ZA200207016B - 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylat and polymorphs. - Google Patents
4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylat and polymorphs. Download PDFInfo
- Publication number
- ZA200207016B ZA200207016B ZA200207016A ZA200207016A ZA200207016B ZA 200207016 B ZA200207016 B ZA 200207016B ZA 200207016 A ZA200207016 A ZA 200207016A ZA 200207016 A ZA200207016 A ZA 200207016A ZA 200207016 B ZA200207016 B ZA 200207016B
- Authority
- ZA
- South Africa
- Prior art keywords
- dimethoxy
- quinazoline
- pyridyl
- amino
- methanesulfonamido
- Prior art date
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- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
4-AMINO-6, 7-DIMETHOXY-2- {5-METHANESULFONAMIDO-1,2, 3, 4~-TETRAHYDROISOQUINOL-Z-¥L) -5- 2-PYRIDYL) QUINAZOLINE MESYLAT AND POLYMORPHS . The present invention relates to a novel salt useful in therapy. More specifically the present invention relates to 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4- % J ; 5 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, to processes for its preparation, to its uses, and to compositions containing it. The present invention also relates to novel non-hydrated polymorphs of the free base. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5- (2-pyridyl)quinazoline has the formula
NHSO,CH,
Hy N ~N
CH,0
NZ | NH
NS and is disclosed in WO 98/30560 (see Example 19) as being useful in the treatment of benign prostatic hyperplasia. The application refers in general terms to pharmaceutically acceptable salts and mentions the hydrochloride, hydrobromide and phosphate salts.
Unfortunately, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydro- isoquinol-2-yl)-5-(2-pyridyl)quinazoline displays some disadvantageous physical properties. It is now known to occur in a number of different forms. In some cases, its aqueous solubility is rather low and it is difficult to prepare reproducibly in the same form, sometimes being obtained in a hydrated form. In addition, it has been found that ’ some forms of the free base are rather hygroscopic. These properties are } disadvantageous for the development of a drug substance because, in particular, a consistent grade of material must be reproducibly manufactured in order to satisfy regulatory requirements.
There is now provided the mesylate salt of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl1)-5-(2-pyridyl)quinazoline having . the formula
NHSO,CH, y
CH,0 ges _N
CH,0 .CH,SO,H > NH, “
This substance has a number of unexpected advantages over the free base and it has surprisingly been found to have a unique combination of properties which make it ideal for development as a drug substance.
Those skilled in the art will appreciate that “mesylate” is an alternative term for “methanesulfonate”.
The mesylate salt has a high melting point, and is a crystalline solid which does not display any hydrated or solvated forms. It is isomorphic, i.e. it exists in a single polymorphic form, and exhibits good stability over a wide range of conditions, e.g. high light intensity. It has acceptable solubility and dissolution characteristics, and can be economically prepared and processed to provide suitable solid dosage forms of the drug.
Its hygroscopicity is substantially lower than the free base (tested as its 198°C melting point polymorph) over a wide range of relative humidity. The mesylate salt is mono- morphic and does not form hydrates; both of these features represent advantageous properties of the mesylate salt in particular.
Tables 1 to 3 below indicate the physical properties of 4-amino-6,7-dimethoxy-2-(5- ) methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate and some free base forms.
Table 1
Physical properties of the mesylate salt
Form Melting Point (°C) Crystallinity | Hygroscopicity %
E (w/w) at 90% RH
Table2
Solubility of the mesylate salt and free base forms (micrograms/ml)
Solvent Free base (mpt | Hydrated form of free | Mesylate salt 198°C) base 0.9% sodium chloride at 36 4 120 22°C
Table3
Hygroscopity of the mesylate salt and free base forms
Moisture sorption (% w/w) at 30°C and 45% RH
Hydrated form of free base 11.24 0.56
Mesylate salt (mpt 279°C)
The present invention also includes the substantially pure anhydrous crystalline forms of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-
R 5-(2-pyridyl)quinazoline (the free base). These anhydrous polymorphs are designated
Form A, Form B, Form C, and Form E in Table 4 below. Form D, which is presented : for comparison, is the hydrated form and exists as a dihydrate.
The term “substantially pure” used above means that a sample of the relevant anhydrous crystalline form contains more than 90% of a single polymorphic form, preferably more . than 99% of a single polymorphic form. . 5 Table4
Polymorphic forms of the free base
Melting point (°C) | Crystallinity Hygroscopity ee
Lc I al CA ce
On dehydration, the hydrated form (Form D) becomes amorphous.
