OA12186A - 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylat and polymorphs. - Google Patents

Description

je ! 1 012186 4-Amino-6,7-Diinethoxv-2-(5-Methanesulfonainido-l,2,3.,4-Tetrahydroisoquinol-2- yl)-5-(2-PvridyI)Ouinazoline Mesylat and Polymorphs

The présent invention relates to a novel sait usefi.il in therapy. More specifically the5 présent invention relates to 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, to processes for itspréparation, to its uses, and to compositions containing it. The présent invention also relates to a novel non-hydrated polymorph of the free base. 10 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-

and is disclosed in WO 98/30560 (see Example 19) as being useful in the treatment ofbenign prostatic hyperplasia The application refers in general terms to 15 pharmaceutically acceptable salts and mentions the hydrochloride, hydrobromide andphosphate salts.

Unfortunately, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydro-isoquinol-2-yl)-5~(2-pyridyl)quinazoline displays some disadvantageous physical 20 properties It is now known to occur in a number of different forms. In some cases, itsaqueous solubility is rather low and it is difficult to préparé reproducibly in the sameform, sometimes being obtained in a hydrated form. In addition, it lias been found thaïsome forms of the free base are rather hygroscopic These properties aredisadvantageous for the development of a drug substance because, in particular, a

O K 2 012186 consistent grade of material must be reproducibly manufactured in order to satisfyregulatory requirements.

There is now provided the mesylate sait of 4-amino-6,7-dimethoxy-2-(5-5 inethanesulfonamido-l,2,3,4~tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline having the formula

This substance has a number of unexpected advantages over the free base and it hassurprisingly been found to hâve a unique combination of properties which make it idéal 10 for development as a drug substance

Those skilled in the art will appreciaîte that “mesylate” is an alternative term for“methanesulfonate”. 15 The mesylate sait has a high melting point, and is a crystalline solid which does notdisplay any hydrated or solvated forms. It is isomorphic, i.e it exists in a singlepolymorphie form, and exhibits good stability over a wide range of conditions, e g. highlight intensity. It has acceptable solubility and dissolution characteristics, and can beeconomically prepared and processed to provide suitable solid dosage forms of the drug. 20 Its hygroscopicity is substantially lower than the free base (tested as its 198°C meltingpoint polymorph) over a wide range of relative humidity. The mesylate sait is mono-morphic and does not form hydrates; both of these features represent advantageousproperties of the mesylate sait in particular PCr ! 5 3 012186

Tables 1 to 3 below indicate the physical properties of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolinemesylate and some free base forms. 5 Table 1

Physical properties of the mesylate sait

Form Melting Point (°C) Crystallinity Hygroscopicity % (w/w) at 90% RH Mesylate Sait 279 Crystalline 1.1

Table 2 10 Solubility of the mesylate sait and free base forms (micrograms/ml)

Solvent Free base (mpt 198°C) Hydrated form of free base Mesylate sait Water at 22°C 420 12 880 0.9% sodium chloride at 22 °C 36 4 120

Table 3 15 Hygroscopity of the mesylate sait and free base forms

Form Moisture sorption (% w/w) at 30°C and 45% RH Free base (mpt 198°C) 1.39 Hydrated form of free base 11.24 Mesylate sait (mpt 279°C) 0 56 A number of anhydrous crystalline forms of 4-amino-6,7-dimethoxy-2-(5-20 methanesulfonamido-l,2;3,4-tetrahydioisoquinol-2-yl)-5-(2-pyridyl)quinazoiine (thefree base) are disclosed herein. These anhydrous polymorphe are designated Form A, °CS1O v 012186

Form B, Form C, and Form E in Table 4 below. Form D, which is presented forcomparison, is the hydrated form and exists as a dihydrate.

The term “substantially pure” used above means that a sample of the relevant anhydrous5 crystalline form contains more than 90% of a single polymorphie form, preferably more than 99% of a single polymorphie form.

Table 4

Polymorphie forms of the free base

Form Melting point (°C) Crystallinity Hygroseopity % (w/w) at 90% RH Form A 198 crystalline 2.2 Form B 218 crystalline 0.27 Form C 147 crystalline - Form E 229 crystalline 0.045 FornrD None crystalline 12 8 10

On déhydration, the hydrated form (Form D) becomes amorphous.

