N-[5-(Aminosulfony1)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate

1. A crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate having a purity above 96 weight-%.

2. A process for preparing the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 1 , comprising

step A:

reacting a compound of formula A*

wherein

R 1 represents a leaving group and

R 2 represents an alkyl residue with 1 to 6 carbon atoms or a cycloalkyl residue with 3 to 6 carbon atoms

with a boronic acid compound, borolane, borinane or diboronic acid reagent under elimination of R 1 —H or R 1 —B(OR) 2 and formation of an intermediate boronic acid compound of compound A,

wherein the intermediate boronic acid compound is then reacted with a pyridine compound of formula B*

wherein

R 3 represents a leaving group

under basic conditions in order to directly obtain (4-pyridin-2-ylphenyl)acetic acid which is then purified

step B:

reacting the obtained (4-pyridin-2-ylphenyl)acetic acid with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide

to obtain N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide of the following formula

and

step C:

converting the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide with methanesulfonic acid in a mixture of an organic solvent and water to crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate of the following formula

3. The process according to claim 2 , wherein R 1 and R 3 are independently of each other selected from the group consisting of —F, —Cl, —Br, —I, —OMs, —OTf and —OTs.

4. The process according to claim 2 , wherein the boronic acid compound, borolane, borinane or diboronic acid reagent is one of the following:

wherein

R′, R″, R a , R b , R e , R d , R e and R f represent independently of each other a substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms.

5. The process according to claim 2 , wherein for the preparation of the intermediate boronic acid compound or borolane reagent, the reagents palladium acetate, triethylamine and triphenylphosphine or PdCl 2 (PPh 3 ) 2 and triethylamine are used.

6. The process according to claim 2 , wherein Step B is carried out with EDC×HCl as coupling agent in a THF/NMP solvent mixture.

7. The process according to claim 2 , wherein the mixture of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in an organic solvent and water yields a supersaturated solution upon addition of methanesulfonic acid at an elevated temperature from which the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide methanesulfonic acid monohydrate crystallizes after either extended stirring, seeding or cooling.

8. The process according to claim 2 further comprising step D:

preparing a pharmaceutical composition of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide methanesulfonic acid monohydrate with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.

9. A crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate, wherein one or more of the following conditions 1, 2, 3 and/or 4 is satisfied:

condition 1:

the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate is a polymorph of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate, wherein the X-Ray diffraction pattern of the polymorph comprises 2-Theta angle values of 6.5, 12.9, 16.8, 18.9, 19.3, 19.5, 20.0, 22.4, 22.5, 23.2, 23.8, 25.5, 25.9, 28.8, 30.5, 32.7, and 35.7 degrees;

condition 2:

the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate exhibits a polymorphic form described as follows:

F(000)

540

description and size of crystal

colorless plate, 0.02 · 0.13 · 0.15 mm3

absorption coefficient

0.370 mm−1

min/max transmission

0.95/0.99

temperature

293K

radiation(wavelength)

Mo Ka(λ = 0.71073 Å)

Crystal system, space group

triclinic, P−1

a

9.4908(7) Å

b

9.5545(7) Å

c

14.4137(9) Å

α

86.130(3)°

β

72.104(3)°

Y

68.253(4)°

V

1153.68(15) Å3

min/max (−)

2.426° / 30.065°

# of collected reflections

43492

# of independent reflections

6761 (merging r = 0.026)

# of observed reflections

4955 (1 > 3.0σ(I))

# of refined parameters

298

r

0.0313 (observed data with )

rW

0.0432 (all data)

goodness of fit

1.0736

residual electron density

−0.28/0.33 e Å3;

condition 3:

The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate is in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir and/or famciclovir;

condition 4:

the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate is a polymorph of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate, wherein the X-Ray diffraction pattern of the polymorph comprises 2-Theta angle values of 6.5, 12.9, 16.8, 20.0 and 23.8 degrees.

10. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 9 , wherein the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate is a polymorph of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate, wherein the X-Ray diffraction pattern of the polymorph comprises 2-Theta angle values of 6.5, 12.9, 16.8, 18.9, 19.3, 19.5, 20.0, 22.4, 22.5, 23.2, 23.8, 25.5, 25.9, 28.8, 30.5, 32.7, and 35.7 degrees.

11. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 8 , which exhibits a polymorphic form described as follows:

F(000)

540

description and size of crystal

colorless plate, 0.02 · 0.13 · 0.15 mm3

absorption coefficient

0.370 mm−1

min/max transmission

0.95/0.99

temperature

293K

radiation(wavelength)

Mo Ka(λ = 0.71073 Å)

Crystal system, space group

triclinic, P−1

a

9.4908(7) Å

b

9.5545(7) Å

c

14.4137(9) Å

α

86.130(3)°

β

72.104(3)°

Y

68.253(4)°

V

1153.68(15) Å3

min/max (−)

2.426° / 30.065°

# of collected reflections

43492

# of independent reflections

6761 (merging r = 0.026)

# of observed reflections

4955 (1 > 3.0σ(I))

# of refined parameters

298

r

0.0313 (observed data with )

rW

0.0432 (all data)

goodness of fit

1.0736

residual electron density

−0.28/0.33 e Å3.

12. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 8 in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir and/or famciclovir.

13. A method for the treatment or prophylaxis of a herpes simplex virus infection or for the prevention of transmission of a herpes simplex virus infection, comprising administering to a subject in need thereof an effective amount of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 9 .

14. The method according to claim 13 , which is for the treatment of a herpes simplex virus infection.

15. A pharmaceutical composition containing crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide methane-sulfonic acid monohydrate according to claim 9 together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.

16. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 9 , wherein the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate is a polymorph of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate, wherein characterised in that the X-Ray diffraction pattern of the polymorph comprises 2-Theta angle values of 6.5, 12.9, 16.8, 20.0 and 23.8 degrees.

17. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate of claim 1 having a purity above 98 weight-%.

18. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate of claim 1 having a purity above 99 weight-%.

19. The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 15 in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir and/or famciclovir.

20. A method for the treatment or prophylaxis of a herpes simplex virus infection or for the prevention of transmission of a herpes simplex virus infection, comprising administering to a subject in need thereof an effective amount of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 1 .

21. The method according to claim 20 , which is for the treatment of a herpes simplex virus infection.

22. A pharmaceutical composition containing crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide methane-sulfonic acid monohydrate according to claim 1 together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.

23. The method according to claim 13 , which is for the prevention of transmission of a herpes simplex virus infection.

24. The method according to claim 20 , which is for the prevention of transmission of a herpes simplex virus infection.

25. A process for preparing the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide methanesulfonic acid monohydrate according to claim 9 , comprising

step A:

reacting a compound of formula A*

wherein

R 1 represents a leaving group and

R 2 represents an alkyl residue with 1 to 6 carbon atoms or a cycloalkyl residue with 3 to 6 carbon atoms

with a boronic acid compound, borolane, borinane or diboronic acid reagent under elimination of R 1 —H or R 1 —B(OR) 2 and formation of an intermediate boronic acid compound of compound A,

wherein the intermediate boronic acid compound is then reacted with a pyridine compound of formula B*

wherein

R 3 represents a leaving group

under basic conditions in order to directly obtain (4-pyridin-2-ylphenyl)acetic acid which is then purified

step B:

reacting the obtained (4-pyridin-2-ylphenyl)acetic acid with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide

to obtain N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide of the following formula

and

step C:

converting the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide with methanesulfonic acid in a mixture of an organic solvent and water to crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate of the following formula