ES2498380T3 - N- [5- (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2-4- [4- (2-pyridinyl) phenyl] acetamide mesylate monohydrate having a specific particle size distribution and a specific surface area range for use in pharmaceutical formulations - Google Patents

Abstract

Crystalline form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] monomethanesulfonic acid monohydrate acetamide of the following formula**Formula** in which the particles of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-monomethanesulfonic acid monohydrate 2-[4-(2-pyridinyl)-phenyl]acetamide have a particle size range of 1 to 500 µm, with a particle size distribution defined by d(0.1) from 2 to 100 µm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm and a specific surface area less than 1.0 m2/g.

Description

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide mesylate monohydrate having a distribution of specific particle size and a specific surface area range for use in pharmaceutical formulations.

Description

[0001] The present invention relates to crystalline salt N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2 - monomesylate) monohydrate. - pyridinyl) phenyl] - acetamide in a definitive particle size distribution and a specific surface range, which has shown an increase in long-term stability and release kinetics of pharmaceutical compositions, as well as pharmaceutical compositions containing said monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide monomesylate having the distribution of particle size mentioned above and a specific surface range.

Background of the invention

[0002] It is known from EP 1244641 B1 the synthesis of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2 - pyridinyl) phenyl] - acetamide, and the use of acidic components including methanesulfonic acid for the formulation of tablets containing a micronized form of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazole - is disclosed 2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide in WO 2006/103011 A1. It is also described that N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide is active in the parenteral, oral and topical formulations (UAK Betz et al., Antimicrob. Agents Chemother. 2002, 46 (6), 1766-1772).

[0003] EP 11007823 A1 is the application of the previous European patent of the applicant related to the present invention and directed to an improved synthesis of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2 - il] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide and the mesylate monohydrate salt thereof using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds and the N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide mesylate monohydrate salt.

[0004] It is the object of the present invention to present a specific form of a salt of the compound N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide which exhibits improved properties with respect to stability and bioavailability and therefore, making this specific salt form preferable for the manufacture of pharmaceutical compositions and presenting pharmaceutical compositions containing said specific salt, so that these pharmaceutical compositions exhibit improved properties with respect to the stability and bioavailability of the specific contained form of a salt of the compound N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide.

[0005] The object of the present invention is to resolve by teaching the independent claims. Other advantageous features, aspects, and details of the invention will be apparent from the dependent claims, the description, the figures, and the examples of the present application.

Description of the invention

[0006] There are four polymorphic forms and an amorphous form of the free base of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - ( 2-pyridinyl) phenyl] -acetamide at room temperature. In addition, several solvates can be detected for the free base of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N

-

methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide depending on the solvent. Based on the existence of the aforementioned forms of the free base of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2 - pyridinyl) phenyl] -acetamide at room temperature, no conclusion can be found on thermal stability. Thus, the free base of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2

-

[4 - (2-pyridinyl) phenyl] -acetamide is not suitable for a long-term stable formulation, since the long-term properties of the free base of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2

-

[4- (2-Pyridinyl) phenyl] -acetamide cannot be determined. In addition, the low solubility is responsible for drug release and unfavorable resorption properties compared to the mesylate monohydrate salt.

[0007] Unexpectedly, it was discovered that the monohydrate salt of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2 -) pyridinyl) phenyl] - acetamide overcomes all the disadvantages of the free base or other salts if said mesylate monohydrate salt has a specific DTP (particle size distribution), an RTP (particle size range) and an SE (specific surface ).

[0008] Thus, the present invention relates to a crystalline monohydrate salt form of the mono methanesulfonic acid of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl- 2 - [4 - (2-pyridinyl) phenyl]

- acetamide of the following formula:

E12762305

09-16-2014

5

10

image 1

where the mono- methanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] - Acetamide have a particle size range of 1 to 500

15 µm, a particle size distribution defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm and a smaller specific surface at 1.0 m2 / g.

[0009] The synthesis of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - () methanesulfonic acid monohydrate is shown below. 2-pyridinyl) phenyl] -acetamide:

twenty

25

30

35

40

Four. Five

fifty

55

E12762305

09-16-2014

image2

[0010] The above synthesis uses a boronic acid derivative, a borolane or a borinan reagent that reacts with ethyl-4-bromophenylacetate in order to obtain the key intermediate of acidic (4-pyridine-2-ylphenyl) acid in a single phase with a general yield of 40% hypothesis. (4-Pyridine-2-ylphenyl) acetic acid reacts with 4-methyl-2 (methyl-amino) -1,3-thiazol-5-sulfonamide in N- [5 - (aminosulfonyl) -4-methyl-1,3 - thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide (also referred to herein as "free base 65") which is then converted into the monomesylate monohydrate salt (referred to as also herein "mesylate monohydrate" or mesylate monohydrate salt ") which exhibits a specific DTP, RTP and SE. Be

E12762305

09-16-2014

summarize below the single reaction steps for the synthesis of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - () mesylate monohydrate. 2-pyridinyl) phenyl] -acetamide.

Stage A: Reaction of compound A of the following general formula A *

[0011]

image3

15 where

R1 represents a leaving group and R2 represents an alkyl residue with 1 to 6 carbon atoms or a cycloalkyl residue with 3 to 6 carbon atoms,

20 with a derivative of boronic acid, borolane, borinan or diboronic acid reagent with removal of R1-H or R1

- B (OH) 2 and formation of a boronic acid intermediate derivative of compound A, in which the preferred catalysts for the reaction are reagent systems of palladium acetate with triethylamine and triphenylphosphine or PdCI2 (PPh3) 2 with triethylamine,

In which the derivative of the boronic acid intermediate is then reacted with the pyridine compound B of the following general formula B *

image4

Where R3 represents a leaving group under basic conditions to obtain (4-pyridine-2-ylphenyl) acetic acid as an alkaline solution of the corresponding carboxylate salt.

[0012] (4-Pyridine-2-ylphenyl) acetic acid was purified by simple washing at different pH stages and filtration followed by precipitation or crystallization, preferably by correctly adjusting the pH of an aqueous acidic acid solution (4-pyridine) - 2-ylphenyl) acetic acid with a suitable base amount of 3.5-5.0, preferably 3.8-4.7. Next to the simple washing and filtration stage, without further purification of the acid (4 -

Pyridine-2-ylphenyl) acetic or any of the intermediates, for example, recrystallization or chromatography is required.

Step B: React the (4-pyridine-2-ylphenyl) acetic acid obtained in step A with 4-methyl-2 - (methylamino) -1,3-thiazol-5-sulfonamide 50

[0013]

55

60

image5

E12762305

09-16-2014

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

5

10

image6

[0014] N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide is converted to then more preferably (as step C) in the now unknown monohydrate of the salt N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [ 4 - (2-pyridinyl) phenyl] -acetamide. Mesylate monohydrate obtained from N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N -

Methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide is formulated as particles with a particle size ranging from 1 µm to 500 µm and a particle size distribution defined by d (0.1) of 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm and a specific surface area of particles smaller than 1.0 m2 / g, and more preferably a DTP defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a particle SE of less than 0.3 m2 / g.

[0015] In the above synthesis, the term "leaving group" as used herein is a molecular fragment that exits with a pair of electrons in the heterolytic bond breakage. The leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl -, Br -, and I -, and sulfonate esters, such as paratoluenesulfonate ("tosylate", TsO -), trifluoromethanesulfonate ("triflate", TfO -, CF3SO2O-),

30 benzenesulfonate ("besylate" C6H5SO2O-) or methanesulfonate ("mesylate", MsO -).

[0016] As shown below, the general formula A *

image7

40 covers all esters of phenylacetic acid having a leaving group in the phenyl residue at position 4.

[0017] Thus, R1 preferably represents -F, -Cl, -Br, -I, -OMs, -OTf and - OTs. The group "-OMs" refers to - Omesylate, the group "-OTf" refers to - Otriflate and the group - "OTs" refers to - Otosylate.

[0018] The group R2 represents an alkyl residue with 1 to 6 carbon atoms or a cycloalkyl residue with 3 to 6 carbon atoms, and preferably -CH3, -C2H5, -C3H7, -CH (CH3) 2, -C4H9 , -CH2 -CH (CH3) 2, -CH (CH3) -C2H5, -C (CH3) 3, -C5H11, -C6H13, cycle -C3H5, cycle -C4H7, cycle -C5H9, cycle -C6H11. More preferred are -CH3, -C2H5, -C3H7, -CH (CH3) 2, -C4H9, -CH2 -CH (CH3) 2, -CH (CH3) -C2H5, -C (CH3) 3, and -C5H11. Especially more preferred are -CH3, -C2H5, -C3H7, and -CH (CH3) 2.

[0019] Various derivatives of boronic acid, borolanes and borinanos as well as the corresponding diboronic acid derivatives can be used in step A of the synthesis of the invention disclosed herein. They prefer

the borolanos of the following general formula:

image8

60

where each R´ and R´´ are independent of any substituted or unsubstituted alkyl group, linear or branched with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms, or R´ and R´´ can also be formed next to the boron atom of a heterocyclic ring where R 'and R' 'together form a linear or branched alkylene group, substituted or unsubstituted with 2 to 10 carbon atoms. Preferably each R´ and R´´ represent -CH3, -C2H5,

E12762305

09-16-2014

C3H7, -CH (CH3) 2, -C4H9, -CH2 -CH (CH3) 2, -CH (CH3) -C2H5, -C (CH3) 3, and -C5H11 independently. Cyclic borolanes are preferred.

