
Priority to US11/574,452 priority patent/US20090215804A1/en
Priority to MX2007002594A priority patent/MX2007002594A/es
Priority to AT05779369T priority patent/ATE550074T1/de
Priority to EA200700534A priority patent/EA011036B1/ru
Priority to ES05779369T priority patent/ES2384715T3/es
Publication of WO2006024667A1 publication Critical patent/WO2006024667A1/fr
Priority to IL181649A priority patent/IL181649A0/en
Priority to NO20071720A priority patent/NO339788B1/no
Priority to HK08101831.3A priority patent/HK1112862A1/xx
Priority to US13/040,465 priority patent/US20110150996A1/en
Priority to HRP20120499TT priority patent/HRP20120499T1/hr
Priority to US15/852,181 priority patent/US20180116964A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to the fumarate salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, pharmaceutical compositions comprising said fumarate salt, to the preparation of the salt and the pharmaceutical compositions.
  • WO 03/16306 discloses HIV replication inhibiting pyrimidine derivatives among which 4- [ [4-[ [4-(2-cyanoethenyl)-2,6-dimethylphenyl] amino] -2-pyrimidinyl]amino] - benzonitrile and the pharmaceutically acceptable salts thereof.
  • WO 04/0162581 disclose processes to prepare 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
  • a good drug candidate should preferably also be stable chemically as well as physically; should have an acceptable toxicity profile; should have an acceptable bioavailability.
  • the bioavailability of the compound influences the dose of the compound required for 30 administration in order to reach a therapeutically effective concentration of the compound in the patient.
  • Compounds having a low bioavailability need to be administered in higher doses compared to compounds having a higher bioavailability.
  • Possible consequences of the need for higher doses may comprise : an increased risk to adverse effects; an increase in the size of the dosage form; an increase in the frequency 35 of administration. These factors may influence adherence to antiretroviral therapy. Therapy adherence is one of the most important factors influencing the effectiveness of HIV treatment. Increase in dosing frequency and increase in pill size may lead to reduced therapy adherence and hence reduced therapy effectiveness.
  • bioavailability of a compound intended to be administered orally is dependent on the compounds solubility in water as well as the compounds permeability (its ability to be absorbed across the intestinal membrane).
  • BCS Biopharmaceutics Classification System
  • Class 2 Low Solubility - High Permeability
  • Class 3 High Solubility - Low Permeability
  • Class 4 Low Solubility - Low Permeability
  • Compounds with a low solubility or a low permeability may suffer from a low bioavailability when administered orally.
  • Free base 4- [ [4- [ [4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino] -2-pyrimidinyl] - amino]benzonitrile can be classified as a BCS class 2 compound and has thus a low solubility in water.
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile does not only exhibit a low solubility in water, but also in an acidic environment. Consequently, when administered orally in a conventional solid dosage form, a low bioavailability may be expected.
  • the prepared salts still belong to BCS class 2. Thus, also for the prepared salts a low bioavailability could be expected.
  • the present salt administered as a solid dosage form has an in vivo bioavailability which is comparable with the bioavailability of the free base administered as an oral PEG 400 solution. Because of the increased bioavailability in vivo, the fumarate salt may be formulated without the need of complex formulation techniques.
  • the fumarate salt of the present invention was also found to be non-hygroscopic and to be chemically and physically stable in different conditions of humidity and temperatures.
  • the present invention relates in particular to a compound of formula (I)
  • iV-oxide forms of the present compound of formula (I) are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called iV-oxide.
  • iV-oxide -A-
  • stereochemically isomeric forms as used hereinbefore defines all the possible stereoisomer ⁇ forms which the compound of formula (I), and the iV-oxides, or quaternary amines may possess. Unless otherwise mentioned or indicated, the chemical designation of the compound denotes the mixture of all possible stereochemically isomeric forms as well as each of the individual isomeric forms of formula (I) and the iV-oxides, solvates or quaternary amines substantially free of the other isomers. Stereochemically isomeric forms of the compound of formula (I) are obviously intended to be embraced within the scope of this invention.
  • the compound of formula (I) may exist in 2 stereochemical configurations at the double bond of the cyanoethenyl chain, i.e. the E (Entadel) configuration (E-isomer) and the Z (Zusammen) configuration (Z isomer).
  • a particular embodiment of the compound of formula (I) is the E-isomer, i.e. a compound of formula (I-a)
  • Another particular embodiment of the compound of formula (I) is the Z- isomer, i.e. a compound of formula (I-b)
  • the pure E-isomer or any isomeric mixture of the E- and the Z- isomers wherein the E-isomer is predominantly present is meant, i.e. an isomeric mixture containing more than 50% or in particular more than 80% of the E-isomer, or even more in particular more than 90% of the E-isomer.