The anhydrous polymorphic forms of the invention are also significantly less hygroscopic than the hydrated free base form. Of these, Forms B and E are preferred on account of their high melting points and low hygroscopicity. Form E is most preferred.
It is now believed that the solid form of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline produced originally following the procedure of WO 98/30560 (see Example 19) was a mixture of Forms B and E, probably in the ratio 1:1 (based on a differential scanning calorimetry experiment showing sharp endotherms at 220 and 227°C). Following the creation of the most stable Form E in pure form, it is likely that this form will be produced predominantly in the future when repeating the above preparation of 4-amino- 6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline.
Also included within the scope of the present invention are radiolabelled derivatives, other isotopic forms and tautomers of 4-amino-6,7-dimethoxy-2-(5-
methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-y1)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5- ’ 5 (2-pyridyl)quinazoline in one of its free base polymorphic forms or as the mesylate salt possesses pharmacological activity in animals. It may be used in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of 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 mesylate salt to a patient suffering from such a disorder.
According to a further aspect of the invention, there is provided 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 mesylate salt for use as a pharmaceutical; 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-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl1)-5-(2-pyridyl)- quinazoline in the form of the anhydrous free base or the mesylate salt in the manufacture of a medicament for the treatment of benign prostatic hyperplasia. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-y1)-5- (2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of i 30 administration and standard pharmaceutical practice.
Hence, according to a further aspect of the invention, there is provided a pharmaceutical formulation including 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 mesylate salt in admixture with a pharmaceutically acceptable adjuvant, : 5 diluent or carrier. The formulation will preferably contain less than 50% by weight of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5- (2-pyridyl)quinazoline in a free base polymorphic form or as the mesylate salt.
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 the anhydrous free base or the mesylate salt can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications. Oral administration is of particular interest. 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 mesylate salt may also be administered via intracavernosal injection.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
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 high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, 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 mesylate salt may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5- - 5 (2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally., intracranially, intramuscularly or subcutaneously, or may be administered by infusion techniques. It is best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of 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 mesylate salt will usually be from about 0.01 to 10mg/kg (in single or divided doses) and preferably about 0.01 to 0.5mg/kg, administered from 1 to 4 times a day.
Thus tablets or capsules of 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 mesylate salt may contain from about 0.1mg to 500mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the ) 30 scope of this invention.
4-Amino-6,7-dimethoxy-2-(3-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5- (2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can i also be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised . 5 container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of 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 mesylate salt and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or “puff” contains from 20pug to 4mg of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-y1)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20ug to 20mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydro- isoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. } 30 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 mesylate salt may also be transdermally administered, for example, by the use of a skin patch. It may also be administered by the ocular route, particularly for treatment of the eye.
For ophthalmic use, it can be formulated as micronised suspensions in isotonic, pH : 5 adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, 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- 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The invention further provides a process for the preparation of 4-amino-6,7-dimethoxy- 2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline mesylate, as defined above, which comprises the addition of methanesulphonic acid to a suspension or solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formula
NHSO,CH, eno 0 . _N
CH,0
SU 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- ‘ 5 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is maintained at a temperature above room temperature before the addition of the methanesulphonic acid; and (b) the solvent used is a mixture of butanone and water, for example a 10:1 by volume 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-dimethoxy-2-(5-methanesulfonamido- 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux; (b) adding butanone/water until a solution is achieved; (©) 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-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is present as Form E, although some of the desired product should result regardless of the starting form.
The formulations of the invention may also contain a human 5-a reductase inhibitory compound [see International Patent Application WO-A-95/28397], or 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl1)-5-(2- pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt could be presented in a pharmaceutical pack also containing a human 5-a reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use. } 30 References herein to treatment include curative, palliative and prophylactic treatment.
The four anhydrous polymorphs of the free base which have been isolated have been designated Forms A, B, C and E. These polymorphic forms were characterised by . powder X-ray diffraction (PXRD), together with the mesylate salt. . 5 The powder X-ray diffraction patterns were determined using a SIEMENS D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The samples were prepared for analysis by packing the powder into 12mm diameter, 0.25mm deep cavities that had been cut into silicon wafer specimen mounts. Each specimen was rotated whilst being irradiated with copper K- alpha, X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 40kV/40mA. The analyses were performed with the goniometer running in step-scan mode set for a 5 second count per 0.02° step over a two theta range of 2° to 55°. The peak intensities are summarised in Table 5. In Table 5, “Angle 2-Theta” is related to the interplanar spacing of the crystal, and the intensity is given as a percentage of the greatest peak (Il). The individual polymorphic forms and the mesylate salt may be characterised by reference to the peak intensities of greater than 50%, and more preferably by the peaks having intensities greater than 20%.