[0020] The following borolanes, borinan and diboronic acid derivatives are preferred:

image9

where each Ra, Rb, Rc, Rd, Re and Rf independently represents a substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms. Linear alkyl residues with 1 to 6 carbon atoms are preferred, and -CH3, -C2H5, -C3H7 and -CH (CH3) 2 are more preferable.

[0021] Especially preferred examples for the above boron containing compounds are 4, 4, 5, 5-tetramethyl [1,3,2] dioxaborolane (pinacolborane), [1,3,2] dioxaborolane, [1,3, 2] dioxaborinan, 5,5-dimethyl [1,3,2] dioxaborinan, 4,6,6-trimethyl [1,3,2] -dioxaborinan, 4,4,6,6-tetramethyl [1,3,2 ] -dioxaborinan, 4,4,5,5,6,6-hexamethyl [1,3,2] -dioxaborinan, diisopropoxiborane, hexahydrobenzo [1,3,2] dioxaborola, 9,9-dimethyl -3,5-dioxa

35 4-bora-tricycle - [6.1.1.62.6] dean, 6,9,9-trimethyl -3,5-dioxa-4-bora-tricycle [6.1.1.62.6] dean, B2Pin2 (bis (pinacolato) diborane), bis (nepentyl glycolate) diboro and catecholborane.

[0022] In step A, this derivative of boronic acid, borolane, borinan or diboronic acid reagent is reacted with a compound of the general formula A * to obtain a borolane or intermediate of the borinano reagent which is not isolated or purified. This reaction can be supported by the use of any catalyst prepared in situ by mixing palladium salts such as [Pd (OAc) 2] and PdCI2 with triphenylphosphine (PPh3), tri-ortho-tolylphosphine (P (or -Tol) 3) , tricyclohexylphosphine (PCy3), tri-tert.-butylphosphine, 1,4-Bis - (diphenylphosphino) -butane (dppb), and 1,1 '- Bis - (diphenylphosphino) - ferrocene dppf or preformed catalysts such as Pd (PPh3) 2Cl2, Pd (PPh3) 4, Fibrecat 1032, and Pd (dppf) Cl2 in the presence of different organic and inorganic bases such as triethylamine (Et3N), NaOAc,

45 KOAc, and K3PO4. To heat this reaction, temperatures between 70 ° C and 150 ° C, preferably between 80 ° C and 130 ° C, more preferably between 90 ° C and 110 ° C are used. In addition, aprotic and preferably apolar solvents and preferably aromatic solvents such as benzene or toluene or xylenes are used.

[0023] The boronic acid reagent intermediate is subsequently reacted with a pyrinidyl compound of the general formula B *. where R3 represents a leaving group. Thus, R3 represents -F, -Cl, -Br, -I, -OMs, -OTf and -OTs and preferably - Cl or -Br.

[0024] The (4-pyridine-2-ylphenyl) acetic acid ester is treated in situ with an aqueous base to cleave the ester bond. It may be advantageous to heat the reaction mixture during the coupling stage /

Saponification at a moderate temperature and preferably at a temperature ranging from 40 ° C to 90 ° C, more preferably between 45 ° C and 80 ° C, even more preferably between 50 ° C and 70 ° C and most preferably between 55 ° C and 65 ° C.

[0025] After purifying and isolating the key intermediate of (4-pyridine-2-ylphenyl) acetic acid, 60 (4-pyridine-2-ylphenyl) acetic acid is obtained in a yield of 40% of the hypothesis that includes a stage of isolation and purification.

[0026] Next, (4-pyridine-2-ylphenyl) acetic acid was reacted with 4-methyl-2 - (methylamino)

- 1,3-thiazol-5-sulfonamide of the formula 65

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

image10

prepared according to the synthesis disclosed in EP 1244641 B1 in order to obtain N - [5 - (aminosulfonyl)

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

image11

[0027] This N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide was converted from hence in the crystalline form of mesylate monohydrate salt, in which the normal particle size range is from 1 to 500 µm and the particle size distribution is preferably defined by d (0.1) from 2 to 100 µm , d (0.5) from 20 to 210 µm and d (0.9) from 70 to 400 µm and in which the crystalline particles have a specific surface area less than 1.0 m2 / g, and more preferably the DTP is defined per d (0.1) of 10 to 75 µm, d (0.5) of 100 to 175 µm and d (0.9) of 200 to 350 µm and the SE of the particles is less than 0.3 m2 / g .

[0028] Parameter d (0.1) refers to the mesh size of a single theoretical sieve that allows 10% of the total of all the particles in the sample to pass. Therefore, d (0.1) = 2 - 100 µm refers to the upper limit of the particle size range that defines 10% of the smallest particles in the sample ranging between 2 µm and 100 µm. Therefore, 10% of the total particles have a particle size of not more than d (0.1), which in this case refers to having a maximum size between 2 µm and 100 µm.

[0029] Therefore, parameter d (0.5) refers to the mesh size of a single theoretical sieve that allows 50% of the total of all the particles in the sample to pass. Therefore, d (0.5) = 30 - 210 µm refers to the upper limit of the particle size range that defines the theoretical half of the sample that contains the smallest particles in the sample that range between 30 µm and 210 µm. Therefore, 50% of the total particles have a particle size of no more than d (0.5), which in this case refers to having a maximum size of between 30 µm and 210 µm. Therefore, parameter d (0.9) refers to the mesh size of a single theoretical sieve that allows 90% of the total of all the particles in the sample to pass, that is, only 10% of the sample is retained . Therefore, d (0.9) = 70-400 µm refers to the lower limit of the particle size range that defines 10% of the largest particles in the sample ranging between 70 µm and 400 µm. Therefore, 90% of the total particles have a particle size of no more than d (0.9), which in this case refers to having a maximum size between 70 µm and 400 µm.

[0030] It is further preferred that the particle size of the particles of the crystalline form N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl- monohydrate monohydrate 2 - [4 - (2-Pyridinyl) phenyl] -acetamide range between 1 µm and 500 µm, preferably between 1.5 µm and 450 µm and more preferably between 2 µm to 400 µm. Therefore, the particle size range (RTP) of the mesylate monohydrate is 1.0 µm to 500 µm, preferably 1.5 µm to 450 µm, more preferably 2.0 µm to 400 µm, even more preferably from 2.5 µm to 300 µm and most preferably from 3.0 µm to 250 µm. If the RTP is not mentioned at all or if RTP is referenced without indicating a certain value, it will refer to a particle size range of 1 to 500 µm.

[0031] In addition, it is preferred that the particle size distribution of the particles of the crystalline form N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N mesylate monohydrate form - methyl - 2 - [4 - (2-pyridinyl) phenyl] -acetamide is characterized by d (0.1) from 4 µm to 100 µm, d (0.5) from 30 µm to 210 µm, d (0, 9) from 70 µm to 400 µm, more preferably d (0.1) from 6 µm to 95 µm, d (0.5) from 50 µm to 200 µm and d (0.9) from 100 µm to 390 µm, even more preferably d (0.1) from 7 µm to 90 µm, d (0.5) from 70 µm to 190 µm and d (0.9) from 130 µm to 380 µm, still more preferably d (0.1) of 8 µm to 85 µm, d (0.5) from 80 µm to 185 µm and d (0.9) from 160 µm to 370 µm, even more

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

preferably d (0.1) from 9 µm to 80 µm, d (0.5) from 9 µm to 180 µm and d (0.9) from 180 µm to 360 µm, even more preferably d (0.1) of 10 µm to 75 µm, d (0.5) from 100 µm to 175 µm and d (0.9) from 200 µm to 350 µm and most preferably d (0.1) from 11 µm to 70 µm, d (0, 5) from 110 µm to 170 µm and d (0.9) from 220 µm to 340 µm.

[0032] In addition, it is preferred that the specific surface area of the crystalline particles is less than 1.0 m2 / g, more preferably less than 0.9 m2 / g, even more preferably less than 0.8 m2 / g, even more preferably less than

0.7 m2 / g, even more preferably less than 0.6 m2 / g, even more preferably less than 0.5 m2 / g, even more preferably less than 0.4 m2 / g, and most preferably that the SE of the particles is less than 0.3 m2 / g.

[0033] As used herein, the term "mesylate monohydrate", or "crystalline form mesylate monohydrate", or "methanesulfonic acid monohydrate", or "crystalline form methanesulfonic acid monohydrate"

or "N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide mesylate monohydrate," or "N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide methanesulfonic acid monohydrate" refers to the crystalline monohydrate form of the mono methanesulfonic acid of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] - acetamide having DTP, RTP and SE as defined herein.

[0034] According to the invention, the crystalline monohydrate form of mono methanesulfonic acid of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - ( 2-Pyridinyl) phenyl] -acetamide is preferably mixed with and used in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir, famciclovir and / or valganciclovir. Especially preferred combinations are with acetylsalicylic acid or acyclovir or penciclovir or acetylsalicylic acid and acyclovir or acetylsalicylic acid and penciclovir.

