Title of Invention

"A PROCESS FOR THE PREPARATION OF 4-[[4-[[4-(2-CYANOETHENYL)-2, 6-DIMETHYLPHENYL]- AMINO]-2- PYRIMIDINYL]AMINO] BENZONITRILE"

Abstract A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2, 6-dimethylphenyl]-amino]-2-pyrimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof, (I) which comprises reacting an intermediate of formula (II), an appropriate acid addition salt or a stereochemically isomeric form thereof with an intermediate of formula (III), an appropriate acid addition salt or a N-oxide thereof wherein Wi represents a suitable leaving group] in the presence of a suitable solvent, optionally followed, if desired, by converting the, free base into an acid addition salt by treatment with an acid, or conversely, by converting the acid addition salt form into the free base by treatment with alkali; and optionally followed, if desired, by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.
Full Text The present invention relates to 4-JI4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-
atiuno]-2-pyrimidinyl]amino]ben2wnitrile, a Akftdde, a phannaceutically acceptable
addition salt, a quaternary amine or a stereochemicalry isomeric form thereof and to the
preparation tiiereof as well as to me preparation of a key intermediate in said
preparation.
WO 99/50250Tiiscloses substituted diammopyrimidine compounds having HIV
(Human Immunodeficienpy Virus) inhibiting properties and the preparation thereof.
WO 03/16306 discloses the preparation of 4-[[4-|I4-(2-(cyanoeftenyl)-2,6-dimethyl phenyl]ammo]-2-pyriniidmyl]amino]ben!xmftrile from a melt of [4-[(4-chloro-2-pyrmiidmyl)ammo]benzonitrile and 3-(4-aminO'3,5-dimylphenyl)-2-prorienenitrile.
4-[[4-[[4-(2-cyanoethenyl)-2,6-dmiethyl^
benzonitrile, N-oxides, phannaceutically acceptable addition salts, quaternary amines and stereochemicalry isomeric forms thereof are novel, very potent HIV, especially HTV-1, replication inhibiting compounds. They have a high ability to inhibit the replication of the wild type Human Immunodeficiency Virus as well as resistant mutant strains thereof.
Therefore, 4-[[4-[{4-(2-eyaaeetheayl)-2,6Hlu
amino]benzonitrile, iV-oxides, phannaceutically acceptable addition salts, quaternary amines and stereochemicalry isomeric forms thereof can be used as a medicine. They may be useful in the prevention or treatment of HIV infection, including the prevention or the treatment of HIV infection of mutant strains, i.e. strains which have become resistant to art-known drug(s) (drug or multidrug resistant HIV strains); they may be useful in the treatment of warm-blooded' animals including humans infected with HTV or infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase, or for the prophylaxis of those infections in these warm-blooded -animals. Thus, the present invention also relates to the use of 4-[[4-[[4-(2-cyano-
emenyI)-2,6-dimethyIphemylJammoJ-2-p^pharmaceuticalry acceptable addition salt, a quaternary amine or a stereochemically isomeric form tiiereof for the manufacture of a medicament for the prevention or the treatment of HTV infection. The invention also relates to a method of treating warm-
blooded animals, including humans, suffering from or a method of preventing -warmblooded animals, including humans, to suffer from viral infections, especially HTV infections. Said method comprises the administration, preferably oral admimstration^ of an effective amount of a compound of formula (I), a JV-oxide form, a phannaceutically acceptable addition salt,« quaternary amine or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for treating viral infections
comprising a therapeutically effective amount of 4-[[4-[[4-(2-cyanoethenyl)-2,6-
dimethylphenyl]ammo]-2-pyri^ a JV-oxide, a
phannaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof and a pharmaceuticaUy acceptable carrier or diluent
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemicaUy administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceuticaUy 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, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, 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 dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, 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 wluchthexarrier comririses-saline solution, glucose solutions 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. Also included, are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In me compositions suitable for percutaneous
administration, 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 me skin. Said addmro may facilitate the admin^ helpful for preparing me desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment The compounds 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. Thus, in general the compounds 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 HIV replication inhibiting activity of 4-jJ4-[[4-(2-cyanoethenyr)-2,6-dimethyl-
phenyl]ammo]-2-pyrimidinyl]ammo]benzo«utrile, a JV-oxide, a pharmaceutical^
acceptable addition salt, a quaternary amine or a stereochemically isomeric form
thereof, can be tested using the following test
Determination of anti-HTV activity
A rapid, sensitive and automated assay procedure was used for the in vitro evaluation of
anti-HTV agents. An HTV-1 transformed T4-cell line, MT-4, which was previously
shown (Koyanagi et al., Int. J. Cancer, M* 445-451,1985) to be highly susceptible to
and permissive for HFV infection, served as the target cell line. Inhibition of the HTV-
induced cytopamic effect was used as the end point The viability of both HTV- and
mock-infected cells was assessed spectrophotometrically via the in situ reduction of
3-(4,5-dmiemylthiazol-2-yQ-2,5-dn)henyltetraa)lium bromide (MTT). The 50% cytotoxic concentration (CC50 in M) was defined as the concentration of compound
that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:
(ODT)fflV-(OPc)H[V (ODcJMoc^CODdHlv «**«»«! m 0/0,
whereby (OD-jOmy is the optical density measured with a given concentration of the test compound in HIV-infected cells; (ODr^grv ^ me optical density measured for the control untreated HIV-infected cells; (ODQ^OCK *S ^e optical density measured for the control untreated mock-infected cells; aO optical density values were determined at
540 nm. The dose acMeving 50% protects accord^g to 1iie above formukw^ defined as the 50% inhibitory concentratioa (IC50 in M). The ratio of CC50 to IC50
(Formula Removed)
was defined as the selectivity-index (SI). The results obtained for Compound X, i.e
(E-isomer), are the following:
ICso^lO'^M;CCso-lO^M;
SI of 10^ M/IO"*^ - 25,119.
1
Compound X was also tested for its replication inhibiting activity towards resistant mutants of HTV-1 (single and double mutants)., The obtained results revealed a high activity of Compound X against resistant strains.
In order to ensure an economical supply of the compounds of the invention for development purposes and marketing, an efficient synthetic process which can be carried out on a large, commercial scale is required for the production of the compounds.
It is an object of the present invention to provide processes for the preparation of 4-[[4-
[[4^2-cyanoemenyl)-2,6-dimemyIph^
iV-oxide, a pharmaceutical!;/ acceptable addition salt, a quaternary amine or a "
stereochemically isomeric form thereof, with a high yield and under conditions which
provide economic advantages for operation on a large, commercial scale.
The present invention therefore provides a process for the preparation of 4-[[4-[[4-(2-
cyanoethenyl)-2,6^dimefhylphenyl]amni0> of
formula (T), a iV-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof
(Formula Removed)
which connprises reacting an mtenhediate of formula (II), an appropriate acid addition salt or a stereochemically isomeric form {hereof
(FORMULA REMOVED)