  • the E-isomer substantially free of the Z- isomer refers to E-Z-mixtures with no or almost no Z-isomer, e.g. isomeric mixtures containing as much as 90%, in particular 95% or even 98% or 99% of the E-isomer.
  • the pure Z-isomer or any isomeric mixture of the Z- and the E-isomers wherein the Z-isomer is predominantly present is meant, i.e. an isomeric mixture containing more than 50% or in particular more than 80% of the Z-isomer, or even more in particular more than 90% of the Z-isomer.
  • the Z-isomer substantially free of the E-isomer refers to E-Z-mixtures with no or almost no E-isomer, e.g. isomeric mixtures containing as much as 90%, in particular 95% or even 98% or 99% of the Z-isomer.
  • Polymorphic forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the polymorphic form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next.
  • a pharmaceutical compound is produced for use, it is important to recognize the polymorphic form delivered in each dosage form to assure that the production process use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single polymorphic form or some known combination of polymorphic forms is present.
  • certain polymorphic forms may exhibit enhanced thermodynamic stability and may be more suitable than other polymorpholic forms for inclusion in pharmaceutical formulations.
  • a polymorphic form of a compound of the invention is the same chemical entity, but in a different crystalline arrangement.
  • Solvent addition forms which the salts of the present invention are able to form also fall within the ambit of the present invention. Examples of such forms are e.g. hydrates, alcoholates and the like. Solvates are herein also referred to as pseudopolymorphic forms. Preferred is an anhydric salt.
  • compound of formula (I), (I-a) or (I-b) is meant to also include the iV-oxide forms, the stereochemically isomeric forms and the polymorphic or pseudopolymorphic forms. Of special interest is a stereochemically pure form of a compound of formula (I).
  • a preferred compound of formula (I) is a compound of formula (I-a).
  • the compounds of formula (I), (I-a) or (I-b) can be prepared by reacting the corresponding free base with iumaric acid in the presence of a suitable solvent, such as for example a suitable acid, e.g. acetic acid.
  • a suitable solvent such as for example a suitable acid, e.g. acetic acid.
  • the compounds of formula (I), (I-a) or (I-b) have antiretroviral activity. They are able to inhibit the replication of HIV, in particular HIV-I.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immune Deficiency Syndrome
  • the HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system.
  • an infected patient has an ever decreasing number of T-4 cells, which moreover behave abnormally.
  • the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers.
  • HIV infection Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
  • PDL progressive generalized lymphadenopathy
  • ARC AIDS-related complex
  • the present compounds also show activity against drug and multidrug resistant HIV strains, in particular drug and multidrug resistant HIV-I strains, more in particular the present compounds show activity against HIV strains, especially HIV-I strains, that have acquired resistance to one or more art-known non-nucleoside reverse transcriptase inhibitors.
  • Art-known non-nucleoside reverse transcriptase inhibitors are those non- nucleoside reverse transcriptase inhibitors other than the present compounds and in particular commercial non-nucleoside reverse transcriptase inhibitors.
  • HIV replication inhibiting activity of 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile is described in WO 03/16306, which is incorporated herein by reference.
  • the present compounds are useful in the treatment of individuals infected by HIV and for the prophylaxis of these infections.
  • the compounds of the present invention may be useful in the treatment of warm-blooded mammals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase.
  • Conditions which may be prevented or treated with the compounds of the present invention include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic Central Nervous System diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis Therefore, the compounds of formula (I), (I-a) or (I-b) can be used as a medicine.
  • the compounds of the present invention may therefore be used as medicines against above-mentioned conditions.
  • Said use as a medicine or method of treatment comprises the administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-I.
  • the present compounds may be used in the manufacture of a medicament for the treatment or the prevention of HIV infection, preferably for the treatment of HIV infection.
  • a method of treating mammals, including humans, suffering from or a method of preventing warm ⁇ blooded mammals, including humans, to suffer from viral infections, especially HIV infections comprises the administration, preferably oral administration, of an effective amount of a salt of the present invention to mammals including humans.
  • therapeutic effective plasma levels may be obtained by administering a pharmaceutical composition comprising a lower amount of the salt compared to what would be needed of the corresponding free base. Therefore, the size of the pharmaceutical composition may be reduced or the frequency of dosing may be reduced.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b).
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
  • compositions for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the compound of formula (I), (I-a) or (I-b) as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the salts of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the salts of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
  • the compounds of the present invention may also be topically administered in the form of drops, in particular eye drops.
  • Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
  • WO 2004/069812 which is incorporated herein by reference, describes the ability of pyrimidine derivatives among which 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]- amino]-2-pyrimidinyl]amino]benzonitrile and pharmaceutically acceptable salts thereof, to prevent HIV infection via sexual intercourse or related intimate contact between partners.
  • the present invention also relates to a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b).
  • the present invention also relates to a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
  • a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcripta
  • compositions usually employed for being applied to the vagina, rectum, mouth and skin such as for example gels, jellies, creams, ointments, films, sponges, foams, intravaginal rings, cervical caps, suppositories for rectal or vaginal application, vaginal or rectal or buccal tablets, mouthwashes.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of administration.
  • bioadhesive in particular a bioadhesive polymer.
  • a bioadhesive may be defined as a material that adheres to a live biological surface such as for example a mucus membrane or skin tissue.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) characterized in that the pharmaceutical composition is bioadhesive to the site of application.
  • the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) characterized in that the pharmaceutical composition is bioadhesive to the site of application provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
  • the site of application is the vagina, rectum, mouth or skin, most preferred is the vagina.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the exact dosage and frequency of administration depends on the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • compositions of the present invention can be administered at any time of the day independently of the food taken in by the subject. Preferably, the present compositions are administered to fed subjects.
  • An interesting embodiment of the present invention concerns an oral pharmaceutical composition, i.e. a pharmaceutical composition suitable for oral administration, comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b); in particular a pharmaceutical composition suitable for oral administration, comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
  • the oral pharmaceutical composition is a solid oral pharmaceutical composition, more in particular a tablet or a capsule, even more in particular a tablet.
  • a tablet according to the present invention may be formulated as a once daily tablet.
  • the pharmaceutical compositions of the present invention contain those quantities of a compound of formula (I), (I-a) or (I-b) equivalent to from about 5 to about 500 mg of the corresponding free base 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl] amino] -2-pyrimidinyl]amino]benzonitrile, its E or Z isomer, more preferably from about 10 mg to about 250 mg of the corresponding free base, even more preferably from about 20 mg to about 200 mg of the corresponding free base.
  • the present pharmaceutical compositions contain those quantities of a compound of formula (I), (I-a) or (I-b) equivalent to 25 mg, 50 mg, 75 mg, 100 mg or 150 mg of the corresponding free base (base equivalent).
  • x means, for example, x ⁇ 10 %.
  • the particle size of the compound of formula (I), (I-a) or (I-b) preferably is less than 50 ⁇ m, more preferably less than 25 ⁇ m, even more preferably less than 20 ⁇ m. Further preferred is a particle size of about 15 ⁇ m or less, or about 12 ⁇ m or less, or about 10 ⁇ m or less, or about 5 ⁇ m or less. Most preferably, the particle size ranges between about 0.2 and about 15 ⁇ m or between about 0.2 and about 10 ⁇ m.
  • compositions of the present invention preferably comprise a wetting agent.
  • wetting agent in the compositions of the invention there may be used any of the physiologically tolerable wetting agent suitable for use in a pharmaceutical composition.
  • a wetting agent is an amphiphilic compound; it contains polar, hydrophilic moieties as well as non-polar, hydrophobic moieties.
  • hydrophilic or hydrophobic are relative terms.
  • the relative hydrophilicity or hydrophobicity of a wetting agent may be expressed by its hydrophilic-lipophilic balance value ("HLB value).
  • HLB value hydrophilic-lipophilic balance value
  • Wetting agents with a lower HLB value are catagorized as being "hydrophobic" wetting agents whereas wetting agents with a higher HLB value are catagorized as being “hydrophilic” wetting agents.
  • wetting agents having a HLB value greater than about 10 are generally considered as being hydrophilic wetting agents; wetting agents having a HLB value lower than about 10 are generally considered as being hydrophobic wetting agents.
  • the present compositions preferably comprise a hydrophilic wetting agent.
  • HLB value of a wetting agent is only a rough guide to indicate the hydrophilicity/hydrophobicity of a wetting agent.
  • the HLB value of a particular wetting agent may vary depending upon the method used to determine the HLB value; may vary depending on its commercial source; is subject to batch to batch variability.
  • a person skilled in the art can readily identify hydrophilic wetting agents suitable for use in the pharmaceutical compositions of the present invention.
  • the wetting agent of the present invention can be an anionic, a cationic, a zwitterionic or a non-ionic wetting agent, the latter being preferred.
  • the wetting agent of the present invention can also be a mixture of two or more wetting agents.