[0035] The mesylate monohydrate of the invention or the drug combinations mentioned above are preferably used for the manufacture of a pharmaceutical composition for the treatment and / or prophylaxis of infectious diseases and the prevention of transmission of an infectious disease and especially Infectious diseases caused by the herpes simplex virus.

[0036] The crystalline form N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N mesylate monohydrate

-Methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide obtained according to the synthesis disclosed above is then used to prepare a pharmaceutical composition, in which N- [5 - (aminosulfonyl mesylate monohydrate) ) - 4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide has a particle size distribution (DTP), a specific surface ( SE) and a range of particle size (RTP) as defined herein. To this pharmaceutical composition could be added acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, and / or their respective prodrugs valacyclovir, famciclovir and / or valganciclovir. Some providers use the name acyclovir instead of acyclovir. In addition, these pharmaceutical compositions are preferably solid pharmaceutical compositions without solvents, diluents,

or liquids that exhibit solubilizing properties in the active pharmaceutical ingredient so that the particles do not dissolve and remain unchanged with respect to their particle size distribution, particle size range and specific surface.

[0037] In WO 2006 7 103011 A, a wet granulation process for the preparation of a tablet for the base form using various acids including methanesulfonic acid has been described. In a series of crystallization experiments from N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] - Acetamide and benzoic acid, lactic acid, and sulfuric acid, a crystalline salt (apparently produced in different polymorphic forms) could be isolated only with sulfuric acid. However, using sulfuric acid in the wet granulation process resulted in a tablet exhibiting unfavorable dissolution properties (see Table 3 of WO 2006/103011 A). Repeating the wet granulation process (see example 5 of WO 2006/103011 A) using 1 equivalent methanesulfonic acid as an acidic component resulted in a granulate, containing a mixture of crystalline free base and mesylate monohydrate salt (approximately 90:10 , detectable by comparison of the X-ray powder diffraction spectra, which did not change significantly for 4 weeks at 40 ° C (see Figure 1). This free base mesylate / mixture was inappropriate for tablet formulation, due to the low solubility and dissolution behavior, the occurrence of at least four polymorphic forms and the additional risk of additional interconversion between the base and the salt form under long-term storage conditions (also depends on the water content and the hygroscopicity of the tablet mixture.) Therefore, it was very surprising that a definitive mesylate monohydrate salt could be obtained ranges from N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide and that this monohydrate salt of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] mesylate

- Acetamide with the characteristic DTP, RTP and SE as described herein, will overcome all the problems of the prior art and present the opportunity to prepare pharmacologically applicable, stable, and stable long-term pharmaceutical compositions that showed clear advantages for the formulations solid.

[0038] In order to form tablets, the fluidity of a mixture of mono- methanesulfonic acid monohydrate of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N- is improved methyl - 2 - [4 - (2-pyridinyl) phenyl]

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

-

Acetamide having DTP, RTP and SE as defined herein with usual pharmaceutical ingredients with larger particles and a narrower particle size distribution. As the particle size decreases, numerous forces between particles such as mechanical interlocking, hydrogen bonding, electrostatic and van der Waals forces on gravity can predominate. These forces act on the surface of the particles and smaller particles that have a larger surface with respect to their mass than larger ones. In addition, these results may be different due to differences in the configuration of the measurement of fluidity, air humidity, and / or particle properties such as the original particle size. A wide distribution of the particle size induces segregation that influences the strength of tablet formation, weight of the tablet and uniformity of the tablet content. A wide particle size distribution causes more segregation problems during tablet formation than the granule batch with a smaller size distribution without a defined range. Therefore, due to the various possible particle size ranges, particle size distributions and specific surfaces adjustable by various techniques, it was unpredictable to the experts that the ranges for DTP, SE and RTP as defined in the present were the most suitable for the preparation of pharmaceutical compositions.

[0039] The narrowest particle size distribution of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl - 2 - [4 - (2-pyridinyl) phenyl]

-

Acetamide, for example for a given average particle size, have a smaller number of large and small particles, is an advantage for direct compression as a method of manufacturing tablets. The resulting particle size distribution of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein and preferably where the particle size distribution by d (0.1) of 2 to 100 µm, d ( 0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more particularly defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm and d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, which has physical characteristics, which are particularly adapted so that are capable of allowing direct compression manufacturing without a wet or dry granulation stage.

[0040] According to the invention, it is preferred that at least 65% v / v, more preferably at least 70% v / v, even more preferably at least 80% v / v, even more preferably at least 85% v / v, even more preferably at least 90% v / v, even more preferably at least 95% v / v and most preferably at least 99% v / v particles of the crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide decrease to a particle size range from 2 to 400 µm. In addition, it is preferred that 40% v / v of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [methanesulfonic acid monohydrate particles. 4 - (2-Pyridinyl) phenyl] -acetamide decrease to a particle size range of 2 - 250 µm.

[0041] It was surprisingly discovered that using the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl]

-

acetamide in a particulate form, where DTP, RTP and SE how are defined herein and preferably where the particle size distribution is defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d ( 0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g in the final mixture showing the free flow and improved cohesive powder characteristics and sample a cohesive compaction and dry granulation behavior, the effects of which are significant for efficient and robust direct compression. If there are too many particles of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2 - pyridinyl) phenyl] - acetamide, particles with a size smaller than 4 µm are present, in the last processing, they tend to cause picking and sticking. If there are too many particles of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl mono methanesulfonic acid monohydrate ] - acetamide, particles larger than 400 µm are present, the compression capacity becomes too poor. Therefore, it is observed that at least 65% v / v of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide decreases to a particle size range of 2 to 400 µm, where the particle size distribution is preferably defined by d (0.1) of 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0 , 1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g. When the crystalline mono-methanesulfonic acid demonohydrate form of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) is processed phenyl] - acetamide, its particle size distribution remains substantially unchanged, usually remains completely unchanged. In view of the improvement of the general characteristics, it is preferred that at least 65% v / v, more preferably at least 70% v / v, even more preferably at least 80% v / v, even more preferably at least 85% v / v, even more preferably at least 90% v / v, even more preferably at least 95% v / v and most preferably at least 99% v / v particles of the crystalline form of acid monohydrate N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] methanesulfonic mono

-

acetamide with DTP, RTP and SE how are defined herein and more preferably decrease to a range of

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

particle size from 2 to 400 µm, where the particle size distribution is preferably defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) of 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d ( 0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g.

[0042] A further advantage of the tablets according to the invention is that the tablet will have an optimized dissolution rate based on its particle size distribution of the crystalline form of mono-methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) - 4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide having the DTP, RTP and SE as defined herein, and by Therefore, the drug can be absorbed into the bloodstream much faster compared to N - [5 - (aminosulfonyl) - 4

-Methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide or salts thereof. Furthermore, the surprising dispersion times obtained with the tablets according to the invention are advantageous for the swallowable tablets. In a further embodiment, the tablets according to the invention can be presented for dispersion in water.

[0043] The crystalline form of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) mesylate monohydrate salt Phenyl] -acetamide, where DTP, RTP and SE as defined herein, exhibit increased long-term stability properties, a desired release kinetics and long-term stability for pharmaceutical compositions, superior to other N-salts. [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, known in the prior art which also includes other mesylate salts

[0044] As is evident, Figure 4 shows a unique analysis of the crystal X-ray structure of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazole-2 - mono-methanesulfonic acid monohydrate crystal. il] - N - methyl

-

2 - [4 - (2-pyridinyl) phenyl] -acetamide, the salt is formed between the mesylate and the protonated pyridinyl ring. In addition, exactly one equivalent mole of methanesulfonic acid and one equivalent mole of water are incorporated into the crystal structure, where the hydrogen atoms of the water molecule form hydrogen bonds with oxygen atoms of two different mesylate molecules.

[0045] Preferred conditions for the crystallization of mono- methanesulfonic acid monohydrate from N - [5

-

(aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, are prepared in a suspension of the base in 10 vol. (vol. = L / kg free base) of ethanol / water (1: 1), 1.15 equivalents of methanesulfonic acid are added at 50-55 ° C for <15 min, seeded with 0.5 mol% of the product Finally, they are aged for 1 - 1.5 h at 50 ° C and cooled to 20-25 ° C for 2.5 h.

[0046] After further stirring for 1 h, the final product can be isolated by filtration and dried in vacuo in a yield of> 95%. Using this procedure, N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] methanesulfonic acid monohydrate - acetamide with DTP, RTP and ASE as defined herein and preferably having a particle size range of 2 to 400 µm, where the particle size distribution is preferably defined by d (0.1) of 2 at 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0, 1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g in purity> 99% containing <2 ppm of residual Pd can be prepared reproducibly with respect to yield, purity, polymorphic form, DTP, RTO and SE from a supersaturated solution of N - [5 - (aminosulfonyl) -4-methyl 1,3 - thiazol - 2 - yl] - N - methyl - 2 - [4

-

(2-Pyridinyl) phenyl] -acetamide by crystallization under controlled conditions as described below.