Table$S
Peak listings for Forms A, B, C and E, and the mesylate salt
Form A
Angle2- | Intensity | Angle2- | Intensity | Angle2- | Intensity | Angle2- | Intensity
Theta ° % Theta © % Theta © % Theta © % rr + 1 1 5002 73282 30469 3293 17.040 23.494 9401 | 251 | 1788 9654 | 85 | TBI _| 167 | 242% 33.065 | 116 11.105 18872 EN CAN 12.000 19287 | 189 | 74602 | 196 | 3488 : 12.071 19336 | 160 | 25674 | 301 | 35.58 13.060 33610 13373 20.1% 26600 | 191 | 362% 13458 | 11.6 | 20951 | 153 | 27036 | 118 | 36634 | 124 3620 | 100 | 2101 | 129 | 27641 38335 | 160 13.708 15.5 21.302 28.888 40.198 [3790 | 108 | 21378 | 199 | 29136 | 146 | 40820
14418 _]__109 | 219% 9915 [94] 417% 15.075 22336 30.197 5320 | 61 | ni 028 | 58 [|] ‘ Form B
Angle 2- | Intensity | Angle2- | Intensity | Angle2- | Intensity | Angle2- | Intensity : Theta ° % Theta © % Theta ° % Theta ° %
INS ES A A EA R EE
19559 | 84 | 26512 | 365 | 34214 19867 | 111 [| 26758 | 305 | 34382 9.725 19964 | 61 | 26918 34.602 10.526 20.407 26.989 35.235 [1.315 20.919 27.302 35.449 11.986 21.101 27.800 36.193 | 68 13.011 21.712 27.871 | 116 | 36668 | BI 13.493 22.551 28.945 37.331 13.897 22.769 29.164 37.727 | 84 14.306 22.843 30.027 38.318 15.569 22.926 30.284 38.977 15.883 23418 | 1000 | 31179 | 199 | 39.646 16.740 23.904 31.443 40.165 17.122 23.997 31629 | 87 [| 40911 | 53 25.049 32.121 | 81 [ 42235 | 108 17.603 25.209 32.318 42.761 | 98 18.094 25.462 32.845 44.287 18.727 25700 | 84 | 33.023 44.775 19176 [| 100 | 26205 | 129 [ 34045 | 95 [
Form C
Angle 2- | Intensity | Angle2- | Intensity | Angle2- | Intensity | Angle2- | Intensity
Theta® % Theta® % Theta® % Theta® % rr rr — 1 1 I IT 5510 T7488 T5357 31939 6.143 18.601 75.885 2689 | 149 7.860 18.964 26.283 33.228 (811 137 | 19330 | 168 | 2664 33.380 9774 | 80 | 19.727 27.083 34.867 10290 | 120 | 20021 27.309 35627 | 169 [10% | 69 | 20440 | 101 | 77.57 36.765 11.262 20.859 27904 | 19.1 | 37.551 2.133 21.261 28.165 38.576 12510 21730 | 1000 | 2889] 39.190 12.850 22310 79.2% 20302 | 168 13.690 22.830 297% 2083 | 168 73.102 30.10] 71.643 15.008 23.598 30287 2238 | 166 15.794 23.884 30.604 297 | 194 16274 24.479 077 _| 169 | 44.714 6781 | 146 | 24777 09% | 11s [ 16.940 25.093 ES IE I I I
Form E
Angle 2- | Intensity | Angle2- | Intensity | Angle2- | Intensity | Angle2- | Intensity
Theta © % Theta © % Theta ° % Theta © %
I RE EE EE ER EE DE
: 5418 13.028 25857 | 1000 | 324% | 148] 3506 18387 24075 | 180 | 32760 | 256 9.675 8787 24.197 | 189 | 34.08 | 86 : (1a | 157 | 1935 24.6% 34.462 12.393 19.358 25280 33.927 25765 | ILI | 35.3% 395 | 164 | 19778 | 266 | 2606l 36.39 14064 2005 | 65 | 26.746 36.954 15978 20398 27269 | 106 | 37.993 16.0% 21522 28.860 39.826 16218 21770 29.534 20.699 16914 | _308 | 2247 29.642 17.042 22.974 31.094 17.5% 23.509 en | a0
Mesylate salt
Angle Intensity %| Angle [Intensity %| Angle (Intensity %| Angle [Intensity % 2-Theta °© 2-Theta © 2-Theta ° 2-Theta © “73 | m9 | 7 | 515 | 635 | 168 | 34607 | 67 20263 26318 35.031 5.129 20.45% 27012 3585996 0075 | 1 | 07m 27.673 36.125 1371 21018 28673 36418 12343 241d | @0 | on 37675 | 10] 3.057 | 186 | 213% 25.305 3292 13 [Ta maw 627 | 91 | 4060 4.733 2.9% 93 | 93 | a1061 | 85
T2313 23.283 0337 | 149_| 416
T5162 282 | #94 | 30663 | 168 | 003 | 104 [715 | 108 | 245 | 144 | 309% 4265 101] 17.694 22795 | 100 | 31097 28 | 89
T8338 25452 #6 | #00 8602 | 61 | 26201 2.84 as
B94 | 40s | | | [ . Differential scanning calorimetry (DSC) was performed using a Perkin Elmer DSC-7 machine fitted with an automatic sample changer. Approximately 2mg of each sample was accurately weighed into a 50 microlitre aluminium pan and crimp sealed with a perforated lid. The samples were heated at 20°C/minute over the range 40°C to 300°C t with a nitrogen gas purge. The thermal events are summarised in Table 6, and may be used to characterize the free base forms and mesylate sait.