The anhydrous polymorphie forms of the invention are also significantly lesshygroscopic than the hydrated free base form. Of these, Forms B and E are preferred on 15 account of their high melting points and low hygroscopicity. Form E is most preferred.

The invention provides Form E, a sample of which contains more than 90% of a singlepolymorphie form Preferably, a sample of Form E contains more than 99% of a singlepolymorphie form 20 lt is now believed that the solid form of 4-amino-6,7-ditnethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yî)-5-(2-pyridy!)quinazolineproduced originally following the procedure of WO 98/30560 (see Example 19) was amixture of Forms B and E, probably in the ratio Tl (based on a differents al scanning 25 calorimetry experirnent showing sharp endotherms at. 220 and 227°C). Following the PC 1 5 012186 création of the most stable Form E in pure form, it is likely that this form will beproduced predominantly in the future when repeating the above préparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline.

Also included within the scope of the présent invention are radiolabelled dérivatives,other isotopic forms and tautomers of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in theform of Form E as defined above or the mesylate sait. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defmed above or as the mesylate saitpossesses pharmacological activity in animais. It may be used in the treatment of anumber of conditions including hypertension, myocardial infarction, male erectiledysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. Thelatter condition is of greatest interest Thus, according to another aspect of theinvention, there is provided a method of treatment of benign prostatic hyperplasia winchcomprises administering a therapeutically effective amount of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline inthe form of Form E as defmed above or the mesylate sait to a patient suffering fromsuch a disorder.

According to a further aspect of the invention, there is provided 4-ainino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of Form E as defmed above or the mesylate sait for use as apharmaceutical, and for use in the treatment of benign prostatic hyperplasia.

According to a further aspect of the invention, there is provided the use of 4-ainino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of Form E as defmed above or the mesylate sait in themanufacture of a médicament for the treatment of benign prostatic hyperplasia. 6 012186 ’CS 10 5? 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait canbe administered alone but will generally be administered in admixture with a suitablepharmaceutical excipient, diluent or carrier selected with regard to the intetided route ofadministration and standard pharmaceutical practice.

Hence, according to a further aspect of the invention, there is provided a pharmaceuticalformulation including 4-amino-6,7-dimethoxy-2-(5-methanesulfonami do-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as definedabove or the mesylate sait in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier. The formulation will preferably contain less than 50% by weight of4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquÎnol-2-yl)-5-(2-pyridyî)quinazoline as Form E as defined above or as the mesylate sait.

For example, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroiso-quinol~2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or themesylate sait can be administered orally, buccally or sublingually in the form of tablets,capsules, ovules, élixirs, solutions or suspensions, which may contain flavouring orcolouring agents, for immédiate-, delayed- or controlled-release applications. Oraladministration is of particular interest. 4-Amino-6,7-dimethoxy-2-(5- methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2~yl)-5~(2-pyridyl)quinazoline in theform of Form E as defined above or the mesylate sali may also be administered viaintracavernosal injection.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such asstarch (preferably corn, potato or tapioca starch), sodium starch glycollate,croscarmellose sodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose(HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnésiumstéarate, stearic acid, glyceryl behenate and talc may be included. pCS 10^85 7 012186

Solid compositions of a similar type may also be employed as fillers in gelatin capsules.Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or highmolecular weight polyethylene glycols. For aqueous suspensions and/or élixirs, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait may becombined with various sweetening or flavouring agents, colouring matter or dyes, withemulsifying and/or suspending agents and with diluents such as water, éthanol,propylene glycol and glycerin, and combinations thereof. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait canalso be administered parenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecalîy, intraventricularly, intrasternally, intracranially,intramuscularly or subcutaneously, or may be administered by infusion techniques lt isbest used in the form of a stérile aqueous solution which may contain other substances;for example, enough salts or glucose to make the solution isotonie with blood. Theaqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), ifnecessary. The préparation of suitable parentéral formulations under stérile conditionsis readily accomplished by standard pharmaceutical techniques well-known to thoseskilled in the art.

For oral and parentéral administration to human patients, the daily dosage level of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-letrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait willusually be from about 0 01 to lOmg/kg (in single or divided doses) and preferably about0.01 to 0.5mg/kg, administered from 1 to 4 limes a day.