[0047] The spontaneous crystallization of a supersaturated solution results in the coprecipitation of the free base. To stimulate this process, a sample of N-[5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - () mono-methanesulfonic acid monohydrate was dissolved. 2-Pyridinyl) phenyl] -acetamide in a mixture of ethanol and water (1: 1) at 50 ° C and then cooled and mixed at 0 ° C for about 5 hours. The precipitate samples were taken by microscopy that mainly exhibits small needles (Figure 3 A) in contrast to the mesylate monohydrate, which crystallizes as prisms (Figure 3 B). By investigating isolated needles that are applied to H1 NMR (nuclear magnetic resonance), mesylate could not be detected, although the existence of the free basic form was exhibited. Maintaining a suspension of this precipitate at 0 ° C at room temperature, a slow growth of the prisms consumed by the needles is shown (Figure 3 C), which sustains a very slow conversion to the form of the mesylate salt. This experiment demonstrates the importance of the selection of well defined crystallization conditions.

[0048] To obtain N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl mono methanesulfonic acid monohydrate ] - Acetamide in the desired DTP, RTP and ASE, it is preferred to stir this mixture from moderate to slow and a flat cooling ramp of this mixture at room temperature. In addition, it is preferred to add the methanesulfonic acid over 5-15 min at high temperature and keep the resulting mixture at this elevated temperature for 1 or 2 hours after the completion of the methanesulfonic acid addition. The cooling is carried out at room temperature between 2 to 3 hours and the mixture is stirred

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

slowly for another hour at room temperature. The crystals were then filtered, washed with alcohol / water and dried under vacuum at a temperature between 20 ° C and 60 ° C, preferably from 20 ° C and ending at 60 ° C.

[0049] A modified form to obtain mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl)

-

4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide in the desired DTP, RTP and SE is applied to the following conditions for crystallization . The methanesulfonic acid is added at elevated temperatures, and preferably between 30 ° C and 90 ° C, more preferably between 35 ° C and 80 ° C, even more preferably between 40 ° C and 70 ° C, still more preferably between 45 ° C and 60 ° C and most preferably at 50 ° C - 55 ° C to the mixture of an organic solvent and water containing N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-Pyridinyl) phenyl] -acetamide that provides a supersaturated solution of the N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide. Organic solvents that are miscible or water-soluble such as MeOH, EtOH, n-PrOH, I-PrOH, acetronitrile, THF, acetone are preferable. In addition, it is preferred to add seed crystals of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-methanesulfonic acid monohydrate) monohydrate. - pyridinyl) phenyl]

-

Acetamide to this supersaturated mixture also at elevated temperatures between 30 ° C to 90 ° C, preferably 35 ° C to 80 ° C, more preferably 40 ° C to 70 ° C, still more preferably 45 ° C to 60 ° C and most preferably at 50 ° C - 55 ° C. It is also preferred to moderately stir slowly this mixture and slowly cool this mixture to room temperature. In addition, it is preferred to add the methanesulfonic acid for 5 to 15 minutes at elevated temperature and keep the resulting mixture at this elevated temperature for 0.5 to 5 hours and more preferably 1 to 2 hours after the completion of the methanesulfonic acid addition. Cooling was carried out at room temperature in 1 to 5 hours and preferably between 2 to 3 hours and the mixture was then stirred slowly for preferably another hour at room temperature. The crystals were filtered, washed with alcohol / water and preferably dried under vacuum at temperatures between 20 ° C and 60 ° C, preferably starting at 20 ° C and ending at 60 ° C.

[0050] The crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) ) phenyl] - acetamide with the DTP, RTP and ASE defined herein, exhibits optimized release kinetics of pharmaceutical compositions and improved bioavailability. In addition, storage properties are excellent, especially the long-term stability of the active pharmaceutical ingredient (IFA), as well as those of pharmaceutical formulations. X-ray powder diffraction spectra of film-coated tablets (concentrations 5 mg, 25 mg, 100 mg, milled for measurement compared to placebo) after 24 months at room temperature revealed no changes in crystallinity ( see Figures 5 to 7).

[0051] Compared to the N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl mesylate salt ] - acetamide, the N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl mesylate salt monohydrate ] - acetamide, where the particle size distribution is preferably defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) of 10 to 75 µm, d (0.5) of 100 to 175 µm, d (0.9) of 200 to 350 µm with a specific particle area of less than 1.0 m2 / g, preferably less than 0.6 m2 / g, and most preferably less than 0.3 m2 / g, surprisingly and unexpectedly has a thermostability up to 170 ° C. A clear advantage of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide mesylate monohydrate , where DTP, RTP and SE are found as defined herein, is their proven long-term stability. Therefore, the invention of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4] mesylate monohydrate

-

(2-Pyridinyl) phenyl] -acetamide, which is characterized by the DTP, RTP and SE disclosed herein, is more suitable for the preparation of long-term stable tablets compared to the N-free base [5

-

(aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide.

[0052] According to the invention, the crystalline form of mono- methanesulfonic acid monohydrate of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-Pyridinyl) phenyl] -acetamide is a compound useful for the treatment and / or prophylaxis of infectious diseases and / or prevention of the transmission of infectious diseases.

[0053] The crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) ) Phenyl] - Acetamide is highly active against herpesviruses and infections caused by herpesvirus and / or transmission of herpes virus (s). In addition, the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl]

- N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide of the invention is especially useful for the preparation of a pharmaceutical composition for the treatment and / or prophylaxis of diseases, which are caused by herpesvirus

or caused by the transmission of one or some herpes viruses.

[0054] The mesylate monohydrate salt of the invention is especially useful for the treatment and / or prophylaxis of infections, which are caused by herpes simplex viruses, or for the prevention of transmission of one or some herpes viruses. Infections with herpes simplex virus (HSV, subtype 1 and 2) are classified into one of the

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

60

65

E12762305

09-16-2014

various disorders based on the place of infection. Orofacial herpes simplex infection, the visible symptoms of colloquially called fever or fever, affect the face and mouth. Orofacial herpes is the most common form of infection. Genital herpes is the second most common form of a herpes simplex infection. Although it is largely believed that genital herpes is caused by HSV-2, HSV-1 genital infections are increasing. Other disorders such as herpetic whites, gladiatorium herpes, ocular herpes (keratitis), herpetic encephalitis, Mollaret meningitis , neonatal herpes and possibly Bell's palsy are also caused by herpes simplex viruses.

[0055] The mesylate monohydrate salt of the invention is therefore useful in the treatment and / or prophylaxis of infections caused by herpes simplex viruses and / or in the prevention of transmission of herpes simplex viruses.

[0056] The mesylate monohydrate salt of the present invention can be mixed and administered with an anti-inflammatory agent such as acetylsalicylic acid and acetaminophen. Thus, combinations of mesylate monohydrate of the invention with acetylsalicylic acid and / or acetaminophen as well as pharmaceutical compositions as a combination are preferred.

[0057] In addition, the mesylate monohydrate of the invention can be mixed and used in combination with an antiviral agent. The antiviral agent is preferably an antimetabolite and most preferably a nucleobase analog, a nucleotide analog or a nucleoside analog drug. It is further preferred if the antiviral agent is useful against herpesviruses and / or against the transmission of one or several herpes viruses and is selected from the group of drugs that comprises in a non-limiting manner or is formed by: trifluridine, idoxuridine, foscarnet, cidofovir , ganciclovir, acyclovir or penciclovir or the respective prodrugs valacyclovir, famiclovir or valganciclovir.

[0058] The mixture of mesylate monohydrate of the invention and an additional active agent such as an anti-inflammatory, immunomodulator, or an antiviral agent, such as therapeutic vaccines, siRNAs, antisense olegonucleotides, nanoparticles, or inhibitors of virus uptake such as n-docosanol , can be administered simultaneously in a single pharmaceutical composition or in more than one pharmaceutical composition, where each composition comprises at least one active agent.

[0059] The pharmaceutical compositions of the present invention can be prepared in a conventional solid and an adjuvant made pharmaceutically conventional in a suitable dosage level in a known manner. Preferred preparations can be adapted to oral application. These forms of administration include, for example, pills, tablets, film tablets, coated tablets, sustained release formulations, and capsules.

[0060] The pharmaceutical compositions according to the present invention comprise between 5 to 70% by weight, more preferably 10 to 30% by weight of the crystalline form of mono-methanesulfonic acid monohydrate of N- [5 - (aminosulfonyl) -4-methyl - 1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide (all percentage data are weight percentages based on the weight of the pharmaceutical preparation), where DTP, RTP and SE are defined herein. The pharmaceutical composition normally comprises 2 to 600 mg of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4- (2-Pyridinyl) phenyl] -acetamide, preferably 5 to 500 mg, more preferably 10 to 300 and particularly preferably 20 to 200 mg, wherein DTP, RTP and SE as defined herein.

[0061] The pharmaceutical composition according to the invention optionally comprises one or more fillers, which, for example, are selected from the group consisting of: microcrystalline cellulose, fiber cellulose, calcium phosphates and mannitol. Preferably, according to the invention, microcrystalline cellulose and mannitol are used. The pharmaceutical composition comprises in a timely manner between 20 and 80%, preferably 40 to 80%, particularly preferably 45 to 70% microcrystalline cellulose and 1 to 40%, preferably 5 to 30%, particularly preferably 10 to 20% mannitol. The pharmaceutical preparation according to the invention may comprise at least one disintegration aid, which is, for example, selected from the group consisting of starch, pregelatinized starch, starch glycolate, crosslinked polyvinylpyrrolidone, sodium carboxymethylcellulose (= croscarmellose sodium) and other salts of carboxymethyl cellulose. A mixture of the two disintegrating agents can also be used. According to the invention, the use of croscarmellose sodium is preferred. The pharmaceutical composition comprises in a timely manner between 3 and 35%, preferably 5 to 30% and particularly preferably 5 to 10% of disintegration aid (s). The pharmaceutical composition of the invention may comprise at least one lubricant selected from the group consisting of fatty acids and their salts. According to the invention, the use of magnesium stearate is particularly preferred.