  • Suitable wetting agents for use in the compositions of the present invention are listed below. It should be emphasized that said list of wetting agents is only illustrative, representative and not exhaustive. Thus the invention is not limited to the wetting agents listed below. In the present compositions, also mixtures of wetting agents may be used.
  • Suitable wetting agents which may be used in the present invention comprise : a) Polyethylene glycol fatty acid monoesters comprising esters of lauric acid, oleic acid, stearic acid, ricinoic acid and the like with PEG 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600 and the like, for instance 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, PEG- 15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30
  • corn oil olive oil, peanut oil, palm kernel oil, apricot kernel oil, almond oil and the like, such as PEG-20 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides, PEG-23 castor oil , PEG-25 hydrogenated castor oil or trioleate, PEG-35 castor oil, PEG-30 castor oil or hydrogenated castor oil, PEG-38 castor oil, PEG-40 castor oil or hydrogenated castor oil or palm kernel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil or hydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides, PEG- 80 hydrogenated castor oil, PEG-100 castor oil or hydrogenated castor oil, PEG-200 castor oil, PEG- 8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, lauroyl macrogol-32 gly
  • succinylated monoglycerides sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters of mono-and diglycerides, citric acid esters of mono-and diglycerides, glyceryl- lacto esters of fatty acids, lactylic esters of fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ether carboxylates and the like; such as sulfates and sulfonates e.g.
  • alkyl sulfates ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, octyl sulfosuccinate disodium, disodium undecyleneamido-MEA-sulfosuccinate and the like; such as cationic wetting agents e.g.
  • hexadecyl triammonium bromide decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (lauryl betaine), ethoxylated amines (polyoxyethylene-15 coconut amine) and the like.
  • PEG-20 oleyl ether or cetyl ether or stearyl ether this means that PEG- 20 oleyl ether and PEG-20 cetyl ether and PEG-20 stearyl ether are intended.
  • PEG-20 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides has to be read as PEG-20 castor oil and PEG-20 hydrogenated castor oil and PEG-20 corn glycerides and PEG-20 almond glycerides.
  • Preferred wetting agents in the present compositions are sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or those wetting agents belonging to the group of the polyethylene glycol sorbitan fatty acid esters, such as wetting agents known as Tween, e.g. Tween 20, 60, 80. Most preferred, the wetting agent is Tween 20.
  • the wetting agent is preferably present at a concentration from about 0.01 to about 5% by weight relative to the total weight of the composition, preferably from about 0.1 to about 3 % by weight, more preferably from about 0.1 to about 1 % by weight.
  • the quantity of wetting agent used in the present compositions may depend on the amount of the compound of formula (I), (I-a) or (I-b) present in the composition or on the particle size of the compound of formula (I), (I-a) or (I-b). A higher amount or a smaller particle size may require more wetting agent.
  • composition may also further contain an organic polymer.
  • the organic polymer may be used as a binder during the manufacture of the composition.
  • the organic polymer used in the compositions of the invention may be any of the physiologically tolerable water soluble synthetic, semi-synthetic or non-synthetic organic polymers.
  • the polymer may be a natural polymer such as a polysaccharide or polypeptide or a derivative thereof, or a synthetic polymer such as a polyalkylene oxide (e.g. PEG), polyacrylate, polyvinylpyrrolidone, etc.
  • a polyalkylene oxide e.g. PEG
  • polyacrylate e.g. polyacrylate
  • polyvinylpyrrolidone e.g. polyvinylpyrrolidone
  • Mixed polymers e.g. block copolymers and glycopeptides may of course also be used.
  • the polymer conveniently has a molecular weight in the range 500D to 2 MD, and conveniently has an apparent viscosity of 1 to 15,000 mPa.s when in a 2% aqueous solution at 20°C.
  • the water-soluble polymer can be selected from the group comprising
  • - alkylcelluloses such as methylcellulose, - hydroxyakylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,
  • hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose
  • carboxyalkylcelluloses such as carboxymethylcellulose
  • - alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose
  • carboxyalkylalkylcelluloses such as carboxymethylethylcellulose
  • heparin and heparinoids - polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guargum and xanthan gum,
  • polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g. poloxamers and poloxamines.
  • Non-enumerated polymers which are pharmaceutically acceptable and have appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing compositions according to the present invention.
  • the organic polymer is starch, polyvinylpyrrolidone or a cellulose ether, e.g. PVP K29-32, PVP K90, methyl cellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose, or hydroxypropyl methylcellulose (HPMC).
  • PVP K29-32 polyvinylpyrrolidone
  • PVP K90 methyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • HPMC contains sufficient hydroxypropyl and methoxy groups to render it water- soluble.
  • HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble.
  • Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule.