(II) with an intermediate of fbrmula (HI), an appropriate acid addition salt or a JV-oxide thereof
(Formula Removed)
(III) wherein W1 represents a suitable leaving group, in the presence of a suitable solvent
Suitable leaving groups represented by W1 are for example halo, triflate, tosylate, methylsulfonyl and the like. Preferably, W1 represents halo, more particularly chloro.
i
Suitable solvents in the above reaction are for example acetonitiile; an alcohol, such as
for example ethanol, 2-propanol, 2-propanol-HCl; N,N-dimemylforrnamide;
JV^-dimethylacetarmdesl-m 1,4-dioxane; propyleneglycol
monomethylether. Preferably the solvent is acetonitiile; an alcohol, such as for example ethanol, 2-propanol, 2-propanotHCI; N,N-dimerayifbrmamide; iV^-dimethylacetamide; propyleneglycol monomethylether. More preferably, the solvent is 2-propanol, 6 N HC1 in 2-propanol or acetonitrile, especially acetonitrile.
Preferably, the intermediate of formula (IX) is used as an acid addition salt, especially
the hydrochloric acid addition salt, and the intermediate of formula (ED) is preferably
useffasTreelJase:
The product resulting from the above described reaction can convenienuy be isolated as a base or as an acid addition salt, and it can farmer be converted into an acid addition
salt by treatment with" an acid, or conversely, five acid addition salt form can be converted into the free base by treatment wife alkali and, if desired, stereochemically isomeric forms, JV-oxide forms or quaternary ainmes of me product can be formed. The isolation of the reaction product from the reaction medium and, if necessary the further purification, can be performed according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
According to another aspect of the present invention, there is provided a process for the preparation of 4-[[4-[[4-(2-cyancoethenyl)-2,6- CO which comprises reacting an intermediate of formula (TV), apt appropriate acid addition
salt or a tf-oxide thereof
(Formula Removed)
(IV) wherein W2 represents a suitable leaving group, with acrylonitrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent
Suitable leaving groups represented by Wa are for example halo, triflate, tosylate, mesylate and the like. Preferably, W2 is halo, more particularly iodo or bromo.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as for example PdflOAck, PdCk?^W^f^W^hPk, Pa)3 (^(*T>en2yMene^cetone) _ dipalladium), palladium tMomemylpheny^giutaxarnide metallacycle and the like, or a heterogeneous Pd catalyst, such as for example palladium on charcoal, palladium on metal oxides, palladium on zeolites.
Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, is stable and relatively inexpensive. It can be easily separated (filtration) from the reaction mixture thereby reducing the risk of Pd traces in the final product ■ The use of Pd/C also avoids the need for ligands, such as for example phosphine Iigands, which are expensive, toxic and contaminants of the synthesized products.
Suitable bases are for example sodium acetate, potassium acetate, JV^T-diethyl-ethanamine, sodium hydrogencarbonate, sodium hydroxide and the like.
Suitable solvents are for example acetonitrfle, iV^-dimethylacetamide, an ionic liquid e.g. [bmimJPFfc tf^klimethylfonnamide, water, tetrahydrofuran, dimemylsulphoxide, l-metihyl-2-pyrrolidinone and the like.
The product resulting from the above described reaction can, if desired, be converted into an acid addition salt by treatment with an acid and, if desired, stereochemically isomeric forms, iV-oxide forms or quaternary amines of the product can be formed. The isolation of the reaction product from the reaction medium and, if necessary the further purification, can be performed accordingto methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Alternatively, the compound of formula (F) can also be prepared by dehydrating the OTffwp^aingamide derivative.
Therefore, the present invention also provides a process for the preparation of 4-[[4-Q4-
(2^anoethenyl)-2,6-dimemylphenyI]amIno]-2-pyrimidmyl]ammo]b^
formula (I), a JV-oxide, a pharmaceutical^ acceptable acid addition salt, a quaternary
(Formula Removed)
amine or a stereochemically isomeric form thereof,
which comprises reacting an intermediate of formula (VT), an appropriate acid addition salt or a stereochemically isomeric form thereof