[0062] The pharmaceutical composition of the invention may comprise a flow agent, which could be an anhydrous colloidal silica or talcum powder. According to the invention, the use of anhydrous colloidal silica is particularly preferred. The flow agent is used in a timely manner in an amount of 0.3 to 2.0%, particularly preferred 0.4 to 1.5% and most preferably 0.5 to 1%.

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

[0063] A particularly preferable pharmaceutical composition comprises: 5% -30% of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N - methyl

- 2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein and preferably the particle size distribution is defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) of 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, 5% -10% croscarmellose sodium, 0.5 to 0.7% magnesium stearate, 40% -70% microcrystalline cellulose, 10% -20% mannitol and 0.5% to 1% anhydrous colloidal silica.

[0064] Additional pharmaceutical compositions according to the invention preferably comprise: 30% to 90%, more preferably 50 to 70% by weight of the crystalline form of mono-methanesulfonic acid monohydrate of N- [5 - (aminosulfonyl) -4-methyl - 1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein and preferably the size distribution particle size is defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a smaller specific surface area of particles at 0.3 m2 / g (all percentage data are weight percentages based on the weight of pharmaceutical preparations). The pharmaceutical composition normally comprises 20 to 750 mg of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4- (2-Pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein and preferably 50 to 500 mg, and particularly preferably 50 to 250 mg based on a single dose.

[0065] The pharmaceutical composition according to the invention optionally comprises one or more dry binders, which, for example, are selected from the group consisting of: microcrystalline cellulose, fiber cellulose, calcium phosphates and mannitol. Preferably, microcrystalline cellulose is used. This is commercially available under the name AviceIB, for example. The pharmaceutical composition comprises in a timely manner 10 to 20%, preferably 1 to 10%, particularly preferably 1 to 5% dry binder (s). The pharmaceutical preparation according to the invention may comprise at least one disintegration aid, which is, for example, selected from the group consisting of starch, pregelatinized starch, starch glycolate, crosslinked polyvinyl pyrrolidone, sodium carboxymethyl cellulose (= croscarmellose sodium) and other carboxymethyl cellulose salts . A mixture of the two disintegrating agents can also be used. The use of croscarmellose sodium and cross-linked polyvinylpyrrolidone or a mixture of the two is preferable. The pharmaceutical composition comprises in a timely manner 3 to 35%, preferably 10 to 30% and particularly preferred 15 to 25% of disintegration aid (s). The pharmaceutical composition of the invention may comprise at least one lubricant selected from the group consisting of fatty acids and their salts. According to the invention, the use of magnesium stearate is particularly preferred.

[0066] A pharmaceutical composition for a tablet with 25 mg of active drug ingredient (calculated as the base form) comprises 32.3 mg of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazole-2 - il] - N

-

methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein and preferably the particle size distribution is defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, 60.9 mg of cellulose microcrystalline, 9.8 mg of croscarmellose sodium, 20.0 mg of mannitol, 1.3 mg of colloidal anhydrous silica and 0.9 mg of magnesium stearate. The total weight of the mixture is 125.0 mg.

[0067] An additional pharmaceutical composition for a tablet with 100 mg of active drug ingredient comprising 129.0 mg of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N - methyl - 2 - [4 - (2

-

pyridinyl) phenyl] - acetamide, 243.4 mg of microcrystalline cellulose, 39.0 mg of croscarmellose sodium, 80.1 mg of mannitol, 5.0 mg of colloidal anhydrous silica and 3.5 mg of magnesium stearate. The total weight of the mixture is 500.0 mg.

[0068] In addition, the present invention also includes pharmaceutical compositions for a sublingual application, whose preparations in addition to typical carriers contain at least mono methanesulfonic acid monohydrate N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazole - 2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE as defined herein, as active ingredient.

[0069] A pharmaceutical composition of the invention may contain the following preservatives: phenoxyethanol, formaldehyde solution, parabens, pentanediol, or sorbic acid.

[0070] As a pharmaceutically acceptable carrier, excipient and / or diluents, carriers such as preferably an inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talcum, mannitol, ethyl alcohol (filled capsules) may be used. with liquid); Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic resins such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

wheat, corn and potato rice, natural resins such as acacia, gelatin and tragacanth, algae derivatives such as alginic acid, sodium alginate and calcium alginate-ammonium, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds as alumino-magnesium silicate; lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting waxes, and other water soluble lubricants such as sodium chloride , sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D, L-leucine; disintegrating agents (disintegrants) such as starch, methylcellulose, guar resin, modified starches such as sodium carboxymethyl starch, natural and synthetic resins such as garrofín, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures; coloring agents, sweetening agents, flavoring agents, preservatives; Sliders are for example silicone dioxide and talc; Suitable absorbents are clay, aluminum oxide, suitable diluents are water or water / propylene glycol solutions for parenteral injections, juice, sugars such as lactose, sucrose, mannitol and sorbitol, wheat-derived starches, corn and potato rice, and cellulose as cellulose microcrystalline

[0071] The following examples are included to demonstrate preferred embodiments of the invention. Those skilled in the art should appreciate that the techniques disclosed in the following examples represent techniques discovered by the inventor that work well in the practice of the invention, and therefore, can be considered to constitute modes for their practice. However, those skilled in the art should, in accordance with the present disclosure, appreciate that some changes can be made to the specific disclosed embodiments and still obtain similar or similar results without departing from the present invention.

[0072] The pharmaceutical compositions according to the invention can be administered to a patient in need thereof at a daily dose of 20 to 750 mg of the crystalline form of mono-methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl - 1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where DTP, RTP and SE are defined herein and preferably the particle size distribution It is defined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g , and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific surface area of particles smaller than 0 , 3 m2 / g, preferably 50 to 500 mg and particularly preferably 50 to 250 mg based on a single dose. The pharmaceutical compositions according to the invention can be administered to a patient in need three times a day, twice a day, once a day, three times a week, twice a week, or once a week. Administration of the base three times a week, twice a week or once a week is preferred and especially preferred is a weekly administration, ie; once a week administration of a pharmaceutical composition containing between 400 mg and 500 mg of monohydrate mono-methanesulfonic acid of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N -Methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide of the invention. In addition, it is preferred to start the administration of the mesylate monohydrate of the present invention with a high loading dosage, for example, with a single initial dose of 400 to 800 mg and to continue administration with a dose of less than 100 mg to 150 mg per day or week during the treatment period.

[0073] Additional modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Consequently, this description has a purely illustrative purpose and is intended to teach those skilled in the art the general way of carrying out the invention. It is understood that the forms of the invention shown and described herein are taken as examples of embodiments. The elements and materials can be replaced by those illustrated and described herein, parts and processes can be modified, and some features of the invention can be used independently, as long as everything is evident to those skilled in the art after having the benefit of This description of the invention. Changes may be made to the elements described herein without departing from the present invention as described in the following claims.

EXAMPLES

Example 1: Synthesis of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] methanesulfonic monohydrate

- N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide with inventive DTP, RTP and SE.

Stage 1 (Suzuki coupling - Miyaura and saponification)

[0074] An inertized reactor is charged with bis (triphenylphosphine) palladium (II) chloride (0.010 eq) and re-inerted. Then, toluene (1.65 vol) is added. After heating at 40 ° C, triethylamine (3.00 eq) is added. A solution of ethyl-4-bromophenylacetate (1.00 eq) in toluene (0.82 vol) is added. The resulting suspension is heated to 90

- 95 ° C before dosing borane pinacol for 60-90 minutes. Stirring at 90-95 ° C is maintained for at least 2 more hours before the conversion is checked by HPLC. After cooling to 10 ° C, 2-chloropyridine (1.00 eq) is charged to the reaction mixture. Then, 30% NaOH (6.00 eq) is added followed by heating at 55-60 ° C. Stirring at this temperature is maintained for at least 4 hours before the conversion is checked by HPLC. Once the conversion is considered complete, the reaction mixture is concentrated at 300 mbar to 0.8 vol (vol refers to Kg of starting material (= 1.00 eq) in the stage

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

respective, that is; L / Kg starting material) of the distillate that has been collected. The reaction mixture is diluted with water (2.72 vol), cooled to 20 ° C and the phases are separated. The organic layer is discarded, while the pH of the aqueous layer is adjusted to pH 1 by adding 33% HCI at 20 ° C. MIBK (2.30 vol) and Celite (165 g / Kg) are added and the resulting mixture is stirred for at least 15 minutes at 20 ° C before the solids are filtered off. The reactor and the filter cake are successively lifted with water and the combined filtrate is transferred back to the reactor. The phases are separated and the aqueous layer is washed twice more with MIBK. After dilution with water, the aqueous acidic product solution was heated to 55 ° C and filtered through a plug with Celite on the bottom and activated carbon on the top. The Celite / carbon plug was washed once more with preheated water (0.5 vol, 55 ° C) and the combined filtrate was reloaded into the reactor. At 20 ° C, the pH was adjusted to ~ 3.0 by adding 30% NaOH before the product solution was heated to 60 ° C. More NaOH was dosed to adjust the pH to 4.1-4.3. The resulting suspension was stirred for 1 - 1.5 h at 60 ° C before being cooled to 20 ° C. After further stirring for at least 1 h at this temperature, the product was filtered, washed twice with water, dried in a flow of N2 and finally dried under vacuum at 50-65 ° C. Normal yield: 38-4%.