Thus tablets or capsules of 4-amino~6,7-dimethoxy-2-(5-methauesulfonamiido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as definedabove or the mesylate sait may contain from about 0.1 mg to 500mg of active compoundfor administration singly or two or more at a time, as appropriate. The physician in anyevent will détermine the actual dosage which will be most suitable for a.ny individual 012186 patient and it will vary with the âge, weight and response of tbe parti cul ar patient. Theabove dosages are exemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited and such are within thescope of this invention 4- Amino-6,7-dimethoxy-2-(5-methanesulfonamido~l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait canalso be administered intranasally or by inhalation and is conveniently delivered in theform of a dry powder inhaler or an aérosol spray présentation from a pressurisedcontainer, pump, spray or nebuliser with the use of a suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, ahydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or othersuitable gas. In the case of a pressurised aérosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurised container, pump, sprayor nebuliser may contain a solution or suspension of the active compound, e.g. using amixture of éthanol and the propellant as the solvent, which may additionally contain alubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, fromgelatin) for use in an inhaler or insufflator may be formulated to contain a powder mixof 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)- 5- (2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate saitand a suitable powder base such as lactose or starch. Aérosol or dry powder formulations are preferably arranged so that each metered doseor “puff” contains from 20pg to 4mg of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4~tetrahydroisoquinol-2-yl)-5~(2-pyridyl)quinazoline in theform of Form E as defined above or the mesylate sait for delivery to the patient. Theoverall daily dose with an aérosol will be in the range of from 20pg to 20mg which maybe administered in a single dose or, more usually, in divided doses throughout the day.

Alternative! y, 4-amino-6,7-dimethoxy~2-(5-niethanesulfonamido-1,2,3,4-tetrahydro-isoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the PCS 1 9 012186 mesylate sait can be administered in the form of a suppository or pessary, or may beapplied topically in the form of a lotion, solution, cream, ointment or dusting powder.4-Amino-6,7-dimethoxy-2-(5-niethanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait mayalso be transdermally administered, for example, by the use of a skin patch. It may alsobe administered by the ocular route, particularly for treatment of the eye.

For ophthalmic use, it can be formulated as micronised suspensions in isotonie, pHadjusted, stérile saline, or, preferably, as solutions in isotonie, pH adjusted, stérilesaline, optionally in combination with a preservative such as a benzylalkonium chloride.Alternatively, it may be formulated in an ointment such as petrolatum.

For application topically to the skin, 4-amino-6,7-dimethoxy-2~(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E asdefined above or the mesylate sait can be formulated as a suitable ointment containingthe active compound suspended or dissolved in, for example, a mixture with one ormore of the following' minerai oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolvedin, for example, a mixture of one or more of the following: minerai oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffm, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The invention further provides a process for the préparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazolinemesylate, as defined above, which comprises the addition of methanesulphonic acid to asuspension or solution of 4~amino-6,7-dimethoxy-2-(5-methanesulfonaîmdo-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formula nCS μ -. 10 012186

in a suitable solvent, and collection of the precipitated solid.

Preferred features of the process include: (a) the solution of 4~amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is maintained at a température aboveroom température before the addition of the methanesulphonic acid; and (b) the solvent used is a mixture of butanone and water, for example a 10:1 byvolume mixture of butanone and water.

The process may be defined more particularly as a process comprising the steps of: (a) heating a suspension of 4-amino-6,7-dimelhoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux; (b) adding butanone/water until a solution is achieved; (c) cooling the solution; (d) adding methanesulfonic acid; and (e) collecting the resulting solid by filtration.

In the above processes, it is preferred that the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline isprésent as Form E as defined above, although some of the desired product should resuitregardless of the starting form.

The formulations of the invention may also contain a human 5-a reductase inhibitorycompound [see International Patent Application WO-A-95/28397], or 4-amino-6,7- PCS 1( 11 012186 dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of Form E as defined above or the mesylate sait couldbe presented in a pharmaceutical pack also containing a human 5-a reductase inhibitorycompound as a combined préparation for simultaneous, separate or sequential use.

References herein to treatment include curative, palliative and prophylactic treatment.

