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
  • C07D239/52—Two oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • 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
  • C07D239/69—Benzenesulfonamido-pyrimidines

Definitions

• the present invention relates to a novel intermediate useful in the preparation of bosentan and to processes for the preparation of said intermediate and bosentan.
• the invention further relates to compositions comprising bosentan prepared according to the processes of the invention and their use in the treatment of endothelin-receptor mediated disorders.
• Bosentan represented by structural formula (i) and chemically named 4-tert-butyl-JV-[6-(2- hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yI
• PAH pulmonary arterial hypertension
• Bosentan was first described in US 5292740.
• the preparation method involves two steps (as shown in Scheme 1) starting from the dichloro compound, 4,6-dichloro-5-(o- methoxyphenoxy)-2,2'-bipyrimidine (1).
• the second reaction step is carried out in ethylene glycol with sodium metal used as the base at a temperature of 100-110 0 C.
• One of the disadvantages of this process is the formation of an undesired ethylene glycol bis-sulfonamide dimer having formula (ii) in which two molecules of the pyrimidine monohalide molecule are coupled with one molecule of ethylene glycol.
• the removal of this impurity requires costly and laborious separation steps.
• To minimize the formation of this impurity a large excess of ethylene glycol is used.
• using a large excess of ethylene glycol is impractical on a large industrial scale, because ethylene glycol is toxic and its high boiling point means that its removal by distillation is energy and time consuming.
• US 6136971 discloses a process (as shown in Scheme 2) for the preparation of bosentan with high HPLC purity (99.1%) and solves the problem of the dimer formation by utilising a mono-protected 1,2-diheteroethylene anion.
• the protecting group is a tert-butyl group used to protect one hydroxyl group of ethylene glycol as an ether.
• the protecting group is then removed with formic acid to produce a formyloxy-protected ethylene glycol sulfonamide derivative.
• the present inventors have found that coupling of a dichloro compound, 4,6-dichloro-5- (2-methoxyphenoxy)-2,2'-bipyrimidine (1), with a mono-protected ethylene glycol of formula HOCH 2 CH 2 OR, wherein R is a hydroxyl protecting moiety, followed by introduction of a sulfonamide group in the next step provides an improved process for the preparation of bosentan with a very high purity.
• This process has the unique and surprising advantage of requiring less sulfonamide than prior art processes, which is an expensive raw material compared to the ethylene glycol derivative.
• the present invention provides an efficient and economical synthesis of bosentan, which is high yielding and affords the product with very high purity on a commercial scale.
• the present inventors have found that coupling the dichloro compound (1) with the mono-protected ethylene glycol component first and then introducing the sulfonamide moiety in a second step as opposed to the prior art processes where the sulfonamide moiety is coupled to the dichloro compound (1) first and the mono-protected ethylene glycol is added in a second step, provides a process with a number of surprising advantages.
• the process which further provides a novel intermediate having formula (2a) according to the invention, results in bosentan having a purity of more than 99.70%, preferably greater than 99.8%, and most preferably more than 99.9%. Such purity levels have not been seen before in the prior art.
• a first aspect according to the invention provides an improved process for the preparation of bosentan utilizing a compound of formula (2a).
• the process comprises the steps of: (a) adding a dichloro compound of formula (1) to a mono-protected ethylene glycol of formula HOCH 2 CH 2 OR, wherein R is a hydroxyl protecting moiety, resulting in a reaction mixture comprising a compound of formula (2a);
• step (c) removing the protecting moiety R; and (d) isolating bosentan from the mixture obtained in step (c).
• R is stable in basic and mildly acidic conditions.
• further groups that may serve as protecting moieties on the ethylene glycol, indeed any hydro xyl protecting groups that are stable under basic and mildly acidic conditions will be suitable for use in the working of the invention. Examples of said protecting groups can be found in T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (3 rd ed., John Wiley & Sons, 1999), which is incorporated herein by reference.
• R groups may be selected from the group comprising alkyl, aryl, arylalkyl, allyl, silyl, benzoate and pivalate moieties.
• R is tert-butyl.
• a preferred reaction temperature for this coupling of the mono-protected ethylene glycol and the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (1) is from about 15°C to about 90 0 C, more preferably from about 30 0 C to about 90 0 C, and most preferably form about 50 0 C to about 60 0 C.
• a preferred reaction time is about 1-10 hours, more preferably about 1-5 hours, and most preferably about 1-3 hours.
• the mono-protected ethylene glycol is reacted with the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidine (1) in the presence of a base.
• the base is selected from the group comprising alkali metal hydroxides (such as lithium and sodium hydroxide), alkaline earth metal hydroxides, sodium metal, DBU, DBN, dimethylaminopyridine (DMAP), and pyridine.