Stage 2 (amide coupling)

[0075] The reactor was charged with the product of step 1 (1.00 eq) and 4-methyl-2 - (methylamino) -1,3-thiazol-5 sulfonamide (01:02 eq). THF (7:08 vol) and NMP (1.11 vol) are added. The resulting suspension is cooled to 0 ° C before the addition of 1-ethyl-3 - (3-dimethylaminopropyl) carbodiimide hydrochloride (1.23 eq) in 4 equal portions for> 90 min. After at least 2 more hours at 0 ° C, the reaction mixture is heated to 20 ° C. At this temperature, stirring is continued for an additional 2 h before the HPLC conversion is checked. Then, at 10-15 ° C over 2% (0.2 vol) of the reaction mixture is added to the water (12.3 vol) for at least 5 min. The resulting fine suspension is stirred at 10-15 ° C for at least 1 h before dosing the remaining majority of the reaction mixture for> 4 h. Stirring at 10-15 ° C is continued for at least 0.5 h before the solids are filtered off, washed with water and dried on a nutsche filter in a constant flow of N2 until it was considered sufficiently dry ( LOD <45% w / w; LOD: loss on drying).

[0076] The reactor feed was charged with the crude product, THF (8.15 vol), and water (up to 1.17 vol. Depending on the loss in drying of the crude product). The resulting suspension was heated at 60-65 ° C and stirred for 1 h at this temperature. An almost clear solution is obtained which is subjected to filtration of the residues using a lens filter that can be heated heated to 60 ° C. The reactor feed, transfer lines and filter were washed successively with a mixture of THF (0.44 vol) and purified water (0.06 vol) at 60-65 ° C. The combined filtrates were collected in a separate reactor and heated to 50-55 ° C. The content of the reactor, water (3.23 vol) was dosed for at least 30 min. Stirring at 50-55 ° C was continued for 1 -1.5 h before gradually adding a portion of water (8.93 vol.) For 2 hours. After stirring for 1 -1.5 hours at 50 ° C, the resulting suspension was cooled to 5 ° C for 2.5 h and stirred for an additional 0.5 h. Then, the solids were filtered off, washed with water (3 x 2.96 vol) and previously dried on the nutsche filter in a constant flow of N2. Final drying was carried out under vacuum at 50-65 ° C using a conical dryer. Normal yield: 78-83%.

Stage 3 (Salt Formation)

[0077] The reactor was charged with the product of step 2 (1.00 eq), ethanol (4.96 vol) and water (4.96 vol). After heating the resulting suspension at 50-55 ° C, methanesulfonic acid (1.15 eq) was added for <15 min. The complete dissolution of the starting materials was normally observed at the end of the addition. Immediately within the next 5 minutes, stirring was reduced to the minimum acceptable rate and the reaction mixture was seeded with N - [5 - (aminosulfonyl) methanesulfonic monohydrate - 4-methyl -1,3-thiazol-2-yl ] -N-methyl-2 [4 - (2-pyridinyl) phenyl] acetamide (0.005 eq) that was prepared in the desired polymorphic form in a preceding experiment. Slow stirring at 50 -55 ° C was continued for 60 -90 min before cooling to 20-25 ° C for> 2.5 h. After stirring for another 1 hour, the solids were filtered, washed with 5.02 v / v ethanol / water (3.10 vol), dried in a nitrogen flow and transferred to a conical dryer for final drying. in vacuo at 20-60 ° C. Normal yield:> 95%.

Particle Analysis and Detection

[0078] For the liquid dispersion a particle size analyzer Malvern Mastersizer 2000 with a Malvern Hydro 2000 S dispersion unit was used. The dispersing agent was Span ™ 80 was used in a concentration of 0.1% (volume / volume) in n-heptane. The stirring speed was 2500 revolutions per minute. Normally, a mixture of 50 milligrams of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 - [4 - ( 2-Pyridinyl) phenyl] acetamide in a vial containing 4 to 5 mL of dispersant. In the event that any agglomerate has occurred, then it was converted into primary particles by ultrasonic treatment for 10 seconds. Those skilled in the art may recognize that ultrasonic treatment is a common practice in the conversion of agglomerates to smaller particles. Once the suspension had been generated, the suspension was transferred to the Malvern Mastersizer 2000 with a Hydro 2000S dispersion unit by pipetting, until an optimum concentration range was reached. The optimum concentration range was evaluated by the darkening value shown in

E12762305

09-16-2014

the Malvern Mastersizer 2000. Normally, the optimal darkening values range between 10 and 20 percent. Then, the measurement was performed with the automatic subtraction of the antecedent. The data was automatically analyzed using the Fraunhofer diffraction equation. For microscopy, the liquid mixture used for particle size analysis or a new batch was used. The size of the observed particles 5 was determined extracted by the analysis software start 5.0 analysis (Olympus Soft Imaging Solutions GmbH). The procedure described above complies with USP 429 (measurement of particle size light diffraction) and Ph. Eur. 2.9.31 (particle size analysis by laser light diffraction). In addition, the particle size analysis by laser light diffraction, an optical investigation was performed using a microscope. In the case of release measurements, a suitability test of the system must be carried out before dispersion,

10 which is a common practice for experts in the field.

Example 2:

[0079] The tests disclosed in Example 2 were carried out in order to investigate the influence of the particle size distribution (DTP) of the active pharmaceutical ingredient (IFA) on the dissolution properties of the tablet cores. .

[0080] The term "particle size distribution" of a powder or granular material, or particles dispersed in the fluid, as used in this application, is a list of values or a mathematical function that defines the 20 relative quantities of particles present, classified according to their size. The values d (0.1), d (0.5) and d (0.9) indicate that 10%, 50% and 90% of the measured particles are less than or equal to the indicated size. For example, the average of values of d (0.1) = 52, d (0.5) = 129 and d (0.9) = 257 of 10% of the particles was less than or equal to 52 µm, 50% it was less than or equal to 129 µm and 90% was less than or equal to 257 µm (see Table 1, test lot G05). In order to study the dissolution properties of the tablet cores with different

DTP of the invention of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl methanesulfonic acid monohydrate ] acetamide, 100 mg and 25 mg (calculated as free base form) of tablet cores containing the invention of N- [5 - (aminosulfonyl) -4-methyl -1,3- mono-methanesulfonic acid monohydrate were prepared. thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide in an amount of 129 and 32.3 mg, respectively.

30

Type and size of tablet cores

[0081]

35 - 100 mg tablet core, diameter 11 mm - 25 mg tablet core, diameter 7 mm

Equipment

40 [0082] Mix: Bohle MC5 with glass tube

Tablet formation

[0083]

Four. Five

•

Kilian rotary press with a filling shoe chamber.

•

100 mg dose concentration stamping: 11 r11 or 12 r11 with marks for cutting on one site

•

Stamping concentration of 25 mg dose: 7r6

50 Analysis

[0084]

• Dissolution (1,000 ml, 0.1 M HCl, vane apparatus according to 2 USP apparatus, pallet speed 50 55 revolutions per minute, n = 6)

Compounds (IFA, active pharmaceutical ingredient)

[0085] IFA: N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol -2-yl] - N - methanesulfonic acid monohydrate

60-methyl - 2 - [4 - (2-pyridinyl) phenyl] -acetamide, in which at least 65% v / v of mono- methanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide which decrease at a particle size range of 2 to 500 micrometers (µm).

[0086] G01, G02, G03, G04, G05 are five different test batches of the N-[5 - (aminosulfonyl) methanesulfonic acid monohydrate - 4-methyl-1,3-thiazole-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl]

E12762305

09-16-2014

acetamide, characterized in that the particle size is in a range of 1 to 400 µm with a particle size distribution of d (0.1) d (0.5) and d (0.9) as shown in Table 1

Table 1: Particle size distribution / DTP) of different batches of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - methanesulfonic acid monohydrate [4 - (2-pyridinyl) phenyl] acetamide.

IFA Lot Number

Assay Lot Number Particle size distribution Specific surface

d (0.1) [µm]

d (0.5) [µm] d (0.9) [µm] [m2 / g]

BXR4FLS

G01 3 51 102 0.7

BXR3NC1

G02 43 118 254 0.1

NE-023932 - A - 4 -26 crude 1 # 1 M1

G03 one 4 eleven 2.4

NE - 023932 - A - 4 -27 IPC 1 # 1

G04 22 66 143 0.2

NE-023932 - lot - 02-2010

G05 52 129 257 0.1

Preparation of the final mixtures [0087] Five final mixtures (batches G01 to G05) were prepared with different IFA batches. Core formulations (dose concentration of 25 mg and 100 mg (calculated as free base form) 25 Table 2: Formulation of 25 mg and 100 mg strength dose (calculated as free base)

Component

Mg per 25 mg tablet Mg per 100 mg tablet

N - [5 (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] -acetamide mono methanesulfonic acid monohydrate

32.3 (salt) 129.0 (salt)

Microcrystalline cellulose

60.9 243.4

Croscarmellose sodium

9.8 39.0

Mannitol

20.0 80.1

Colloidal anhydrous silica

1.3 5.0

Magnesium stearate

0.9 3.5

Total final mix

125.2 500.0

[0088] The final mixtures were prepared by sieving the raw materials using a 1.0 mm sieve. Mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) -phenyl] -acetamide that is, the IFA, in which the particle size distribution ranges from 1 to 400 mm, microcrystalline cellulose, croscarmellose sodium, mannitol and anhydrous colloidal silica were mixed for 30 minutes in a free fall mixer. Magnesium stearate was added, and the mixtures were mixed for an additional 5 minutes. No problems were observed during the process.