(Formula Removed)
with an intermediate of formula (ED), an appropriate acid addition salt or a TV-oxide thereof
(Formula Removed)


wherein Wi represents a suitable leaving groups in the presence of a suitable solvent,
followed by dehydration of the thus obtained intermediate of formula (VII), a
(Formula Removed)
phaimaceutically acceptable acid addition salt* a stereochemically isomeric form or a
Suitable leaving groups represented by Wt are for example halo, Inflate, tosylate, methylsulfonyl and me like. Preferably, W( represents halo, more particularly chloro.
Suitable solvents in the above reaction are for example acetonitrile; an alcohol, such as for example ethanol, 2-propanol, 2-propanotECl; i^-dimemylformamide; 7V^-dime1hylacetemide;l-memyl-2-pynx>BdirKjne; 1,4-dioxane; propylenegrycol monomethylether. Preferably the solvent ia acetonitrile; an alcohol, such as for
exampleeman6C2^p^^
7V,7V-dimemylacetarnide; propyleneglycoLnionomethylether. More preferably, the solvent is 2-propanol, 6 N HC1 in 2-propanol 0? acetonitrile.'
The conversion of the intermediate of formula (VH) into the compound of formula (T), i.e. the dehydration step, can be performed according to methodologies well-known to the person skilled in the art, such as the ones disclosed in "Comprehensive Organic Transformations. A guide to functional group preparations' by Richard C. Larock, John Wiley & Sons, Inc, 1999, p 1983-1985, which is incorporated herein as reference. Different suitable reagents are enumerated tot sdd reference, such as for example SOCk, HOSO2NH2, CISOjNCO, MeCfeCNSQj NEt* PhS02CI, TsCl, P2Os, (Ph3P03SCF3)03SCF3, polyphosphate ester, (EtO)2POP(OEt)2, (BtOftPh, 2-chloro-1,3,2-dioxaphospholane, 2,2i2-tricUoro-2^-dihydro-l,3^-dioxaphospholane, POCfe, PPh3, P(NC12)3, P(NEt^3,C(X;i2, NaClAlClj, ClCOCOCl, ClCQaJMe, CI3CCOCI, (CF3CO)20, CfeCN^CCla, 2,4,6-trichloro-l,3>triazine, NaClAlCls, HN(SiMe2)3, N(SiMe2)4, methane sulfbnyl chloride and me like. All the reagents listed in said publication are incorporated herein by reference.
The product resulting from the above described reaction can conveniently be isolated as a base or as an acid addition salt, and it can further be converted into an acid addition salt by treatment with an acid, or conversely, the acid addition salt form can be converted into the free base by treatment with alkali and, if desired, stereochemically. isomeric forms, tf-oxide forms or quaternary amines of the product can be fonned. The isolation of the reaction product from the reaction medium and, if necessary the further purification, can be performed according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Further, the present invention also concerns a process for the preparation of 4-[[4-[[4-
(2-cyanoethenyl)-2,6Klimetiiylphenyl]a
formula (I), a JV-oxide, a pharmaceuticalry acceptable acid addition salt, a quaternary
amine or a stereochemically isomeric form thereof
(Formula Removed)
which comprisesTeactinganiiiten addition,
salt or JV-oxide thereof
(IV) wherein Wjj represents a suitable leaving group, with acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent; followed by dehydration of the thus obtained intermediate of formula (VII), a pharmaceutically acceptable acid addition oak, a stereochenricatty isomeric form or jY-oxide thereof.
(Formula Removed)
Suitable leaving groups represented by W; are for example halo, triflate, tosylate, mesylate and the like. Preferably, W2 is halo, more particularly iodo or bromo.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as for example Pd(OAc)2, PdCfc, Pd(PPh3)4, PdOPPhafcCfe. Pda(dba)3 (tris(dibenzyUdene acetone) dipalladium), palladium tMomemylphenyU^utaxarnide metaUacycle and the like, or a heterogeneous Pd catalyst, such as for example palladium on charcoal, palladium on metal oxides, palladium on zeolites.
Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, is stable and relatively inexpensive. It can be easily separated (nitration) from the reaction mixture thereby reducing the risk of Pd traces in like find product The use of Pd/C also avoids the need for Uganda, such as for example phosphine tigands, which are expensive, toxic and contaminants of the synthesized products.
Suitable bases are for example sodium acetate, potassium acetate, i\^V-diemyl-
ethanamine. s^miiy^XQgpDcaAaDatet sodiumhydroxide and the like.
Suitable solvents are for example acetanttriJe, jV^-dmethylacetamide, an ionic liquid e.g. [bmim]PF6, iV^-Klimethylfoimamide, water, tetrahydroturan, dimethylsulphoxide, l-methyl-2-pyrrolidinone and me like.
The conversion of me intermediate of formula (VII) into me compound of formula (I), Le. me dehydration step, can be performed according to methodologies well-known to the person skilled in the art, such as the ones dl jelosed m "Comprehensive Organic Transformations. A guide to functional group preparations" by Richard C. Larock, John Wiley & Sons, Inc, 1999, p 1983-1983, Which is incorporated herein as reference. Different suitable reagents are enumerated in said reference, such as for example SOCl2, HOSO2NH2, CISO2NCO, MeCfeCNSOiNEts, PhSCfcCl, TsCl, P265, (Ph3P03SCF3)03SCF3, polyphosphate ester, (DO)2POP(OEt)2, (EtO^Pfc, 2-chloro-1,3,2-dioxaphospholane, 2^^-trichloro-2^^i£rydro-l,3)2-dioxaphosphoJlane, POCI3, PPha, P(NCla)3, P(NEt2)3,COCfc, NaClAlClfc C1COCOC1, CICCfeMe, CfeCCOCl, (CF3CO)20, CfeCN^CCla, 2,4,6-trichloro-13,5-triazine, NaClAlCfe, HN(SiMe2)3, N(SiMe2)4, methane sulfonyl chloride and the like. Ail the reagents listed in said publication are incorporated herein by reference.
The product resulting from the above described reaction can, if desired, be converted into an acid addition salt by treatment wiflj an acid and, if desired, stereochemically isomeric forms, JV-oxide forms or quaternary amines of the product can be formed. The isolation of the reaction product from the reaction medium and, if necessary the further purification, can be performed according to methodologies generally known in the art such as, for example, extraction, crystallization distillation, trituration and chromatography.
In.order.to arrive, at an. efficient, synthetic proccs, it is not sufficient to optimize only the final reaction step, i.e. the reaction step in which the desired product is formed, but the synthesis of the intermediates also needs to be optimized.
Therefore, a further aspect of the present invention relates to the provision of a process for the preparation of a key intermediate, Le, t'le intermediate of formula (II), in the synthesis of the compound of formula (I), or a W-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or stereochemically isomeric form thereof.
Thus, the present invention also provides a process for the preparation of an intermediate-of formula-(II)ran appropriate acid-additionsalMluateraaiamine or a stereochemically isomeric form thereof
(Formula Removed)
which comprises reacting an intenmediatD of formula (V), an appropriate acid addition salt or a quaternary amine thereof
(Formula Removed)
wherein W3 represents a suitable leaving group, with acrylomtrile in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent
Suitable leaving groups represented by W3 are for example halo, triflate, tosylate, mesylate and the like. Preferably, W3 is ha Jo, more particularly iodo or bromo. Most preferred is iodo.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as for example Pd(OAc)2, PdCl2, Pd(PPh3)4, PdCPPha^C^ Pd^dbafe (tris(dibenzylidene acetone) dipailadium), palladium thiomemylphenvlf^utaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as for example palladium on charcoal, palladium on metal oxides, palladium on zeolites.
Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, is stable and relatively inexpensive. It can be easily separated (fBtratfon) from me reaction mixture thereby reducing Ihe risk of Pd traces in me final product The use of Pd/C also avoids the need for ligands, such as for example phosphine tigands, which are expensive, toxic and contaminants of the synthesized products.
Suitable bases-are-for- example-sodium acetate; potasshmi^cetate, J^i^diethyl-erthanamme, sodium hydrogencarbonate, sodium hydroxide and the like.
Suitable solvents are for example acetonihile, ^V-dimemylacetamide, an ionic liquid e.g. [bmim]PF6, i^-dimemylfonnamide^ water, tetrahydrofuran, dimetirylsulphoxide, l-methyl-2-pyrrolidinone and me like.
The product resulting fiom the above described reaction can, if desired, be converted into an acid addition salt by treatment with an acid and, if desired, stereochemically isomeric forms, JV-oxide forms or quaternary amines.of the product can be formed. The isolation of the reaction product fixnn the reaction medium and, ifnecessaiy the farmer purification, can be performed according to methodologies generally known in the art such as, for example, extraction, crystallizition^distulation, trituration and chromatography.
Alternatively, me intermediate of formula (IT) can also be prepared by dehydrating the corresponding amide derivative.
Thus, the present invention also relates to a process for the preparation of an intermediate of formula (II), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof
(Formula Removed)