The four anhydrous polymorphs of the free base which hâve been isolated hâve beendesignated Forms A, B, C and E. These polymorphie forms were characterised bypowder X-ray diffraction (PXRD), together with the mesylate sait

The powder X-ray diffraction patterns were determined using a SIEMENS D5000powder X-ray diffractometer fitted with an automatic sarnple changer, a theta-thetagoniometer, automatic beam divergence slits, a secondary monochromator and ascintillation counter. The samples were prepared for analysis by packing the powderinto 12,mm diameter, 0.25mm deep cavities that had been eut into Silicon waferspecimen mounts. Each specimen was rotated whilst being irradiated with copper K-alpha; X-rays (wavelength = 1.5406 Ângstroms) with the X-ray tube operated at40kV/40mA. The analyses were performed with the goniometer running in step-scanmode set for a 5 second count per 0.02° step over a two thêta range of 2° to 55°. Thepeak intensities are summarised in Table 5. In Table 5, “Angle 2-Theta” is related tothe interplanar spacing of the crystal, and the intensity is given as a percentage of thegreatest peak (1/1;). The individual polymorphie forms and the mesylate sait may becharacterised by reference to the peak intensities of greater than 50%, and morepreferably by the peaks having intensities greater than 20%

Table 5

Peak listings for Forms A, B, C and E, and the mesylate sait

Form A

Angle 2-Theta O lutensit y% Angle 2-Theta O Intensif y% Angle 2-Theta O Intensif y % Angle 2-Theta O intensify % 12 012186 6.002 21.1 15.669 4.7 23.282 40.8 30.469 15.3 8.893 22.9 17.040 30.0 23.494 37.3 31.498 17.4 9.401 25.1 17.888 33.4 23.884 92.4 32.257 8.8 9.654 8.5 18.111 16.7 24.298 42.7 33.063 11.6 11.105 33.4 18.872 51.9 24.554 18.7 33.797 14.1 12.000 100.0 19.287 18.9 24.602 19.6 34.889 17.1 12.071 50.2 19.336 16.0 25.674 30.1 35.158 21.2 13.060 25.1 19.714 7.2 26.087 13.8 35.610 12.5 13.373 10.3 20.126 6.5 26.600 19.1 36.226 13.8 13.458 11.6 20.951 15.3 27.036 11.8 36.634 12.4 13.620 10.0 21.021 12.9 27.641 24.4 38.335 16.0 13.708 15.5 21.302 15.4 28.888 18.3 40.198 17.2 13.790 10.8 21 378 19.9 29.136 14.6 40.820 13.7 14.418 10.9 21.925 57.5 29.915 9.4 41.279 15.7 15.075 4.3 22.346 94.6 30.197 19.4 43.943 20.5 15.320 6.1 22.821 22.7 30.282 25.8

Form B

Angle 2-Theta 0 Intensit y % Angle 2-Theta 0 Intensit y% Angle 2-Theta 0 Intensit y% Angle 2-Theta 0 Intensit y% 6.943 1 4 19.559 8.4 26.512 36.5 34.214 9.3 9.004 37 5 19.867 11 1 26.758 30.5 34 382 12.2 9 725 41.2 19.964 6.1 26.918 20.7 34.602 7.7 10.526 40.7 20.407 62.2 26.989 25.4 35.235 10.4 11.315 3.4 20.919 31.2 27.302 7.2 35.449 13.0 11.986 2.1 21.101 17.3 27.800 17.4 36.193 6.8 13.011 2.2 21.712 14.4 27.871 11.6 36.668 8.1 13„493. ....30.2.. . ... 22.55.1 „ .....72...7. ...28.945... ..9 5 ... . .3.7.331.. 12.6... 13.897 74 4 22.769 20.2 29.164 14.4 37 727 8.4 14.306 3.3 22.843 13.9 30.027 7.5 38.318 5.4 15.569 25.2 22.926 15.3 30.284 10.2 38.977 11.3 15.883 48.3 23.418 100.0 31.179 199 39.646 15.8 16.740 5.9 23.904 24.9 31.443 10.2 40.165 7.8 17.122 30.0 23.997 24.5 31.629 8.7 40.911 5.3 17.407 12.3 25.049 21 4 32.121 8.1 42.235 10.8 17.603 5.7 25.209 32.4 32.318 7.9 42.761 9.8 18.094 4.1 25 462 170 32.845 12.2 44.287 7.2 18.727 62.9 25.700 8.4 33.023 14 8 44.775 9 5 19.176 10.0 26.205 129 1 34.045 9.5