[0089] The residual properties of lots G01 to G05 are shown in Tables 3 and 4.

Table 3: Residual properties of final mixtures

Parameter

G01 G02 G03 G04 G05

Bulk Density [g / ml]

0.413 0.435 0.385 0.403 0.440

Density compacted [g / ml]

0.510 0.526 0.563 0.500 0.550

Fluency [cot]

1.25 1.16 0.893 1.09 1.28

[0090] A significant difference in bulk density was observed in lot G03. This was the final mixture, which contains the micronized IFA. Therefore, the bulk density was lower compared to mixtures containing thicker IFA.

[0091] Lot G03 also had the worst fluidity of all final mixtures. This can also be explained by the use of micronized IFA.

Tablet formation

[0092] The final mixtures from batches G01 to G04 and a portion of lot G05 of the final blend are

65 compressed as a dose concentration of 100 mg. The other part of lot G05 of the final mixture was compressed as a dose concentration of 25 mg.

E12762305

09-16-2014

[0093] No further problems occurred during the compression of batches G01, G02, G04 and G05 of 100 mg dose concentration,

[0094] Surprisingly, it was discovered that the weight of the tablet was fluctuating during batch compression

5 G03. Unexpectedly, there were problems with weight uniformity. In addition, the mass of the tablet adhered to the prints. It was obvious that both problems were caused by the use of micronized IFA. Therefore, it is advantageous to omit a micronization stage for tablet formation, which will result in better handling and less production time.

[0095] Compression of the G05 batch of 25 mg dose concentration was performed without problems.

[0096] The IPC data (controls during the process) of lots G01-G05 are shown in Tables 4 and 5.

fifteen

Table 4: CPI data of the 100 mg concentration

Parameter

Nominal value G01 G02 G03 G04 G05

Weight [mg]

485-515 498 500 497 506 516

Diameter [mm]

10.8 - 11.2 12.1 12.1 12.1 12.1 12.1

Height [mm]

decide 5.7 - 5.8 5.7 5.7 - 5.8 5.7 5.6 - 5.7

Hardness [N]

> 50 73 70 67 74 87

Disintegration [min]

<5 20 -30 sec 15 -25 sec 20 -30 sec 20 -25 sec 15 -25 sec

Table 5: CPI data of 25 mg concentration

Parameter

Nominal value G05

Weight [mg]

122-128 127

Diameter [mm]

6.8 - 7.2 7.1

Height [mm]

decide 3.6 - 3.7

Hardness [N]

> 50 56

Disintegration [min]

<5 20-28 sec

Analysis

[0097] Oral tablets or capsules remain one of the most effective means of treatment available. The effectiveness of such dosage forms is based on the dissolution of drugs in the fluids of the gastrointestinal tract before absorption in the systemic circulation. Therefore, the dissolution rate of the tablet or capsule is crucial.

[0098] Dissolution: The criteria for dissolution in media with a pH of 1 is Q = 75 after 45 minutes.

Influence of the particle size distribution on the solution:

[0099] Dissolution of batch cores G01 to G05 was carried out. The dissolution results are shown in Figure 8 and Table 6.

Table 6: Dissolution results for lots G01 - G05

fifty

55

Lot

fifteen 30 Four. Five

Half [%]

Min [%] Max [%]  Half [%] Min [%] Max [%]  Half [%] Min [%] Max [%]

G01 100 mg

90 83 97 93 85 99 96 90 99

G02 100 mg

82 80 84 90 88 91 91 90 94

G03 100 mg

100 98 101 100 97 102 100 98 102

G04 100 mg

99 97 100 100 98 102 101 101 102

G05 100 mg

90 87 93 99 98 102 103 102 105

G05 25 mg

102 101 104 104 102 105 104 102 105

[0100] The dissolution results of lots G01-G05 are according to the specification. There are no significant differences in the dissolution of nuclei, which contains thinner or thicker IFA.

[0101] Content uniformity (UC): Content uniformity of lots G01 to G04 was tested. The results are shown in Table 7.

65

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

Table 7: Results of the UC of lots G01 - G04

Lot

Test average (%) Standard deviation Acceptance Value

G01

98.2 1.1917 3.2

G02

101.2 1.2599 3.0

G03

97.9 3.1110 8.1

G04

103.3 1.3640 5.1

[0102] All results comply with the European Pharmacopoeia 2.9.40. The uniformity of the content of lot G03 is lower compared to the uniformity of content of the other lots. It is obvious that this is related to problems during compression based on micronized IFA.

CONCLUSIONS

[0103] The IFA particle size distribution has an influence on the residual properties of the final mixture and the tablet formation characteristics. Lot G03, which contains the micronized IFA, has a worse fluidity. Therefore, problems with a uniform weight occurred during compression. In addition, adhesion problems were observed and the UC results of the nuclei are not as good as the results of the nuclei with non-micronized IFA. Through the use of non-micronized IFA, there was no influence of the particle size distribution, where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 at 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0, 5) 100 to 175 µm, d (0.9) 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, obtained in weight uniformity and UC. The results do not show a marked influence of the particle size distribution on the dissolution of the nuclei since they are all within the predefined ranges.

Example 3:

[0104] Tablet containing 60 mg of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 [4 - (2-pyridinyl) -phenyl] acetamide (corresponding according to the invention to 76.9 mg of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide), where at least 65% v / v are mono-methanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) - 4-methyl -1,3 - thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide, where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d ( 0.5) from 30 to 210 µm and D (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) of 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm, with a specific surface of particles smaller than 0.3 m2 / g; Active compound content over 59% (based on an unpainted tablet):

Shape

crystalline from monohydrate from acid monkey 76.9 mg

N methanesulfonic

-[5 - (aminosulfonyl) - 4 –methyl -

1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl]

-acetamide

Avicel PH 101

118.0 mg

Lactose, fine

40.0 mg

Ac - Say -Sol

20.0 mg

Polyvinylpyrrolidone 25

10.0 mg

Magnesium stearate

2.0 mg

Total weight

266.9 mg

Example 4:

[0105] Tablet containing 50 mg of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 [4 - (2-pyridinyl) -phenyl] acetamide (corresponding according to the invention to 76.9 mg of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide), where at least 65% v / v are mono-methanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) - 4-methyl -1,3 - thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide, where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d ( 0.5) from 30 to 210 µm and D (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g,

E12762305

09-16-2014

and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm, with a specific surface area of particles smaller than 0.3 m2 / g; Active compound content over 59% (based on an unpainted tablet):

5

Crystalline form of mono acid monohydrate 64.0 mg methanesulfonic acid from N - [5 - (aminosulfonyl) -4-methyl 1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide Polyvinylpyrrolidone 25 3.5 mg

10

Microcrystalline cellulose 20.0 mg Croscamellose sodium 10.0 mg Magnesium stearate 0.9 mg

3.0 mg

Optional HPMC varnish 15 Total weight 101.4 mg

Example 5:

[0106] The crystalline structure of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl 20 -1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2 - pyridinyl) phenyl] - acetamide of the Formula C19H24N4O7S3, M = 516.62, F

(000) = 540, color plate, size 0.02 · 0.13 · 0.15 mm3, triclinic space group P -1, Z = 2, a = 9.4908 (7) A, b = 9.5545 (7) A, c = 14.4137 (9) A, α = 86,130 (3) º, β = 72,104 (3) º, γ = 68,253 (4) º, V = 1153.68 (15) Å3, Dcalc . = 1,487 Mgm-3. The crystal was measured on a Nonius KappaCCD diffractometer at 293 K using monochromatic graphite Mo-Kα radiation with λ = 0.71073 Å, Θmax = 30.065 °. Minimum / maximum transmission 0.95 / 0.99, µ = 0.370 mm

25 1. The COLLECT suite has been used for data collection and integration. Of the 43,492 reflexes in total, 6761 were independent (fusion r = 0.026). Of these, 4955 were considered observed (l> 3.0σ (l)) and were used to refine 298 parameters. The structure was solved by direct methods using the SIR92 program. The refinement of minimum squares against F was carried out on all atoms without hydrogen using the CRYSTALS program. R = 0.0313 (observed data), wR = 0.0432 (all data), GOF = 1.0736. Electronic density

30 minimum / maximum residual = -0.28 / 0.33 and Å-3. Chebychev polynomial weights were used to complete the refinement. [0107] Table 8 shows parameters of the single crystal structure of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl -2 - [4 - (2 pyridinyl) phenyl] acetamide.