. (TO which comprises reacting an intermediate of formula (V), an appropriate acid addition salt or a quaternary amine thereof
(Formula Removed)
V) wherein W3 represents a suitable leaving group, with acrylamide in the presence of a
sunable palladhati c5aialystra~suitaWe base antfa suitable solvent; -
followed by dehydration of the thus obtained intermediate of formula (VT), an appropriate acid addition salt, a quaternary amine or a stereochemically isomeric form thereof
(Formula Removed)
suitable leaving groups represented by W* are for example halo, triflate, tosylate, mesylate and the like. Preferably, W3 is halo, more particularly iodo or bromo.
The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as for example Pd(OAc)2, PdCla, Pd(PPh3)4, PdCPPh&Cfc. PfeKdba)3 (trk(dfbenzylidene acetone) dipalladium), palladium tbaomemyhAearylglirtaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as for exarapfc palladium on charcoal, palladium on metal oxides, palladium on zeolites.
Preferably, the palladium catalyst is a heterogeneous Pd catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a -recoverable catalyst, is stable and relatively inexpensive. It can be easily separated (filtration) from the reaction mixture thereby -reducmg the risk of Pd traces in the final product The use of Pd/C also avoids the need for ligands, such as for example phosphinc ligands, 'which are expensive, toxic and contaminants of the synthesized products,
Suitable bases are for example sodium acetate* potassium acetate, iV,2V-diethyl-ethanamine, sodium hydrogencarbonate, sodium hydroxide and the like.
Suitable solvents are for example acetonitrik, jVJV-dlmemylacetamide, an ionic liquid e.g. [bmhn]PF6, JVffi-dimemylfarmamide, water, tetrahydrofuran, dimethylsulphoxide, l-memyl-2-pyrrolidinone and the like.
The conversion of the intermediate of formula (VI) into the intermediate of formula (II), i.e. the dehydration step, can be performed according to methodologies well-known to the person skilled in the art s ucb as the ones disclosed in "Comprehensive Organic Transformations. A guide to functional group preparations" byRich^C. I^ocl^JolnrWile3rj,
(EtO)3pI% 2-chJoro-l,3,2^dioxaphosphofene, .^^-trichloro^^-dihydro-l^^-dioxaphospholane, POCfe, PPh3, PCNC1&, PpflBtakCOCfe, NaCLAlCk, ClCOCOCl, CICQaMe, CfeCCOGl, (CFaCO^O, CI3CNKXI2,2,4,6-trichloro-l,3,5-triazine, NaCLAlCfe, HN(SiMe2)3, N(SiMe^)4, methane sulfonyl chloride and the like. All me reagents listed in said publication are incorpof ated herein by reference.
The product resulting from the above described reaction can; if desired, be converted into an acid addition salt by treatment with an acid and, if desired, stereochemically isomeric forms, AT-oxide forms or quaternary amines of the product can be formed. The isolation of the reaction product from the icaction medium and, if necessary the further purification, can be performed according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
As used hereinbefore or hereinafter, the term halo is generic to fluoro, chloro, bromo andiodo.
For therapeutic use,, salts of the. compound of formula (T) are those wherein the counterion is phannaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find, use, for example, in the preparation or purification of a phannaceutically acceptable compound. All salts, whether phannaceutically acceptable or not are included within the ambit of the present-invention.
The phannaceutically acceptable addition suits as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compound of formula (1) is able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, bydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-Jiy Conversely the salt form can be converted by treatment with alkali into the free base form.
The term addition salt also comprises the hydrates and solvent addition forms which the compound of formula (I) is able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term "quaternary amine" as used hereinbefore or hereinafter defines the quaternary ammonium salts which the compound of formula (I) is able to form by-reaction between a basic nitrogen of the compound of formula Q) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromemanesulfonates, alkyl methanesulfbnates, and alkyl p-toluenesulfbnates. A quaternary amine has a positively charged nitrogen. Pharmaceuticalry acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
The jy-oxide forms of the present compounds are meant to comprise the compound of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called JV-oxide.
The compound of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said JV-oxidation reaction may generally be carried out by reacting the starting, material of formula (1) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper-oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo-peroxoic acid, peroxoalkanoic acids, e.g, peroxoacetic acid, alkylhydroperoxides, e.g. tertbutyl hydro-peroxide. Suitable solvents are* for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e It will be appreciated mat me compound of formula (I) and the JV-oxides, addition salts,
quaternary amines and stereochemicauy isomeric forms thereof may contain one or
more centers of chirality-and-exists as stereochctnically isomeric-forms.
The term "stereochemically isomeric forms'* as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compound of formula (T), and the N-oxidss, addition salts, quaternary amines or physiologically functional derivatives
thereof may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemicalry isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (1) and the JV-oxides, salts, solvates or quaternary amiaes thereof substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less man 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration or the da- or frflny-configuration; e.g. substituents on bivalent cyclic (partially) saturated radicals may have either the cur- or trans-configuration. The compound of formula (!) can have an E (entgegen) or Z (zusammen) -stereochemistry at the doublo bond. When the compound of formula (I) A. is specified as (E), mis means that the compound is substantially free of the (Z) isomer. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art Stereochemicalry isomeric forms of the compound of formula (I) are obviously intended to be embraced within the scope of mis invention.
Whenever used hereinbefore or hereinafter, the term "compound of formula (I)" is meant to also include the tf-oxide forms, the addition salts, the quaternary amines and the stereochemically isomeric forms thereof. Of special interest are those compounds of formula (I) which are stereochemically pure. A preferred compound is Compound X.
The Z-isomer of 4-[[4-[[4-(2-cyanoemenyI)-2,6-dimethylphenyI]amino]-2-pyrimidinyl]amino]benzonitrile can also be prepared according to the reactions of the . present invention and can be isolated according to art-known methodologies. Hence, 4-[[4-[[4-(2-cyanoemenyl)-2,6-dimethylphem l]an imo]-2-pyriinidroyl]ammo]benzonhrile (Z) is also embraced by the present invention.
The following examples illustrate the present Invention.
Experimental part
A. Preparation of the intermediate compffituft
Preparation of intermediate (D)
[-CN
(Figure Removed)
a) To a solution of 159 g of 4-iodo-2,6-dimemyl-b«nzxaiarame in 650 ml of NJSf-dhnefhylacetamide was added 63.8 g of sodium acetate. The reaction mixture was kept under nitrogen atmosphere. 7 g of moistened palladium on charcoal (Pd/C 10 %) and 64.4 ml of acrylonitrile was added. The reaction mixture was heated to 130°C and stirred overnight After cooling to room temperature, 0.S 1 of toluene and 0.51 of JVJV-dimemylacetamide was added. The reaction mixture was filtered over Dicalite and the residue was washed with 0.51 of toluene. Water (61) was added to the mixture which was stirred for 30 minutes. The layers were separated. To the aqueous layer, 11 of toluene was added and the mixture was stirred for 30 minutes. The layers were separated again. The separated organic layers were collected and the solvent was evaporated. Yield: 123 g of the intermediate of formula (Q).