  • Hydroxy ⁇ propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
  • a preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5mPa.s, especially hypromellose 2910 15 mPa.s.
  • Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435).
  • the first two digits represent the approximate percentage of methoxy 1 groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups ; 15 mPa.s or 5 mPa.s is a value indicative of the apparent viscosity of a 2 % aqueous solution at 20°C.
  • the organic polymer may conveniently be present up to about 10% by weight, preferably from about 0.1 to about 5%, more preferably from about 0.5 to about 3% by weight (relative to the total weight of the composition).
  • composition may also further contain a diluent and/or a glidant.
  • Pharmaceutical acceptable diluents comprise calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray- dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac ® , a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), commercially available as Prosolv ® .
  • Preferred is lactose monohydrate, microcrystalline cellulose or silicified microcrystalline cellulose.
  • glidants comprise talc, colloidal silicon dioxide, starch. magnesium stearate. Preferred is colloidal silicon dioxide.
  • the composition may also further comprise a disintegrant and a lubricant.
  • Pharmaceutically acceptable disintegrants comprise starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g. croscarmellose sodium (e.g. Ac-di-Sol ® ), sodium starch glycollate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate, powdered cellulose.
  • Pharmaceutically acceptable lubricants comprise magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulphate.
  • Tablets of the present invention may in addition include other optional excipients such as, for example, flavors, sweeteners and colors.
  • Solid pharmaceutical compositions according to the present invention may comprise by weight based on the total weight of the composition : (a) from 5 to 50% of a compound of formula (I), (I-a) or (I-b);
  • Tablets according to the present invention may comprise by weight based on the total weight of the tablet core :
  • Tablets of the present invention may optionally be film-coated following art-known coating procedures. Film-coated tablets are easier to swallow than uncoated tablet cores, are usually easier to distinguish from other tablets - in particular when the film- coat contains a dye or a pigment -, may have reduced tackiness, and may furthermore have an improved stability (increased shelf-life), e.g. because the coating may protect the active ingredient from the influence of light.
  • the film coat is an immediate release coat.
  • Film coatings may comprise a film- forming polymer and optionally a plasticizer or a pigment.
  • An example of a suitable film- forming polymer is hydroxypropyl methylcellulose, and an example of a suitable plasticizer is polyethyleneglycol, e.g.
  • the film coating is a non-transparant film coating.
  • An example of a suitable coating is Opadry ® , in particular coating powder Opadry ® II White. Tablets of the present invention can be prepared by direct compression or wet granulation.
  • the present invention is also concerned with a process of preparing a tablet comprising a compound of formula (I), (I-a) or (I-b) comprising the steps of : (i) dry blending the active ingredient, the disintegrant and the optional glidant with the diluent;
  • step (ii) optionally mixing the lubricant with the mixture obtained in step (i); (iii) compressing the mixture obtained in step (i) or in step (ii) in the dry state into a tablet; and (iv) optionally film-coating the tablet obtained in step (iii).
  • the present invention is also concerned with a process of preparing a tablet comprising a compound of formula (I), (I-a) or (I-b) comprising the steps of :
  • step (iii) spraying the binder solution obtained in step (ii) on the mixture obtained in step (i); (iv) drying the wet powder obtained in step (iii) followed by sieving and optionally mixing;
  • step (v) mixing the remaining part of the diluent, the disintegrant and the optional glidant in the mixture obtained in step (iv);
  • step (vi) optionally adding the lubricant to the mixture obtained in step (v); (vii) compressing the mixture obtained in step (vi) into a tablet;
  • step (viii) optionally film-coating the tablet obtained in step (vii).
  • the present compound of formula (I), (I-a) or (I-b) can be used alone or in combination with other therapeutic agents, such as anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They may also be used alone or in combination with other prophylactic agents for the prevention of viral infections.
  • the present compounds may be used in vaccines and methods for protecting individuals against viral infections over an extended period of time.
  • the compounds may be employed in such vaccines either alone or together with other anti- viral agents in a manner consistent with the conventional utilization of reverse transcriptase inhibitors in vaccines.
  • the present compounds may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against HIV infection.
  • the combination of an antiretro viral compound and a compound of formula (I), (I-a) or (I-b) can be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of formula (I), (I-a) or (I-b), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.
  • the invention also relates to a product containing (a) a compound of formula (I), (I-a) or (I-b), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment provided that the one or more other antiretroviral compounds are other than nucleoside reverse transcriptase inhibitors and/or nucleotide reverse transcriptase inhibitors.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) and (b) one or more other antiretroviral agents.
  • Said other antiretroviral compounds may be known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors, e.g.
  • zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (2',3'-dideoxyinosine; ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (2'-3'-dideoxy-3'-thiacytidine, 3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir, abacavir sulfate, emtricitabine ((-) FTC), racemic FTC and the like; non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl- 5,l l-dihydro-4-methyl-6H-dipyrido-[3,2-b : 2',3'-e][l,4]diazepin-6-one), efavirenz, delavirdine, T
  • CCR5 antagonists e.g. ancriviroc, aplaviroc hydrochloride,
  • Combination therapies as described above exert a synergistic effect in inhibiting HIV replication because each component of the combination acts on a different site of HIV replication.
  • the use of such combinations may reduce the dosage of a given conventional anti-retro viral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
  • These combinations may reduce or eliminate the side effects of conventional single anti-retro viral therapy while not interfering with the anti- viral activity of the agents.
  • These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
  • These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
  • the compounds of the present invention may also be administered in combination with immunomodulating agents, e.g. levamisole, bropirimine, anti-human alpha interferon antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, e.g. pentamidine isethiorate and the like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil, galantamine and the like; NMDA channel blockers, e.g. memantine to prevent or combat infection and diseases or symptoms of diseases associated with HIV infections, such as AIDS and ARC, e.g. dementia.
  • immunomodulating agents e.g. levamisole, bropirimine, anti-human alpha interferon antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithiocarba
  • the present invention focuses on the use of the present compounds for preventing or treating HIV infections, the present compounds may also be used as inhibitory agents for other viruses which depend on similar reverse transcriptases for obligatory events in their life cycle.
  • Table 1 lists solubility data of free base (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl- phenyl]amino]-2-pyrimidinyl]amino]benzonitrile and of the compound of formula (I-a).
  • the free base as well as the fumarate salt have a poor solubility in water as well as in 0.01 N HCl.
  • Free base and fumarate salt may be classified as BCS class 2 compounds.
  • the solubility of the free base is significantly increased in PEG 400.
  • the compound of formula (I-a) was also found to be not hygroscopic.
  • compositions illustrating the present invention are :
  • Composition Ia Tablet core Composition Ia Tablet core :
  • Composition Id Tablet core :
  • Composition 2a Tablet core
  • Composition 2b Tablet core
  • Composition 2c Tablet core
  • Tablet core Compound of formula (I-a) 65.8 mg (i.e. 50 mg base equivalent)
  • the above tablets are prepared by dissolving hypromellose or polyvinylpyrrolidone and polysorbate 20 in purified water (q.s.) followed by spraying said solution on fluidized powder consisting of a mixture of Form A and lactose monohydrate.
  • the obtained granulate is dried, sieved and mixed with microcrystalline cellulose or silicified microcrystalline cellulose, croscarmellose sodium and optionally colloidal silicon dioxide.
  • Magnesium stearate the powder mixture is compressed into tablets followed by film coating the tablets with a suspension of Coating powder Opadry ® II White in purified water.
  • microcrystalline cellulose is preferably Avicel ® PHlOl, croscarmellose sodium is preferably Ac-Di-Sol ® ; silicified microcrystalline cellulose is preferably Prosolv ® HD90; polyvinylpyrrolidone is preferably PVP K29-32.
  • the formulations used for oral administration were :
  • the formulations of group II were orally administered at a dose level of 5 mg base equivalent/kg.
  • the formulations were prepared based on previously determined body weights of the animals. The exact administered dose was calculated using the body weights just before dosing and amounted on average to 5 mg base equivalent/kg.
  • the reference PEG400 formulation (group I) was administered orally via gavage by use of a stomach tube at a daily volume of 0.2 ml/kg body weight.
  • the stomach tube was flushed with 2 ml of PEG400 per dog, followed by the placement of a syringe of 10 ml filled with air on the stomach tube.
  • the tube was removed after a pause of 10 to 15 seconds.
  • the reference PEG400 solution (group I) and the compound of formula (I-a) (group II) were dosed according to a cross-over design.
  • the first group of 2 dogs was dosed with the reference formulation of group I at 5 mg eq./kg (0.2 ml/kg) and the second group of 2 dogs was dosed with the iumarate salt formulation of group II at 5 mg basd eq./kg (2 capsules/dog).
  • the first group of dogs was dosed with the fumarate salt (group II) and the second group with the reference formulation (group I).
  • Plasma samples were analysed individually for (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile by means of a validated LC-MS/MS method.
  • Peak plasma concentrations (C max ) and corresponding peak times (T max ) were calculated.
  • the area under the plasma concentration-time curve (AUC 0-t ) was calculated using the linear up/log down trapezoidal rule.