5 Forin C

Angle 2- Intensit Angle 2- Intensit Angle 2- Intensit Angle 2- Intensit Theta° y % Thêta0 y % Theta° y% Theta° y % 012186 5.510 4.2 17.488 24.7 25.257 52.6 31.939 28.9 6.143 4.4 18.601 76.6 25.885 19.4 32.689 14.9 7.860 63.2 18.964 32.9 26.283 22.0 33.228 13.6 8.141 13.2 19.230 16.8 26.634 28.5 33.880 16.4 9.774 8.0 19.727 51.4 27.085 17.6 34.867 15.1 10.290 12.0 20.121 29.0 27.309 20.8 35.627 16.9 11.076 6.9 20.440 10.1 27.574 28.7 36.765 14.7 11.262 6.3 20.859 14.5 27.904 19.1 37.551 19.7 12.133 24.3 21.261 19.4 28.165 14.3 38.576 20.2 12.510 7.5 21.730 100.0 28.891 19.3 39.190 23.3 12.860 14.2 22.310 39.0 29.226 15.1 40.302 16.8 13.690 37.3 22.830 72.0 29.792 30.7 40.824 16.8 14.446 8.5 23.102 27.7 30.101 19.7 41.643 15.1 15.008 35.4 23.598 75.9 30.287 15.7 42.238 16.6 15.794 32.6 23.884 24.7 30.604 17.0 42.971 19.4 16.274 27.9 24.479 50.5 30.771 16.9 44.714 16.4 16.781 14.6 24.777 21.2 30.995 11.5 16.940 10.7 25.093 59.3 31.590 22.4

Form E

Angle 2-Theta 0 intensity % Angle 2-Theta 0 Intensity % Angle 2-Theta 0 Intensit y% Angle 2-Theta 0 intensit y% 8.416 6.3 18.028 12,3. 23.852 100.0 32.434 14.8 8.506 3.9 18.387 6.4 24.075 18.0 32.760 25.6 9.675 23.0 18.787 17.0 24.192 18.9 34.083 8.6 11.994 15 7 19.315 38.5 24.696 10.7 34.462 7.8 ..J2.193L. ... 13.7 . . 19...35.8. . . 42.2..... .2 5.28,0... 282... 34.927 5.6. 13.116 8.2 19.444 31.1 25.765 11.1 35.552 7.1 13.952 16.4 19.778 26.6 26.061 12.1 36.390 7.2 14.064 17.2 20.056 6.9 26.746 8.5 36.954 6.3 15.978 5.8 20.398 3.5 27.269 10.6 37.993 7.1 16.096 3.7 21.522 7.5 28.860 13.0 39.826 4.7 16.218 3.6 21 770 7.7 29.534 5.3 40.699 8.4 16.914 30.8 22 479 8.2 29.642 7.9 42.316 7.0 37.042 13.4 22 974 5.0 31 094 4.3 43.410 7.0 17.596 10.3 23.509 7.0 31.652 4.0 5 Mesylate sait

PCS 14 012186

Angle2-Theta ° Intensity % Angle2-Theta 0 Intensity % Angle2-Theta 0 Intensity % Angle2-Theta 0 Intensity % 7.392 22.9 19.297 57.9 26.55 16.8 34.607 6.7 7.56 12.1 20.265 51 26.818 15.3 35.031 8.4 9.129 18.4 20.494 7.3 27.012 30.3 35.834 9.6 10.179 11 20.772 13.8 27.675 15.9 36.125 9.2 11.871 17.8 21.018 15.1 28.673 22.3 36.418 9.3 12.343 7.6 21.414 40 28.904 16.3 37.675 10 13.057 18.6 22.136 24 29.305 24.6 38.92 6.3 14.5 11.1 22.804 16.7 29.627 9.1 40.614 5.9 14.733 22.6 22.934 32.8 29.93 9.3 41.061 8.8 14.813 40.1 23.283 8.7 30.327 14.9 41.65 13.3 15.162 5.4 23.842 49.4 30.663 16.8 42.03 10.4 17.155 10.6 24.5 14.4 30.999 16.7 42.65 10.1 17.694 31 24.795 100 31.297 12.8 42.878 8.9 18.358 6.5 25.452 7.6 31.841 6 44.003 7.7 18.602 6.1 26.201 5.2 32.844 16 5 44.817 9.3 18.964 40.5

