Salt form and polymorphs

NEW SALT FORM 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-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

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-tetrahydroisoquinol-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-yl)-5-(2-pyridyl)quinazoline having the formula

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

Hygroscopicity %

Form

Melting Point (° C.)

Crystallinity

(w/w) at 90% RH

Mesylate Salt

279

Crystalline

1.1

TABLE 2

Solubility of the mesylate salt and free base forms (micrograms/ml)

Hydrated form

Free base (mpt

of free

Solvent

198° C.)

base

Mesylate salt

Water at 22° C.

420

12

880

0.9% sodium chloride at

36

4

120

22° C.

TABLE 3

Hygroscopity of the mesylate salt and free base forms

Moisture sorption (% w/w)

Form

at 30° C. and 45% RH

Free base (mpt 198° C.)

1.39

Hydrated form of free base

11.24

Mesylate salt (mpt 279° C.)

0.56

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)-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.

TABLE 4

Polymorphic forms of the free base

Hygroscopity

Form

Melting point (° C.)

Crystallinity

% (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

Form D

None

crystalline

12.8

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-yl)-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-(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-yl)-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-yl)-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 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, 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-tetrahydroisoquinol-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-(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, intrastemally, 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 10 mg/kg (in single or divided doses) and preferably about 0.01 to 0.5 mg/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 0.1 mg to 500 mg 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 scope of this invention.

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 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 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 (HEFA 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 20 μg to 4 mg 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 for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 μg to 20 mg 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-tetrahydroisoquinol-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.

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 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

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 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;

(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-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-α 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-yl)-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-α reductase inhibitory compound as a combined preparation 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 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.

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 12 mm diameter, 0.25 mm deep cavities that had been cut into silicon wafer specimen mounts. Each specimen was rotated whilst being irradiated with copper K-alpha

1

X-rays (wavelength=1.5406 Angstroms) with the X-ray tube operated at 40 kV/40 mA. 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 (I/I

i

). 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 5

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

Angle 2-

Intensity

Angle 2-

Intensity

Angle 2-

Intensity

Angle 2-

Intensity

Theta °

%

Theta °

%

Theta °

%

Theta °

%

Form A

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

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

22.551

72.7

28.945

9.5

37.331

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

19.9

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

17.0

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

12.9

34.045

9.5

Form C

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

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

12.393

13.7

19.358

42.2

25.280

28.2

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

17.042

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

Mesylate salt

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-7 machine fitted with an automatic sample changer. Approximately 2 mg 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. 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 salt.

TABLE 6

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

Form

Melting point (° C.)

Form A

198

Form B

218

Form C

147

Form E

229

Mesylate

279

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 FIG.

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 FIG.

8

)

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

FIG. 1

shows the PXRD for the mesylate salt;

FIG. 2

shows the DSC thermogram for the mesylate salt;

FIG. 3

shows the PXRD for all the free base forms A, B, C, D and E;

FIG. 4

shows the DSC thermogram for Form A;

FIG. 5

shows the DSC thermogram for Form B;

FIG. 6

shows the DSC thermogram for Form C;

FIG. 7

shows the DSC thermogram for Form E;

FIG. 8

shows the DSC thermogram for form D;

FIG. 9

shows the moisture sorption of the mesylate salt;

FIG. 10

shows the moisture sorption of Forms A, B and E; and

FIG. 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

Example 1

Free Base Polymorphs of 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydro-2-isoguinolyl)-5-(2-pyridyl)quinazoline

(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), 97 g, 0.31 mol] and N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride [see WO 98/30560, Example 19(b), 89 g, 0.34 mol] in n-butanol (1.91) was added triethylamine (161 ml, 1.16 mol). 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 (15 g) added. The resulting slurry was stirred over 3 nights, filtered, the solid washed with water (500 ml) and dried overnight in vacuo at 50° C. to give 158 g of material.

The majority of the material (156 g) was combined with a further portion of material (139 g) 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 287 g of material.