• alkali metal hydroxides such as lithium and sodium hydroxide
• the base is an alkali metal hydroxide and a particularly preferred base is sodium hydroxide.
• the reaction is carried out in an organic solvent, which is preferably toluene but alternative solvents can be selected from the group comprising toluene, xylene, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF) and dimethylacetamide.
• step (b) compound (2a) is coupled with 4- tert-butyl phenyl sulfonamide.
• a base such as potassium carbonate.
• a preferred reaction temperature is from about 100 0 C to about 150 0 C, preferably about 120 0 C.
• a preferred reaction time is about 8-15 hours, preferably about 10 hours.
• the reaction is carried out in an organic solvent, such as DMSO.
• the ethylene glycol protecting moiety can be removed by any means known in the art.
• acidification followed by treatment with a base is particularly efficient at removing the protecting group.
• Particularly preferred removal conditions involve treatment with formic acid followed by treatment with sodium hydroxide, particularly in the preferred embodiment wherein the protecting group is a tert-butyl ether moiety.
• the bosentan is isolated in step (d) by filtration and dried under reduced pressure until a constant weight is achieved.
• the process according to the first aspect of the present invention is preferably carried out on an industrial scale, preferably providing bosentan in batches of about 50Og, lkg, 2kg, 5kg, 10kg, 50kg, 100kg or more.
• the process according to the first aspect of the present invention preferably provides bosentan in a molar yield of 30%, 40%, 50%, 60% or more from the dichloro compound of formula (1).
• the process according to the first aspect of the present invention is preferably carried out without the use of chromatography.
• the bosentan obtained by the process according to the first aspect of the present invention preferably has an HPLC purity of 97% or more, preferably 98% or more, preferably 99% or more, preferably 99.3% or more, preferably 99.5% or more, preferably 99.7% or more, preferably 99.8% or more, preferably 99.9% or more.
• the bosentan comprises less than about 0.1%, preferably less than about 0.05% of the dimer impurity (ii) (as measured by HPLC).
• salts selected from the following group are particularly useful, said group comprising: a tartrate, succinate, oxalate, pimelate, adipate, acetate, suberate, salicylate, mesylate, malate, malonate, maleate, camphorsulfonate, mandelate, hydrochloride, hydrogen sulfate, sulfate, hydrobromide, besylate, benzoate, dihydrogen phosphate, glutarate, or citrate salt.
• the salts may be prepared by any means known in the art, in particular by reaction with the corresponding acid.
• a process for the preparation of a compound of formula (2a) comprising coupling a dichloro compound of formula (1) to a mono-protected ethylene glycol having formula HOCH 2 CH 2 OR, wherein R is as previously described.
• R is stable in basic and mildly acidic conditions, particularly preferred is wherein R may be selected from the group comprising alkyl, aryl, arylalkyl, allyl, silyl, benzoate and pivalate moieties, but most preferably R is tert-butyl.
• R is stable in basic and mildly acidic conditions, particularly preferred is wherein R may be selected from the group comprising alkyl, aryl, arylalkyl, allyl, silyl, benzoate and pivalate moieties, but most preferably R is tert-butyl.
• a preferred reaction temperature for this coupling is from about 15°C to about 90 0 C, more preferably from about 30 0 C to about 90 0 C, and most preferably from about 50 0 C to about 60 0 C.
• a preferred reaction time is about 1-10 hours, more preferably about 1-5 hours, and most preferably about 1-3 hours.
• Preferably from about 1 equivalents (eq) to about 10 equivalents (eq) of mono-protected ethylene glycol relative to the dichloro compound of formula (1) are used, more preferably about 1 eq to about 5 eq, and most preferably about 3 eq.
• the mono-protected ethylene glycol is reacted with the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidine (1) in the presence of a base.
• a base is selected from the group comprising alkali metal hydroxides (such as lithium and sodium hydroxide), alkaline earth metal hydroxides, sodium metal, DBU, DBN, DMAP, and pyridine.
• the base is an alkali metal hydroxide and a particularly preferred base is sodium hydroxide.
• the reaction is carried out in an organic solvent, which is preferably toluene but alternative solvents can be selected from the group comprising toluene, xylene, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF) and dimethylacetamide.
• organic solvent which is preferably toluene but alternative solvents can be selected from the group comprising toluene, xylene, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF) and dimethylacetamide.
• Preparing the mono-protected ethylene glycol pyrimidine derivative of formula (2a) or (2) using a mono-protected ethylene glycol derivative prevents formation of the undesired ethylene glycol bis-sulfonamide compound of formula (ii).