Table 6 . 5 Thermal Events for Forms A, B, C, E and the mesylate salt
The water content of the hydrated form of the free base (Form D) at ambient conditions is commonly of the order of 9 to 10% (w/w). This is equivalent to 2.5 to 2.8 moles of water per mole of the free base. The water content at 90% RH was found to be 12.8% (w/w), this is equivalent to 3.6 moles of water, only 2 moles of which were found to represent bound water. The first mole was lost below 5% RH the second retained down to 1% RH see figure 11. It is likely that extended storage of the hydrated form below about 18% RH would result in dehydration. Furthermore, removal of the crystalline water results in the loss of the crystal lattice, the product being predominantly amorphous. This highlights a potential problem in using the conventional hydrated form in manufacturing a pharmaceutical formulation. Dehydration was observed on thermal analysis as a broad double endotherm at 97/113°C (See Figure 8)
The present invention is also illustrated by the following drawings in which:
Figure 1 shows the PXRD for the mesylate salt;
Figure 2 shows the DSC thermogram for the mesylate salt;
Figure 3 shows the PXRD for all 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 salt;
Figure 10 shows the moisture sorption of Forms A, B and E; and
Figure 11 shows the moisture sorption of Form D.
The invention is illustrated by the Examples below, in which the following abbreviations may be used: min minute
NMR nuclear magnetic resonance h hour
Examplel
Free Base Polymorphs of 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1,2.3.4-tetrahydro-2-isoquinolyl)-5-(2-pyridvl)quinazoline (i) FormA
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 N-(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. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue slurried in water (1.51) and sodium hydrogen carbonate (15g) added. The resulting slurry was stirred over 3 nights, filtered, the solid washed with water (500ml) and dried overnight 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 in methanol (31). The solution was filtered, concentrated in vacuo and the resulting solid dried 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 by ‘ 5 volume, 1.41), filtered, the solid was washed with acetone/water 4/1 (300ml) and dried over 3 nights in vacuo at 50°C to give 251g of material.
The majority of the material was sieved through a 500uM sieve to afford the title compound (242g). (i) FormB
Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2- pyridyl)quinazoline (166g, 0.53mol) and N-(1,2,3,4-tetrahydro-5-isoquinolyl)- methanesulfonamide hydrochloride (152g, 0.58mol) in n-butanol (2.01) was added triethylamine (161ml, 1.16mol) and further n-butanol (1.31). The reaction was warmed to reflux and stirred at this temperature for 11h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue slurried in water (2.651) and sodium hydrogen carbonate (28.5g) added. The resulting slurry was stirred overnight, filtered and the solid washed with water (500ml). The resulting damp solid was added to methanol (4 1) and the resulting suspension concentrated in vacuo until a thick suspension was obtained. Further methanol (150 ml) was added, and resulting slurry filtered and washed with methanol (3 x 50 ml). The resulting solid was dried over 3 nights 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). (i) FormC
To a mixture of 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydro-2-isoquinolyl)- 6,7-dimethoxy-5-(2-pyridyl)quinazoline (0.1g of a batch of approximately 90% purity, a
Form D/amorphous mixture, 1.7mmol) and adipic acid (0.027g, 1.8mmol) was added acetone (1.25ml) and the resulting suspension stirred at room temperature over 3 nights.