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

The majority of the material was sieved through a 500 μM sieve to afford the title compound (242 g).

(ii) Form B

Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2-pyridyl)quinazoline (166 g, 0.53 mol) and N-(1,2,3,4-tetrahydro-5-isoquinolyl)-methanesulfonamide hydrochloride (152 g, 0.58 mol) in n-butanol (2.01) was added triethylamine (161 ml, 1.16 mol) and further n-butanol (1.31). The reaction was warmed to reflux and stirred at this temperature for 11 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue slurried in water (2.651) and sodium hydrogen carbonate (28.5 g) added. The resulting slurry was stirred overnight, filtered and the solid washed with water (500 ml). 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 (3×50 ml). The resulting solid was dried over 3 nights in vacuo at 41° C. The dried solid was then slurried overnight in acetone/water (¼ by volume, 1250 ml), filtered, the solid washed with acetone/water ¼ (3×50 ml) and dried over 2 nights in vacuo at 54° C. to afford the title compound (245 g).

(iii) Form C

To a mixture of 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydro-2-isoquinolyl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline (0.1 g of a batch of approximately 90% purity, a Form D/amorphous mixture, 1.7 mmol) and adipic acid (0.027 g, 1.8 mmol) was added acetone (1.25 ml) 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) Form E

Under nitrogen, to a stirred suspension of 4-amino-2-chloro-6,7-dimethoxy-5-(2-pyridyl)quinazoline (105 g, 0.33 mol) in n-butanol (2.11) was added N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride (152 g, 0.37 mol) and triethylamine (106 ml, 0.73 mol). The reaction was warmed to reflux and stirred at reflux for 6 h, cooled to room temperature and stirred overnight at room temperature. The mixture was then returned to reflux, stirred at reflux for 6 h 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 (17.9 g) 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 (2×100 ml). The damp solid was slurried in acetone/water (¼ by volume, 800 ml) overnight at room temperature, filtered, the solid washed with acetone/water ¼ (2×50 ml) and dried overnight in vacuo at 45° C. to give 158 g of material.

The majority of the material obtained from the above preparation (155 g) was combined with further portions of material (596 g) 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 (734 g).

Example 2

4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-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 (2.0 g) in butanone/water (10/1 by volume, 24 ml) was heated to reflux over 20 mins. Butanone/water 10/1 was added until a solution was achieved (an extra 3 ml was added, bringing the total solvent volume to 27 ml). The solution was left to cool to 50° C. and methanesulfonic acid (0.38 g, 4.0 mmol) was added dropwise over 30 seconds. The addition vessel was washed with butanone/water 10/1 (2×0.25 ml) 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 2 h. The solid was collected by filtration, washed with acetone (2×2 ml), left to pull dry for 30 min and dried overnight in vacuo at 54° C. to afford the title compound (2.2 g) as a white solid.

1

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).

(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 (1.0 g, 1.97 mmol) in acetone/water (12/7 by volume, 9.5 ml) was heated to reflux. Methanesulfonic acid (0.19 g, 1.99 mmol) was added in one portion. The addition vessel was washed with water (1 ml) 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 (1.14 g) as a white solid.

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 pharmacological activity of the compound: however, there was no evidence of adverse effects.

Number	Date	Country	Kind
0005200	Mar 2000	GB
0015900	Jun 2000	GB

Number	Date	Country
WO8801998	Mar 1988	WO
WO9830560	Jul 1998	WO

	Number	Date	Country
	60/192912	Mar 2000	US
	60/218188	Jul 2000	US

Salt form and polymorphs

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Date Filed

Date Issued

Inventors

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Examiners

Agents

CPC

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US

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Abstract

Description

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Priority Claims (2)

CROSS-REFERENCE TO RELATED APPLICATIONS

US Referenced Citations (1)

Foreign Referenced Citations (2)

Non-Patent Literature Citations (1)

Provisional Applications (2)