  • the AUCo- ⁇ was calculated as the sum of AUC 0- %h and C%h/ ⁇ , with ⁇ , the elimination rate constant, determined by log- linear regression of the terminal plasma concentration-time data.
  • Mean plasma concentrations and mean pharmacokinetic parameters were calculated per formulation.
  • Table 3 Mean ( ⁇ S.D) plasma concentrations together with some basic pharmacokinetic parameters of (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in male beagle dogs after oral administration of formulation of group I and II dosed at 5 mg base eq./kg.
  • the fumarate salt capsule formulation seems bioequivalent to the reference PEG400 solution of (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.

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Abstract

Sel de fumarate de 4-[[4-[[4-(2-cyanoéthényl)-2,6-diméthylphényl]amino]-2-pyrimidinyl]amino]benzonitrile, compositions pharmaceutiques comprenant le sel précité servant de principe actif et ses procédés de préparation.
PCT/EP2005/054341 2004-09-02 2005-09-02 Furamate de 4- ( (4- ( (4- (2-cyanoethenyl) -2, 6-dimethylphenyl) amino) -2-pyrimidinyl) amino) benzonitrile WO2006024667A1 (fr)

Priority Applications (22)

Application Number Priority Date Filing Date Title
CA2577273A CA2577273C (fr) 2004-09-02 2005-09-02 Fumarate de 4- ( (4- ( (4- (2-cyanoethenyl) -2, 6-dimethylphenyl) amino) -2-pyrimidinyl) amino) benzonitrile
ES05779369T ES2384715T3 (es) 2004-09-02 2005-09-02 Fumarato de 4-[[4-[[4-(2-cianoetenil)-2,6-dimetilfenil]amino]-2-pirimidinil]amino]benzonitrilo
JP2007528885A JP4922937B2 (ja) 2004-09-02 2005-09-02 ４−（（４−（（４−（２−シアノエテニル）−２，６−ジメチルフェニル）アミノ）−２−ピリミジニル）アミノ）ベンゾニトリルのフマル酸塩
AU2005279157A AU2005279157B2 (en) 2004-09-02 2005-09-02 Fumarate of 4-[[4-[[4- (2-cyanoethenyl) -2,6-dimethylphenyl]amino)-2-pyrimidinyl)amino]benzonitrile
BRPI0514861-8A BRPI0514861A (pt) 2004-09-02 2005-09-02 furamato de 4-((4-((4-(2-cianoetenil)-2,6-dimetilfenil)amino)-2-pirimidi nil)amino)benzonitrila
EP05779369A EP1789139B1 (fr) 2004-09-02 2005-09-02 Hydrochloride de 4-((4-((4-(2-cyanoéthényl)-2,6-diméthylphényl amino -2-pyrimidinyl amino benzonitrile
NZ553322A NZ553322A (en) 2004-09-02 2005-09-02 Furamate of 4-( (4-( (4- (2-cyanoethenyl) -2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile, also named TMC278
AP2007003933A AP2487A (en) 2004-09-02 2005-09-02 Fumarate of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]amino]benzonitrile
CN2005800380936A CN101068597B (zh) 2004-09-02 2005-09-02 4-((4-((4-(2-氰基乙烯基)-2,6-二甲基苯基)氨基)-2-嘧啶基)氨基)苄腈的富马酸盐
KR1020077006376A KR101276571B1 (ko) 2004-09-02 2005-09-02 4-((4-((4-(2-시아노에텐일)-2,6-디메틸페닐)아미노-2-피리미딘일)아미노)벤조니트릴의 푸마레이트
DK05779369.7T DK1789139T3 (da) 2004-09-02 2005-09-02 Fumarat af 4-((4-((4-(2-cyanethenyl)-2,6-dimethylphenylamino-2-pyrimidinylaminobenzonitril
SI200531539T SI1789139T1 (sl) 2004-09-02 2005-09-02 Fumarat 4-((4-((4-(2-cianoetenil)-2,6-dimetifenil amino-2-pirimidinil amino benzonitrila
AT05779369T ATE550074T1 (de) 2004-09-02 2005-09-02 Fumarat aus 4-((4-((4-(2-cyanoethenyl)-2,6- dimethylphenyl amino -2-pyrimidinyl amino benzonitril
MX2007002594A MX2007002594A (es) 2004-09-02 2005-09-02 Fumarato de 4-((4-((4- (2-cianoetenil)-2, 6-dimetilfenil) amino)-2-pirimidinil) amino) benzonitrilo.