The resulting suspension was filtered and dried overnight in vacuo at 48°C to afford a quantity of the title compound. (iv) FormE
Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2- pyridyl)quinazoline (105g, 0.33mol) in n-butanol (2.11) was added N-(1,2,34- tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride (152g, 0.37mol) and triethylamine (106ml, 0.73mol). The reaction was warmed to reflux and stirred at reflux for 6h, cooled to room temperature and stirred overnight at room temperature. The mixture was then returned to reflux, stirred at reflux for 6h and cooled to room temperature and stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue slurried in water (1.681) and sodium hydrogen carbonate (17.9g) added. The resulting slurry was stirred overnight, filtered, and the damp solid was added to acetonitrile (1.161). The resulting slurry was heated to reflux, then allowed to cool to room temperature and stirred at room temperature overnight.
The resulting slurry was filtered and washed with acetonitrile (2 x 100ml). The damp solid was slurried in acetone/water (1/4 by volume, 800ml) overnight at room temperature, filtered, the solid washed with acetone/water 1/4 (2 x 50ml) and dried overnight in vacuo at 45°C to give 158g of material.
The majority of the material obtained from the above preparation (155g) was combined with further portions of material (596g) prepared in a similar manner and suspended in acetonitrile (5.281). The suspension was warmed to reflux, stirred at reflux for 90 min, cooled to room temperature and stirred at room temperature overnight. The solid was collected by filtration, washed with acetonitrile (100 ml) and dried overnight in vacuo at 50°C to give the title compound (734g).
Example 2 4-Amino-6.7-dimethoxy-2-(5-methanesulfonamido-1.2,3.4-tetrahvdroisoquinol-2- yl) 5-(2-pyridyl)quinazoline mesylate
(i) The salt formation process described below was used to process Form B free base to the methanesulfonate salt.
Under nitrogen, a suspension of Form B 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-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 3ml was added, bringing the total solvent volume to 27ml). The solution was left to cool to 50°C and methanesulfonic acid (0.38g, 4.0mmol) was added dropwise over 30 seconds. The addition vessel was washed with butanone/water 10/1 (2 x 0.25ml) and the washings were added to the reaction vessel. The resulting suspension was left to cool to room temperature and then stirred at this temperature for 2h. The solid was collected by filtration, washed with acetone (2 x 2ml), left to pull dry for 30min and dried overnight in vacuo at 54°C to afford the title compound (2.2g) as a white solid. 'H-NMR (300 MHz, DMSO) 5 : 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). (ii) The following preparation was used to process Form E free base to the methanesulfonate salt.
A suspension of Form E 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4- tetrahydro-2-isoquinolyl)-5-(2-pyridyl)quinazoline (1.0g, 1.97 mmol) in acetone/water (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) and the resulting solution left to cool to room temperature overnight. The solid from the resulting suspension was collected by filtration and dried overnight in vacuo at 45°C to afford the title compound (1.14g) as a white solid. ) 30
Example 3
In vivo activity
The daily oral administration of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate to male and female
Sprague-Dawley rats at 30 mg/kg for 1 month induced changes linked to the : 5 pharmacological activity of the compound: however, there was no evidence of adverse effects.