The retention time of intermediate (II) onCPSIJ^8CB O25mx0.32mmx0.5um) purged with He with an initial temperature of 40°C increased with 10°C/minute till a ternr>erature of 300°C, was 17.50 minutes for me (Z) isomer and 18.77 minutes for the (E) isomer.
Preparation of the hydrochloric acid salt (1:1) of the intermediate of formula CD)
(Formula Removed)
NH3 .HC1 a) To a rnixtuxe of 123 g of the intermediate of formula (II) in 630 ml of emanol was added 1,251 of diisopropyl ether. The reaction mixture was kept under nitrogen
atmosphere. The mixture was heated to 66"C and stirred for 30 minutes. 120 ml of a 6 N solution of hydrochloric acid in 2-propanol was added and the mixture was stirred for 30 minutes. After cooling to room tempetaturejthe reaction mixture was filtered and the residue was washed with 100 ml of 2-propanoJ. The resulting residue was dried under reduced pressure at SOX. Yield: 103 g (77 %) of the hydrochloric acid salt (1:1) of me intermediate of formula (II).
b) 1,012 kg of moistened palladium on charcoal (Pd/C 10%), 9,361 kg of sodium acetate and 34,41 kg of N,N-dtoetirylacetBinide were introduced in a reactor and put under nitrogen atmosphere. The mixture was stirred and heated at 140°C. 23,497 kg of 4-iodo-2,6-dimethyl-benzeneamine, 7,569 kg of acrylonhrile and 54,98 kg ofNJf-dimethylacetamide were introduced in a second reactor and put-under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. The solution of me second reactor was tranferred to the first reactor over 1 hour and the temperature of the first reactor was maintained at 140°C The reaction mixture was stirred at 140°C overnight and men allowed to cool to room temperature. The reaction mixture was then filtered (1) and the filter was washed with 95,11 of toluene (2). To the thus obtained organic phase., i.e. (1) + (2), was added 380,4 I of water and the mixture was stirred vigourously. Then agitation was stopped and the phases were separated (3). The water layer was washed once with 95,11 of toluene and me phases were separated again (4). The combined organic phases, i.e. (3) + (4), were tranferrred to the second reactor and distilled under reduced pressure. 190,21 of EtOH was added and the mixture was stirred at room temperature. A solution of HC1 (6N) in 2-propanol (18,13 1) was added at room temperature and me reaction mixture was stirred overnight at room temperature, followed by filtration (*). The obtained solid was washed with 14,741 of 2-propanol (**) and dried under reduced pressure at 50°C. Yield: 50-60 % of the hydrochloric acid salt (1:1) of the intermediate of formula (H). Additional product (10-15%) was recuperated by distillation of the filtrate (*) and wash liquid (**) followed by filtration at room temperature.
Example A3
Preparation of the intennediate of formula (III) wherein Wi represents chloro, said intermediate being represented by formula (III-a)
(Formula Removed)
(III*) The intermediate of formula (EOf-a) was prepared based on me procedure as described in WO 99/50250. - %)*)H1 lib** , (0.12 mol)inPOCl3 (90 ml) was stirred and refluxed under Argon far 20 minutes. The
reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated
by filtration. The solid was suspended in 500 ml of water, and the pH of the suspension
was adjusted to neutral by. adding a 20% NaOH- solution. The solid was again... ..
separated by filtration, suspended in 200 ml of 2-propanone, and 1000 ml of CH2C12
was added. The mixture was heated until all solid had dissolved. After cooling to
room temperature, the aqueous layer was separated, and the organic layer was dried.
During removal of the drying agent by filtration, a white solid formed in the filtrate.
Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g
(77.2%) of [4-[(4- formula (Hl-a).
The retention time of intermediate (Ql-a) Rypt^lft A4
Preparation of me intermediate of formula (IV) wherein W2 is bromo, said intermediate being represented by foxmual (EV-a)
(Formula Removed)
A mixture of 4-bromo-2,6-dimethylbeo2etia«iJne (0.013 mol) and intermediate (HI-a) (0.013 mol) was stirred at 1S0°C for 1 hour. The mixture was poured into K2CO3 10% aqueous solution and extracted with GHgCV MeOH (95/5). The organic layer was separated, dried (MgSCU), filtered and the solvent was evaporated. The residue was crystallized from diisopropyl ether. The psec^pitate was filtered off and dried. Yield: 2.3g (45%). The mother layer was purified by column chromatography over silica gel (eluent: CFfcCk/OH3OH-NHtOH 980/02; 25 The retention time of intermediate (IV-a) on Hypersil BDS (10cmx4mmx3ujn) elated with 0.5% NH4AC/CH3CN 90/10 at time 0 and 0/100 at 15 minutes was 10.31 minutes.
Intermediate (TV), wherein W2 represents iodo, said intermediate being represented by formula (IV-b), can be prepared on an analogous manner.
(Formula Removed)
(IV-b) The retention time of intermediate (IV-b) on Hypersil BDS (10cmx4mmx3|un) eluted with 0.5% NH4AC/CH3CN 90/10 at time 0 and 0/100 at 15 minutes was 10.54 minutes.
^flfyipl^ AS
a) Preparation of intermediate of formula (VI) (E)
(Formula Removed)
(VI) m 10 ml acetonitrile, dry, was dissolved 2.00 g (10.0 mol) of 4-bromo-2,6-dimethyl-anfline, 1.07 g (1.5 eq) of acrylamide, 224mg (0.1 eq) of Pd(OAc)z> 609 mg (0.2 eq) of 1ris(2-memyh>henyl)phosphme and 1.52 g of N,N-diethyletbariamme. The mixture was purgedwimN2for20mmute3andstirj^oveniightat70oC. The mixture was diluted with 150 ml of methylene chloride, washed with sat N8HCO3 solution, dried (sat. NaCI, Na2S04) and filtered. The solvent was evaporated and the residue was stirred in
diisopropyl ether followed by filtration. Yield; 1.51 g (79.5 %) of mtennediate (VI)
(E).
b) Preparation of intermediate of formula (II) (E)
(Formula Removed)
POCI3 (3 ml) was cooled to 0°C and 500 mg{2.'63 mmol) of intermediate (VI) (E) was
added. After 30 minutes, the cooling bam was removed and the mfclure was stirred
overnight at 20 °C. The mixture was added dropwise to 150 ml of diisopropyl ether
while stirring vigorously. The precipitate was filtered and washed with diisopropyl
ether. The residue was added to 100 ml ethyl acetate/100 ml of saturated NaHCCb
solution and stirred. The ethyl acetate layer was separated, dried (sat NaCl, Na2SC>4)
and filtered. The solvent was evaporated. Yield: 380 mg (84 %) of intermediate (IT) .
(E).
c) Preparation of intermediate of formula (Vfl)(E)
(Formula Removed)
hi a 100 ml flask under N2 were introduced 03g (4,33mmol; 1 eq.) of intermediate (VT> (E), lg (4,33 mmol; 1 eq.) of intermediate (III-a) and 16 ml of 2-propanol. To this mixture 0,72 ml of HC16N in 2-propanol were added. The mixture was stirred under reflux for 72 hours and then cooled, yielding intermediate (VII) (E) HCL
Intermediate (VII) (E) HC1 can be converted into the free base according to art-known methodologies (see also Example Bl). Intermediate of formula (VH) (E) can be converted into compound X according to tile method described above in Example A5b.
fixample A6
Preparation of intermediate of formula (V71) (E)
(Formula Removed)
2.53 ml of acetonitrile, 0.056 g (0.253 mmol) of PdXOAc^ and 0,154 g (0.506 mmol) of tris(2-memylphenyl)phosphine were brought m a 100 ml flask under nitrogen and the mixture was stirred for 10 minutes. To tht mixture was added 1 g (2.53 mmol) of intermediate (IV-a), 0.51 ml (3.8 mmol) of A^Y-diethylelhanamine and 0.36 g (5.06 'mmol) of acrylamide. The mixture was heated at reflux (80°C) for 5 days yielding 28 % of intermediate (VH) (E).
The retention time of intermediate (VH) (E) on Hypersil BDS (10cmx4mmx3jim) eluted with 0.5% NH4AC/CH3CN 90/10 at tinw 0 and 0/100 at 15 minutes was 6.59 minutes.
Intermediate of formula (VH) (E) can be converted into compound X according to the method described above in Example A5b.
B. Preparation of 4-rr4-rr4-f2-cvanoemenyn-2 6-dmiethvlphenvnaTnino1-2- CE\ fCarqpourtfX) fmeltinp point 245 °C1
(Formula Removed)