Differential scanning calorimetry (DSC) was performed using a Perkin Elmer DSC-7machine fitted with an automatic sample changer. Approximately 2mg of each sample 5 was accurately weighed into a 50 microlitre aluminium pan and crimp sealed with aperforated iid. The samples were heatéd at 20°C/minute over the range 40°C to 300°Cwith a nitrogen gas purge. The thermal events are summarised in Table 6, and may beused to characterize the free base forms and mesylate sait. 10 Table 6

Thermal Events for Forms A, B, C, E and the mesylate sait

Form Melting point (°C) Form A 198 Form B 218 Form C 147 Foim E 229 Mesylate 279 PC · , «· 012186 15

The water content of the hydrated form of the free base (Form D) at ambient conditionsis commonly of the order of 9 to 10% (w/w). This is équivalent to 2.5 to 2.8 moles ofwater per mole of the free base. The water content at 90% RH was found to be 12.8%(w/w), this is équivalent to 3.6 moles of water, only 2 moles of which were found torepresent bound water. The first mole was lost below 5% RH the second retained downto 1% RH see figure 11. It is likely that extended storage of the hydrated form belowabout 18% RH would resuit in déhydration. Furthermore, removal of the crystallinewater results in the loss of the crystal lattice, the product being predominantlyamorphous. This highlights a potential problem in using the conventional hydratedform in manufacturing a pharmaceutical formulation. Déhydration was observed onthermal analysis as a broad double endotherm at 97/113°C (See Figure 8)

The présent invention is also illustrated by the following drawings in which:

Figure 1 shows the PXRD for the mesylate sait;

Figure 2 shows the DSC thermogram for the mesylate sait;

Figure 3 shows the PXRD for ail the free base forms A, B, C, D and E,

Figure 4 shows the DSC thermogram for Form A;

Figure 5 shows the DSC thermogram for Form B;

Figure 6 shows the DSC thermogram for Form C;

Figure 7 shows the DSC thermogram for Form E;

Figure 8 shows the DSC thermogram for form D;

Figure 9 shows the moisture sorption of the mesylate sait;

Figure 10 shows the moisture sorption of Forms A, B and E, andFigure 11 shows the moisture sorption of Form D.

The invention is illustrated by the Examples below, in which the followingabbreviations may be used: min

NMR h minute nuclear magnetic îesonancehour PC.S K 8-‘ 16 012186

Example 1

Free Base Polymorphs of 4-Amino-6,7-dimethoxv-2-(5-inethanesulfonamido- l,2,3,4-tetrahvdro-2-isoquinolyl)-5-(2-pvridvl)qiiinazoline

(i) Form A

Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2-pyridyl)quinazoline [see WO 98/30560, Example 12(a), 97g, 0.31mol] and 7/-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride [see WO 98/30560,Example 19(b), 89g, 0.34mol] in n-butanol (1.91) was added triethylamine (161ml,1.16mol). The reaction was warmed to reflux and stirred at reflux overnight. Thereaction mixture was cooled to room température, concentrated in vacuo and the residueslurried in water (1.51) and sodium hydrogen carbonate (15g) added. The resultingslurry was stirred over 3 nights, filtered, the solid washed with water (500ml) and driedovernight in vacuo at 50°C to give 158g of material.

The majority of the material (156g) was combined with a further portion of material(139g) prepared using a similar method and the combined solids were dissolved inmethanol (31) The solution was filtered, concentrated in vacuo and the resulting soliddried overnight in vacuo at 50°C to give 287g of material.

The majority of the material (285g) was slurried overnight in acetone/water (4/1 byvolume, 1.41), filtered, the solid was washed with acetone/water 4/1 (300ml) and driedover 3 nights in vacuo at 50°C to give 251g of material.

The majority of the material was sieved through a 500μΜ sieve to afford the titlecompound (242g).

(ii) Form B

Under nitrogen, to a stiried suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2-pyridyl)quinazoline (166g, 0 53mol) and 7/-(1,2,3,4-tetrahydro-5-isoquinolyl)-methanesulfonamide hydrochloride (152g, 0.58mol) in n-butanol (2.01) was added 17 012186 triethylamine (161ml, l.lômol) and further n-butanol (1.31). The reaction was warmedto reflux and stirred at this température for llh. The reaction mixture was cooled toroom température, concentrated in vacuo and the residue slurried in water (2.651) andsodium hydrogen carbonate (28.5g) added. The resulting slurry was stirred overnight,filtered and the solid washed with water (500ml). The resulting damp solid was addedto methanol (4 l) and the resulting suspension concentrated in vacuo until a thicksuspension was obtained. Further methanol (150 ml) was added, and resulting slurryfiltered and washed with methanol (3 x 50 ml). The resulting solid was dried over 3nights in vacuo at 41°C. The dried solid was then slurried overnight in acetone/water(1/4 by volume, 1250ml), filtered, the solid washed with acetone/water 1/4 (3 x 50ml)and dried over 2 nights in vacuo at 54°C to afford the title compound (245g).