US11/574,452 US20090215804A1 (en) 2004-09-02 2005-09-02 Fumarate of 4- [[4- [[4- (2-cyanoethenyl) -2,6-dimethylphenyl)amino] -2-pyrimidinyl]amino]benzonitrile
EA200700534A EA011036B1 (ru) 2004-09-02 2005-09-02 Фумарат 4-[[4-[[4-(2-цианоэтенил)-2,6-диметилфенил]амино]-2-пиримидинил]амино]бензонитрила
IL181649A IL181649A0 (en) 2004-09-02 2007-03-01 Furamate of 4-((4-((4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino) benzonitrile
NO20071720A NO339788B1 (no) 2004-09-02 2007-04-02 Fumarat av 4-[[4-[[4-(2-cyanoetenyl)-2,6-dimetylfenyl]amino]-2-pyrimidinyl]amino]benzonitril
HK08101831.3A HK1112862A1 (fr) 2004-09-02 2008-02-20
US13/040,465 US20110150996A1 (en) 2004-09-02 2011-03-04 Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino] -2-pyrimidinyl]amino]benzonitrile
HRP20120499TT HRP20120499T1 (hr) 2004-09-02 2012-06-14 Fumarat cijanoetenil dimetilfenil amino pirimidinil amino benzonitrila
US15/852,181 US20180116964A1 (en) 2004-09-02 2017-12-22 Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile

Applications Claiming Priority (6)

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
EPPCT/EP2004/052028 2004-09-03
PCT/EP2004/052028 WO2005021001A1 (fr) 2003-09-03 2004-09-03 Combinaisons d'une pyrimidine renfermant nnrti avec des inhibiteurs de rt
EP05101447 2005-02-25
EP05101447.0 2005-02-25

Related Child Applications (2)

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US11/574,452 A-371-Of-International US20090215804A1 (en) 2004-09-02 2005-09-02 Fumarate of 4- [[4- [[4- (2-cyanoethenyl) -2,6-dimethylphenyl)amino] -2-pyrimidinyl]amino]benzonitrile
US13/040,465 Division US20110150996A1 (en) 2004-09-02 2011-03-04 Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino] -2-pyrimidinyl]amino]benzonitrile

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EP (1) EP1789139B1 (fr)
KR (1) KR101276571B1 (fr)
AP (1) AP2487A (fr)
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JP2010511663A (ja) * 2006-12-05 2010-04-15 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ （アルファｓ，ベータｒ）−６−ブロモ−アルファ−［２−（ジメチルアミノ）エチル］−２−メトキシ−アルファ−１−ナフタレニル−ベータ−フェニル−３−キノリンエタノールのフマル酸塩
WO2012125993A1 (fr) 2011-03-17 2012-09-20 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de base rilpivirine et sels de rilpivirine

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JP2008127430A (ja) * 2006-11-17 2008-06-05 Nippon Shokubai Co Ltd ポリカルボン酸系コンクリート混和剤の製造方法
JP2010511663A (ja) * 2006-12-05 2010-04-15 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ （アルファｓ，ベータｒ）−６−ブロモ−アルファ−［２−（ジメチルアミノ）エチル］−２−メトキシ−アルファ−１−ナフタレニル−ベータ−フェニル−３−キノリンエタノールのフマル酸塩
JP2015028049A (ja) * 2006-12-05 2015-02-12 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプＪａｎｓｓｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａ Ｎａａｍｌｏｚｅ Ｖｅｎｎｏｏｔｓｃｈａｐ （アルファｓ，ベータｒ）−６−ブロモ−アルファ−［２−（ジメチルアミノ）エチル］−２−メトキシ−アルファ−１−ナフタレニル−ベータ−フェニル−３−キノリンエタノールのフマル酸塩
KR101514700B1 (ko) * 2006-12-05 2015-04-24 얀센 파마슈티카 엔.브이. （알파 ｓ, 베타 ｒ）―６―브로모―알파―［２―（디메틸아미노）에틸］―２―메톡시―알파―１―나프탈레닐―베타―페닐―３―퀴놀린에탄올의 푸마레이트 염
WO2012125993A1 (fr) 2011-03-17 2012-09-20 Teva Pharmaceutical Industries Ltd. Formes à l'état solide de base rilpivirine et sels de rilpivirine

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AU2005279157B2 (en) 2011-07-14
AU2005279157A1 (en) 2006-03-09
KR20070053284A (ko) 2007-05-23
AP2487A (en) 2012-10-03
AP2007003933A0 (en) 2007-04-30
KR101276571B1 (ko) 2013-06-18
CA2577273C (fr) 2013-11-19
CA2577273A1 (fr) 2006-03-09
EP1789139B1 (fr) 2012-03-21

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