Example Bl
a) A mixture of 93.9 g (0.45 mol) of the hydrochloric acid salt of intermediate (H), prepared according to Example A2, and 109 g (0.4725 mol) of intermediate (Dl-a) in 1.81 of acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxedfbr 69 hours, then allowed to cod to 55 °C. The mixture was filtered and the residue was washed with 200 ml of acetanirrile, followed by drying under reduced pressure at 50°C overnight 144,6 g (0.3666 mol) of the obtained solid was brought in 11 of K4CO3 10% aqueous solution. The mixture was stared at room temperature followed by filtration. The obtained residue was washed twice with water followed by drying at 50°C under reduced pressure. The residue was brought in 6 J51 isopropanol and the mixture was refluxed, then stirred overright and filtered at Toomlemperature.
The residue was dried at 50°C under reduced pressure. Yield: 113.2 g (68.6 %) of
4-[[4-[[4-(2-cyance1heny])-2,6-dmie^
benzonitrile (E) (Compound X).
b) A mixture of 93.9 g (0.45 mol) of the hydrochloric acid salt of intermediate (II), prepared according to Example A2, and 103.9 g (0.4S mol) of intermediate (M-a) in 0.91 of acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxed for 24 hours, then allowed to cool to 50 °C. A solution of K2CO3 (124.4 g, 0.9 mol) in H20 (0.451) was added over a period of 15-20 minutes at 40-50 °C, followed by stirring for 1 hour at 50 CC. The precipitate was separated and washed twice with 0.0451 of acetonitrile, followed by drying at 50°C under reduced pressure. 73.3 g of the obtained solid and 400 ml of EtOH were mixed andtefluxed for 2 hours, then allowed to cool to room temperature. The precipitate was filtered and the residue was washed with 50 ml of EtOH. The obtained residue was dried overnight at 50°C under reduced pressure. Yield: 65.7 g (89.6 %) of 4-[[4-[[4-(2-cyanoethenyl>2,6-d1memylphenyl]ammo]-2-pyrimidmyI]ammo]benzordtrile (E) (Compound X).
ffxftinplftP?.
A mixture of intermediate (IV-a) (0.00021 mol), prepared according to Example A4, acrylonitrile (CH2=CH-CN) (0.00213 mal), Pd(OAc)2 (0.000043 mol), NJT-diethylethanamine (0.000043 mol) and tris(2-methylphenyl)phosphine (0.00021 mol) in CH3CN (7 ml) was stirred in a sealed vessel at 150°C overnight HfeO was added. The mixture was extracted with CH2CI3. The organic layer was separated, dried (MgSCU), filtered and the solvent was evaporated. The residue (0.15 g) was purified by column chromatography over silica gel (eluent CHjCb/ethyl acetate 80/20; 15-40jun). Fraction 1 was collected and the solvent was evaporated, yielding 0.045g of 4-[[4-[[4~ (2-cyanoetiieaiyl)-2,6-dhnemylphenyI]aml^
(E/Z=80/20). The solid was crystallized from dfethylether. Yield: 0.035g of 4-[[4-[[4-(2^yanoemenyl)-2,6^dimemylphenyl]ammo^^ (Compound X) (55%).
]Rxftmpleft3
4,41g (10 mmol) of intermediate (TV-b) and 15 ml of JV^-dimemylacetamide were brought irr a 100 ml fiasKTmoef nitrogen. To mi$ mixture were added" 0,98g of sodium acetate (12 mmol), 107 mg (0,1 mmol Pd) of Pd/C 10% (wet) and 1 ml (15 mmol) of acrylonitrile. The mixture was healed at 140°C and the evolution of the reaction was followed by liquid chromatography. The reaction yielded 4-[[4-[[4-(2-cyanoethenyl)-
2,6-4mie1hylphenyl]amino]-2-pyriminyl]amion]benzonitrile(E/Z=80/20) which can
be woiicsd up to yield 4-[[4-|I4^2K;yanoetfie^l>2,6-dime%h)heiiyl]amino]-2-pyrhnidinyl]amMo]benzonitrile (E) as described above in Example B2.