(iii) Form C

To a mixture of 4-amino-2-(5-methanesulfonamido-l,2,3,4-tetrahydro-2-isoquinolyl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline (0.1g of a batch of approximately 90% purity, aForm D/amorphous mixture, 1.7mmol) and adipic acid (0.027g, l.Smmol) was addedacetone (1.25ml) and the resulting suspension stirred at room température over 3 nightsThe resulting suspension was filtered and dried overnight in vacuo at 48°C to afford aquantity of the title compound.

(iv) Form E

Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2-pyridyl)quinazoline (105g, O.33rnol) in n-butanol (2.11) was added /7-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonainide hydrochloride (152g, 0.37mol) andtriethylamine (106ml, 0.73mol) The reaction was warmed to reflux and stirred at refluxfor 6h, cooled to room température and stirred overnight at room température. Themixture was then returned to reflux, stirred at reflux for 6h and cooled to roomtempérature and stirred at room température overnight. The reaction mixture was thenconcentrated in vacuo and the residue slurried in water (1 681) and sodium hydrogencarbonate (17.9g) added. The resulting slurry was stirred overnight, filtered, and thedamp solid was added to acetonitrile ( 1.161) The resulting slurry was heated to reflux,then allowed to cool to room température and stirred at room température overnight. 18 012186

The resulting slurry was filtered and washed with acetonitrile (2 x 100ml). The dampsolid was slurried in acetone/water (1/4 by volume, 800ml) overnight at roomtempérature, filtered, the solid washed with acetone/water 1/4 (2 x 50ml) and driedovernight in vacuo at 45°C to give 158g of material.

The majority of the material obtained from the above préparation (155g) was combinedwith further portions of material (596g) prepared in a similar manner and suspended inacetonitrile (5.281). The suspension was warmed to reflux, stirred at reflux for 90 min,cooled to room température and stirred al room température overnight. The solid wascollected by filtration, washed with acetonitrile (100 ml) and dried overnight in vacuo at50°C to give the title compound (734g).

Example 2 4-Amino-6,7-dimethoxv-2-(5-methanesulfonain»do-l,2,3,4-tetrahydroisoquinol-2- yl)- 5-(2-pvridvl)quinazoline mesylate (i) The sait formation process described below was used to process Form B freebase to the methanesulfonate sait.

Under nitrogen, a suspension of Form B 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol~2-yl)-5-(2-pyridyl)quinazoline (2.0g)in butanone/water (10/1 by volume, 24ml) was heated to reflux over 20mins.Butanone/water 10/1 was added until a solution was achieved (an extra 3nrl was added,bringing the total solvent volume to 27ml). The solution was left to cool to 50°C andmethanesulfonic acid (0.38g, 4.0mmol) was added dropwise over 30 seconds. Theaddition vessel was washed with butanone/water 10/1 (2 x 0 25ml) and the washingswere added to the reaction vessel The resulting suspension was left to cool to roomtempérature and then stirred at this température for 2h. The solid was collected byfiltration, washed with acetone (2 x 2ml), left to pull dry for 30min and dried overnightin vacuo at 54°C to afford the title compound (2.2g) as a white solid 19 012186 'H-NMR (300 MHz, DMSO) δ : 2.30 (3H, s), 2.99 (3H, s), 3.04 (2H, m), 3.44 (3H, s),3.93 (2H, m), 4.01 (3H, s), 4.91 (2H, s), 7.15 (1H, d), 7.28 (2H, m), 7.44 (1H, s), 7.57(2H, m), 8.02 (1H, m), 8 77 (1H, m), 9.19 (1H, s). 5 (ii) The following préparation was used to process Form E free base to themethanesulfonate sait. A suspension of Form E 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydro-2-isoquinolyl)-5-(2-pyridyl)quinazoline (1.0g, 1.97 mmol) in acetone/water 10 (12/7 by volume, 9.5ml) was heated to reflux. Methanesulfonic acid (0.19g, 1.99 mmol) was added in one portion. The addition vessel was washed with water (1ml) andthe resulting solution left to cool to room température overnight. The solid from theresulting suspension was collected by filtration and dried overnight in vacuo at 45°C toafford the title compound (1 14g) as a while solid. 15