Claims (1)
- Claims:1. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol- 2-yl)-5-(2-pyridyl)quinazoline mesylate of the formula . NHSO,CH, CH,0 N 0 Nr ~N CH,0 .CH,SO,H NH, NZ Xn2. The mesylate salt as claimed in claim 1, characterised in that it exhibits an endothermic thermal event at about 279°C during differential scanning calorimetry.3. The mesylate salt as claimed in claim 1 or claim 2, characterised by a powder X- ray diffraction pattern obtained by irradiation with copper K-alpha; X-rays of wavelength 1.54064, having the following main peaks: Angle 2- Intensity % Theta ° sa | 494 24795 | 100 4, A substantially pure anhydrous crystalline free base form of 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl1)-5-(2- pyridyl)quinazoline.5. A free base form as claimed in claim 4, characterised in that it exhibits an endothermic thermal event at about 198°C during differential scanning calorimetry (designated Form A).6. A free base form as claimed in claim 4 or claim 5, characterised by a powder X- ray diffraction pattern obtained by irradiation with copper K-alpha; X-rays of wavelength 1.54064, having the following main peaks: Angle 2-Theta ° a0 | 25112.000 100.013.06018.87221.92522.82173.28223.88427.64130.28235.1587. A free base form as claimed in claim 4, characterised in that it exhibits an endothermic thermal event at about 218°C during differential scanning calorimetry (designated Form B).8. A free base form as claimed in claim 4 or claim 7, characterised by a powder X- ray diffraction pattern obtained by irradiation with copper K-alpha; X-rays of wavelength 1.54064, having the following main peaks: Angle 3-Theta ® 9725 loss | 40713.49313.89715.369 : 15.88318.727 2040723418 | 10009. A free base form as claimed in claim 4, characterised in that it exhibits an endothermic thermal event at about 147°C during differential scanning calorimetry (designated Form C).10. A free base form as claimed in claim 4 or claim 9, characterised by a powder X- ray diffraction pattern obtained by irradiation with copper K-alpha, X-rays of wavelength 1.54064, having the following main peaks: Angle Intensity % ae 23310 | 39011. A free base form as claimed in claim 4, characterised in that it exhibits an endothermic thermal event at about 229°C (designated Form E).12. A free base form as claimed in claim 4 or claim 11, characterised by a powder X-ray diffraction pattern obtained by irradiation with copper K-alpha; X-rays of : 5 wavelength 1.54064, having the following main peaks: ss [100013. A pharmaceutical formulation containing 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 mesylate salt, as defined in any one of claims 1 to 12, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.14. 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 mesylate salt, as defined in any one of claims 1 to 12, for use as a pharmaceutical.15. The use of 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 mesylate salt, as defined in any one of claims 1 to 12, in the manufacture of a medicament for the treatment of benign prostatic hyperplasia.16. A method of treatment of benign prostatic hyperplasia, which comprises administering a therapeutically effective amount of 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 mesylate salt, as defined in any one of claims 1 to 12, to a patient suffering from such a disorder.17. A process for the preparation of 4-amino-6,7-dimethoxy-2-(5- methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline mesylate, as defined in claim 1, which comprises the addition of methanesulphonic acid to a suspension or solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formulaNHSO,CH, CH,0 JC __N CH,0 NF NH, “ in a suitable solvent, and collection of the precipitated solid.18. A process as claimed in claim 17, 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 temperature above room temperature before the addition of the methanesulphonic acid.19. A process as claimed in claim 17 or claim 18, wherein the solvent used is a mixture of butanone and water.20. A process as claimed in any one of claims 17, 18 and 19, wherein the solvent is a 10:1 by volume mixture of butanone and water.21. A process as claimed in claim 19 or claim 20, comprising the steps of: (2) heating a suspension of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido- 1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux; (b) adding butanone/water until a solution is achieved; (co) cooling the solution; (d adding methanesulfonic acid; and (e) collecting the resulting solid by filtration.22. A process as claimed in any one of claims 17 to 21, wherein the 4-amino-6,7- dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2- pyridyl)quinazoline is present as Form E, as defined in claim 11 or claim 12.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0005200A GB0005200D0 (en) | 2000-03-03 | 2000-03-03 | New salt form |
Publications (1)
Publication Number | Publication Date |
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ZA200207016B true ZA200207016B (en) | 2003-09-02 |
Family
ID=9886942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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ZA200207016A ZA200207016B (en) | 2000-03-03 | 2002-09-02 | 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylat and polymorphs. |
Country Status (4)
Country | Link |
---|---|
GB (1) | GB0005200D0 (en) |
GT (1) | GT200100032A (en) |
PA (1) | PA8513001A1 (en) |
ZA (1) | ZA200207016B (en) |
-
2000
- 2000-03-03 GB GB0005200A patent/GB0005200D0/en not_active Ceased
-
2001
- 2001-02-28 GT GT200100032A patent/GT200100032A/en unknown
- 2001-03-02 PA PA8513001A patent/PA8513001A1/en unknown
-
2002
- 2002-09-02 ZA ZA200207016A patent/ZA200207016B/en unknown
Also Published As
Publication number | Publication date |
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PA8513001A1 (en) | 2002-02-21 |
GT200100032A (en) | 2001-10-19 |
GB0005200D0 (en) | 2000-04-26 |
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