We Claim:
1. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2, 6-dimethylphenyl]-amino]-2-pyrimidinyl}amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof,
(Formula Removed)
which comprises reacting an intermediate of formula (II), an appropriate acid addition salt or a stereochemically isomeric form thereof
(Formula Removed)
with an intermediate of formula (III), an appropriate acid addition salt or a N-oxide thereof
(Formula Removed)
wherein Wi represents a suitable leaving group, in the presence of a suitable solvent of the kind such as hereindescribed
optionally followed by converting the free base into an acid addition salt by treatment with an acid, or conversely, by converting the acid addition salt
form into the free base by treatment with alkali; and optionally followed, if desired, by preparing stereochemically isomeric forms, N-oxide forms or quaternary amines thereof.
2. A process as claimed in claim 1 wherein the solvent is acetonitrile.
3. A process as claimed in claim 1 wherein the solvent is l-methyl-2-pyrrolidinone.
4. A process as claimed in any one of claims 1 to 3 wherein the intermediate of formula (II), an appropriate acid addition salt or a stereochemically isomeric form thereof, is reacted with an intermediate of formula (III) or an appropriate acid addition salt thereof.
5. A process as claimed in any one of claims 1 to 3 wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-diniethylphenyl]amtino]~2-pyTimidinyl]amino]benzonitrile of formula (I), a N-oxide, a pharmaceutically acceptable acid addition salt, a quaternary amine or a stereochemically isomeric form thereof, is 4-f[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]arnino}-2-pyrimidinyl]amino]benzonitrile (E),
6. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino] -2-pyrimidinyl} amino] ben zonitrile (E) or a pharmaceutically acceptable acid addition salt thereof as claimed in any one of the preceding claims wherein
(Formula Removed)
optionally followed, if desired, by converting the free base into an acid addition salt by treatment with an acid.
7. A process for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-
dimethylphenyll-amino]-2-pyrimidinyl]amino]benzonitriie (E) or a
pharmaceutically acceptable acid addition salt thereof as claimed in any one of the preceding claims wherein an acid addition salt of
(Figure Removed)
followed, if desired, by converting the acid addition salt form into the free base by treatment with alkali.
8, A process as claimed in any one of the preceding claims wherein W1 is
halo.
9. A process as claimed in claim 8 wherein W1 is chloro.