Example 3In vivo activitv

The daiiy oral administration of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 20 l,2,3,4-tetrahydroisoquinol-2-yî)-5-(2-pyridyl)quinazoline mesylate to male and femaleSprague-Dawley rats at 30 mg/kg for 1 month induced changes linked to thepharmacological activity of the compound: however, there was no evidence of adverseeffects.

Claims (8)

1. 20 012188 Claims: 1. 4-Amino-6,7-dimethoxy-2-(5-methanesuÎfonamido- J ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate of the formula
2. 2. The mesylate sait as clairned in claim 1, characterised in that it exhibits anendothermie thermal event at about 279°C during differential scanning calorimetry. 3 The mesylate sait as clairned in claim 1 or claim 2, characterised by a powder X- ray diffraction pattern obtained by irradiation with copper K-alphai X-rays of10 waveiength 1.5406Â, having the foliowing main peaks: A ngk 2-Theta 0 Intensity % 7 392 22.9 14.733 22.6 14.813 40.1 17.694 31 18.964 40.5 19 297 57.9 20.265 51 21.414 40 22.136 24 22.934 32.8 23.842 49.4 24.795 100 27.012 30 3 28.673 22.3 29.305 24.6 4 An anhydrous crystalline free base form of 4-amino-6,7-dimethoxy-2-(5methanesulÎQnamido-l,2.3,4-tetrahydroisoquinol-2~yl)-5-(2-pyridyl)quinazo]Îne PCS lt 21 012186 (designated Form E), a sample of which cùntaïns more than 90% of a singlepolymorphie form, cbaracterised in that it exhibits both an endothermie thermal event atabout 229°C and a powder X-ray diffraction pattern obtained by irradiation with copperK-aiphai X-rays of wavelength 1.5406Â having the following main peaks. Angle 2-Theta 0 ïntensity % 9 675 23 0 16.914 30.8 19.315 38.5 19.358 42.2 19.444 31.1 19.778 26.6 23.852 100.0 25.280 28.2 1 32.760 25.6
3. 5. The free base form as claimed in claim 4, characterized in that a sample of itcontains more than 99% of a single polymorphie form. 6 A pharmaceutical formulation containing 4-amino-6,7-dimethoxy-2-(5-inethanesulfonamido-1,2,3,4-tetrahydroisoquinoi-2-yl)~5-(2-pyridyl)quinazoline in the 10 form of the anhydrous free base or the mesylate sait, as defined in any one of claims 1to 5, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier7. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)~5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylatesait, as defined in any one of claims 1 to 5, for use as a pharmaceutical.
4. 8. The use of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous freebase or the mesylate sait, as defined in any one of claims 1 to 5, in the manufacture of amédicament for the treatment of benign prostatic hyperplasia. ’ 20
5. 9. A process for the préparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline 25 PCS 1 22 017188 mesylate, as defined in claim 1, which comprises the addition of methanesulphonic acidto a suspension or solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formula NHSO,CH CH,O CH 5 in a suitable solvent, and collection of the precipitated solid. 1θ· A process as claimed in claim 9, wherein the solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido~ 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline is maintained at a température above rooin température before the additionof the methanesulphonic acid. 10 11. A process as claimed in claim 9 or claim jq, wherein the solvent used is a mixture of butanone and water
6. 12. A process as claimed in any one of daims 9, 10 and 11 , wherein the solvent isa 10:1 by volume mixture of butanone and water.
7. 13. A process as claimed in claim 11 or claim 12, comprising the steps of 15 (a) heating a suspension of 4~amino-6,7-dimethoxy-2-(5-rnethanesulfonamido- l,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux; (b) adding butanone/water until a solution is achieved; (c) cooling the solution, (d) adding methanesulfonic acid; and 20 (e) collecting the resulting solid by filtration.
8. 14. A process as claimed in any one of daims 9to 13 wherein the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-y 1)-5-(2-pyridyl)quinazoline is présent as Form E, as defined in. claim 4 or claim 5