• the hydroxy group of some of the initially formed ethylene glycol derivative reacts with unreacted sodium ethylene glycol (NaOCH 2 CH 2 OH) or other bases which may be present in the reaction mixture to form an anion which then reacts with another molecule of pyrimidine mono-halide to produce the undesired ethylene glycol bis- sulfonamide derivative.
• the present invention eliminates any possibility of forming such an anion, thus completely eliminating production of the undesired ethylene glycol bis-sulfonamide derivative.
• This elimination of the production of the undesired ethylene glycol bis- sulfonamide derivative results in a higher overall product yield and easier product purification.
• the process according to the third aspect of the present invention is preferably carried out on an industrial scale, preferably providing compound (2a) in batches of about 50Og, lkg, 2kg, 5kg, 10kg, 50kg, 100kg or more.
• the process according to the third aspect of the present invention preferably provides compound (2a) in a molar yield of 80%, 85%, 90% or more from the dichloro compound of formula (1).
• the process according to the third aspect of the present invention is preferably carried out at a temperature of 90 0 C, 80 0 C, 70 0 C, 60 0 C or less.
• the process according to the third aspect of the present invention is preferably carried out without the use of chromatography.
• R is a hydroxyl protecting moiety.
• R is selected from the group comprising alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, allyl, silyl, benzoate and pivalate moieties.
• R is selected from the group comprising alkyl, aryl, arylalkyl, allyl, silyl, benzoate and pivalate moieties.
• Alkyl, alkenyl and alkynyl moieties preferably comprise 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
• a preferred alkyl moiety is tert-butyl.
• an aryl moiety comprises 4 to 14 carbon atoms, preferably 6 to 10 carbon atoms.
• a typical aryl moiety is phenyl.
• Arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl and alkynylaryl moieties preferably comprise 5 to 20 carbon atoms, preferably 7 to 15 carbon atoms.
• a typical arylalkyl moiety is benzyl.
• R is hydrogen.
• a silyl moiety is a -SiR 3 group, wherein R is independently selected from hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group.
• Typical silyl moieties are trimethylsilyl (TMS), triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl-t-hexylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzyl silyl, tri-p-xylylsilyl, triphenylsilyl (TPS), diphenylmethylsilyl (DPMS), and t-butylmethoxyphenylsilyl (TBMPS).
• TMS trimethylsilyl
• TMS triethylsilyl
• triisopropylsilyl dimethylisopropylsilyl
• diethylisopropylsilyl dimethyl-t-hexylsilyl
• TDMS t-butyldi
• composition comprising bosentan prepared by a process according to the invention.
• the composition is a solid composition, most preferably a tablet or capsule composition.
• Illustrative of the invention is a pharmaceutical composition made by mixing bosentan according to the invention and a pharmaceutically acceptable carrier.
• a method for the treatment of an endothelin-receptor mediated disorder in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of bosentan prepared according to the invention.
• a composition for use in the treatment of circulatory and cardiovascular disorders.
• the disorder is one or more of: hypertension, ischemia, pulmonary hypertension, vasospasm and angina pectoris.
• Endothelin-receptor mediated disorders compfise circulatory and cardiovascular disorders such as hypertension, ischemia, pulmonary hypertension, vasospasm and angina pectoris.
• the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g.
• Avicel microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
• Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
• Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ® ), carboxymethyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ), hydroxypropyl methyl cellulose (e.g.
• Methocel liquid glucose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon ® , Plasdone ® ), pregelatinized starch, sodium alginate and starch.
• povidone e.g. Kollidon ® , Plasdone ®
• the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
• Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-SoI , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon , Polyplasdone j, guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ® ) and starch.
• alginic acid include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-SoI , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon
• Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
• Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
• a dosage form such as a tablet
• the composition is subjected to pressure from a punch and dye.
• Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
• a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
• Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
• flavouring agents and flavour enhancers make the dosage form more palatable to the patient.
• Common flavouring agents and flavour enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
• Solid compositions may also be dyed using any pharmaceutically acceptable colourant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
• the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
• the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
• the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. For solid oral dosage forms amounts of active ingredient between the ranges of about 10-200mg per unit dose are preferred, particularly preferred is an amount between about 50-130mg per unit dose.
• the composition is a solid composition, most preferably a tablet or capsule composition.
• the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell.
• the shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant.
• compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
• a composition for tableting or capsule filling may be prepared by wet granulation.
• wet granulation some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powder to clump into granules.
• the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
• the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
• a tableting composition may be prepared conventionally by dry granulation.
• the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
• a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
• Direct compression produces a uniform tablet without granules.
• Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
• a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
• composition of the invention may further comprise one or more additional active ingredients.
• composition according to the invention is provided for use in the treatment of disorders which are associated with endothelin activities.
• a process according to the invention is represented below as a schematic diagram.
• the compound number descriptors refer to the numbered compounds in the schematic diagram.

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