Documents:

263-delnp-2005-abstract.pdf

263-DELNP-2005-Claims.pdf

263-delnp-2005-complete specification(as files).pdf

263-delnp-2005-complete specification(granted).pdf

263-DELNP-2005-Correspondence Others-(09-11-2011).pdf

263-DELNP-2005-Correspondence Others-(19-09-2011).pdf

263-delnp-2005-correspondence-others.pdf

263-delnp-2005-correspondence-po.pdf

263-DELNP-2005-Description (Complete).pdf

263-delnp-2005-form-1.pdf

263-delnp-2005-form-13.pdf

263-DELNP-2005-Form-18.pdf

263-DELNP-2005-Form-2.pdf

263-delnp-2005-form-3.pdf

263-delnp-2005-gpa.pdf

263-delnp-2005-others-document.pdf

263-delnp-2005-pct-210.pdf

263-delnp-2005-pct-306.pdf

263-delnp-2005-pct-409.pdf

263-delnp-2005-pct-416.pdf

263-DELNP-2005-Petition-137-(09-11-2011).pdf

263-delnp-2005-petition-137.pdf

263-DELNP-2005-Petition-138-(19-09-2011).pdf

263-delnp-2005-petition-138.pdf

263-delnp-2005-Post-Grant Opposition-(09-11-2011).pdf

263-DELNP-2005-Post-Grant Opposition-(14-12-2011).pdf

263-DELNP-2005-Post-Grant Opposition-(17-10-2011).pdf

263-DELNP-2005-Post-Grant Opposition-(18-07-2011).pdf

abstract.jpg


Patent Number 242945
Indian Patent Application Number 263/DELNP/2005
PG Journal Number 39/2010
Publication Date 24-Sep-2010
Grant Date 21-Sep-2010
Date of Filing 24-Jan-2005
Name of Patentee JANSSEN PHARMACEUTICA N.V.
Applicant Address TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
Inventors:
# Inventor's Name Inventor's Address
1 DIDIER PHILIPPE ROBERT SCHILLS C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
2 JOANNES JOSEPHUS MARIA WILLEMS C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
3 BART PETRUS ANNA MARIA JOZEF MEDAER C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
4 ELISABETH THERESE JEANNE PASQUIER C/O JOHNSON & JOHNSON PHARMACEUTICAL RESEARCH & DEVELOPMENT, JANSSEN-CILAG, CAMPUS DE MAIGREMONT, BP 615, 27106 VAL DE REUIL CEDEX, FRANCE.
5 PAUL ADRIAAN JAN JANSSEN C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
6 JAN HEERES C/O JANSSEN PHARMACEUTICA N.V., TURNHOUTSEWEG 30, 2340 BEERSE, BELGIUM.
7 RUBEN GERARDUS GEORGE LEENDERS C/O MERCACHEM, TOERNOOIVELD 100, NL-6503 CB NIJMEGEN, THE NETHERLANDS.
8 JEROME EMILE GEORGES GUILLEMONT C/O JOHNSON & JOHNSON PHARMACEUTICAL RESEARCH & DEVELOPMENT, JANSSEN-CILAG, CAMPUS DE MEIGREMONT, BP 615, 27106 VAL DE REUIL CEDEX, FRANCE
PCT International Classification Number C07C 255/42
PCT International Application Number PCT/EP2003/050366
PCT International Filing date 2003-08-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/EP2003/050366 2003-08-07 PCT