35

Table 8. Parameters of the single crystal structure of N-[5 (aminosulfonyl) mono-methanesulfonic acid monohydrate crystal-4-methyl -1,3-thiazol-2-yl] - N-methyl -2 - [4 - ( 2-pyridinyl) phenyl] acetamide.

40

Four. Five

fifty

55

60

65

Parameter

Value

Formula

C19H24N4O7S3

Formula Weight

516.62 g / mol

Z, calculated density

2, 1,487 Mg X m-3

F (000)

540

Crystal description and size

Color plate, 0.02 X 0.13 X 0.15 mm3

Absorption coefficient

0.370 mm-1

Min / max transmission

0.95 / 0.99

Temperature

293 K

Radiation (wavelength)

Mo Kα (λ = 0.7103 Å)

Crystal system, space group

Triclinic, P -1

TO

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 Θ

2,426 ° / 30,065 °

Number of reflections collected

43492

Number of independent reflections

6761 (fusion r = 0.026)

Number of observed reflexes

4955 (l> 3.0σ (l))

Number of refined parameters

298

R

0.0313 (data observed with)

rW

0.0432 (all data)

Goodness of fit

1.0736

Residual electron density

-0.28 / 0.33 eÅ-3

E12762305

09-16-2014

[0108] An advantage of the tablets according to the invention is that the tablet will have an optimized dissolution rate based on the particle size distribution of the crystalline form of mono-methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4 - methyl -1,3-thiazol-2-yl] - N-methyl -2 - [4 - (2 pyridinyl) phenyl] acetamide, where the particle size distribution is preferably determined by d (0.1) of 2 5 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1 ) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, and therefore, the drug it can be absorbed into the bloodstream much faster than compared to N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) ) -phenyl ] crystalline base acetamide. In addition, the amazing

10 dispersion times obtained with the tablets according to the invention are advantageous for swallowable tablets. In a further embodiment, the tablets according to the invention can be presented for dispersion in water.

[0109] Therefore, pharmacokinetic studies were carried out in human subjects after administration of both single and multiple doses of the monohydrate salt of N- [5 - (aminosulfonyl) -4-mesylate monohydrate.

- methyl -1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] -acetamide, where the particle size distribution is preferably determined by d (0.1 ) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of the particles of less than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm, with a specific surface area of particles smaller than

20 0.3m2 / g.

[0110] The single oral doses of the salt mesylate monohydrate of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) ) phenyl] -acetamide using the formulations according to example 2, Table 2, were administered to six volunteers per dose stage. The general form of plasma concentrations against

25 time profiles were similar in all doses.

[0111] There was a rapid and continuous increase in interchangeable plasma switching concentrations in a period of markedly slower absorption rate and evidence of a stagnation effect on exposure. From there to there, for all the doses investigated, there was a decrease in concentrations

30 departure after 4.0 to 4.5 hours after administration. This phase was followed by a prolonged exposure phase, which was characterized by a long half-life, which is favorable for the treatment of infectious diseases. The mean terminal elimination half-life (t1 / 2z) ranged between 52 h and 85 h.

[0112] For doses of 5 mg to 480 mg there was a proportional increase in the dose in the AUC∞ (AUC, area under the

35 curve); a single dose of 600 mg did not cause any further increase in exposure, as shown by AUC0-∞ (see Figure 9).

[0113] Maximum plasma concentrations were linearly related to doses of 5 mg to 400 mg. At the highest dose of up to 600 mg, no further increase in exposure was obtained, as shown

40 for both the Cmax and the AUC0-∞. The average tmax ranged between 1.5 and 4.25 hours without any obvious dose relationship. A summary of the single dose pharmacokinetic parameters is shown in Table 9.

[0114] Table 9: Pharmacokinetic parameters after increasing single oral doses of the monohydrate salt of N - [5 - (aminosulfonyl) - 4-methyl -1,3-thiazol-2-yl] -N-methyl - 2 - [4 - (2

45 -pyridinyl) phenyl] -acetamide in the formulations according to the formulation described on page 20 where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 at 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0, 5) 100 to 175 µm, d (0.9) 200 to 350 µm, with a specific surface area of particles smaller than 0.3 m2 / g.

50 [0115] Next, the abbreviations used in Table 9 are defined.

[0116] AUC0-∞: Area under analyte versus concentration time from the moment of administration to infinity, calculated as

55

image12

where AUC0-last is defined as the area under the analyte versus the concentration time to the time of the last qualifying concentration, calculated by the linear sum up / down and Clast is defined as the last observed concentration of the quantifiable analyte. λz is the apparent terminal elimination rate constant, determined

65 due to the linear regression of the terminal points of the Inlinear analyte time-concentration curve.

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

Cmax is the maximum analyte concentration observed and tmax is the time to reach Cmax; t1 / 2z is defined as the apparent terminal elimination half-life, calculated as

image13

where λz is defined as above.

[0117] TMR: Average residence time; Calculated AUMC divided by the AUC, in which AUMC is the area under the first moment of the concentration-time curve from zero to ∞ with the extrapolation of the terminal phase and the AUC is the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase.

[0118] CL / F refers to the distance after oral administration of a drug and Ae refers to the amount of drug that is excreted in the urine.

Table 9:

Dose [mg]

Parameter (mean; n = 6 volunteers / dose)

AUC0-∞∞ [ng · h / mL]

Cmax [ng / mL] tmax to [h] t1 / 2z [h] TMR [h] CL / F [L / h] Ae [% of dose]

5

5800 74 4.00 80 117 0.89 0

10

11670 170 1.50 85 116 0.87 0

twenty

18540 2. 3. 4 2.77 76 105 1.10 0

40

40680 608 3.50 72 94 1.00 0

80 men

87220 (99790) b 1306 (1499) b 2.50 74 94 0.94 0.16

80 women

96230 (90050) b 1999 (1853) b 4.00 58 77 0.85 0.31

160

130800 2613 3.50 63 83 1.28 0.15

240

216900 3600 4.00 64 82 1.15 0.21

320

241100 4648 2.25 57 70 1.47 0.16

400

320300 6926 4.25 57 64 1.31 0.15

480

387200 6921 3.25 53 72 1.33 0.26

600

320800 6442 4.25 52 65 2.00 0.09

to. For tmax, the average is given; b. normalized value for the body weight of a 70 kg subject;

[0119] Based on data for the 80 mg dose, women appeared to exhibit greater exposure compared to men according to AUC∞ and Cmax (see Table 9). However, normalization of body weight revealed that this apparent difference could be explained by the lower body weight of volunteer women compared to men. Therefore, clinical relevance of any differences related to the gender of pharmacokinetics should not be expected.

[0120] Summary of the results of Example 6: For doses of 5 mg to 400 and 480 mg, respectively, there was an increase in AUC∞ and Cmax with the linear dose, that is, proportional to the dose; higher doses do not increase exposure. The mean terminal elimination half-life (t1 / 2z) ranged between 52 h and 85 h. No clinical difference related to the relevant gender was detected in the exposure of a single dose of 80 mg.

Example 7:

Multiple doses staggered and pharmacokinetics

[0121] For the three doses of the monohydrate salt of N- [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) mesylate ) phenyl] acetamide in the formulation according to example 1, Table 2, where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 a 175 µm, d (0.9) 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, was investigated (5, 25, and 100 mg, one oral administration per day, 20 days), Individual concentration curves - N - [5 - (aminosulfonyl) - 4 - methyl - 1,3 - thiazol - 2 - yl] N methyl - 2 - [4 - (2 pyridinyl) phenyl] acetamide on day 1 ( after the first administration) they were very similar in their general form and the slope in those profiles obtained in the staggered single dose test (see Example 6). As for the single-dose step test presented in Example 6, there were proportional increases in the dose in AUC0-24h and Cmax on day 1.

[0122] During the 20-day treatment with the administrations of the mesylate monohydrate salt of N- [5 (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide, where the

fifteen

25

35

Four. Five

55

65

E12762305

09-16-2014

Particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a smaller specific surface area of particles at 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm with a specific surface of particles less than 0.3 m2 / g, once a day, the achievement of constant state conditions was demonstrated by virtually identical minimum concentrations or "minimum point" concentrations of N - [5 - (aminosulfonyl) - 4 - methyl -1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide achieved between days 9 and 13. In a constant state, there was a low interindividual variability of the minimum concentrations or "minimum point" with CVs (coefficient of variation) between 16.7 and 21.7% (day 21). For all doses, the individual and the mean concentration curves - N-time [- 5 - (aminosulfonyl) - 4 - methyl -1,3 - thiazol - 2 -il] - N - methyl - 2 - [4 - (2 pyridinyl) phenyl] acetamide on day 21 was very similar in shape and pending the profiles obtained on day 1.

[0123] Table 10 summarizes the pharmacokinetics of the constant state of N - [5 - (aminosulfonyl) -4-methyl-1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) ) phenyl] acetamide.

[0124] Table 10: Pharmacokinetic parameters of the steady state of N- [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl ] acetamide on day 21 after daily administrations of 5, 25,

or 100 mg of the monohydrate salt of N - [5 - (aminosulfonyl) -4-methyl -1,3-thiazol-2-yl] - N-methyl -2 [4 - (2-pyridinyl) phenyl] acetamide mesylate in the formulation according to example 2, Table 2, where the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9 ) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) 200 to 350 µm, with a specific surface area of particles smaller than 0.3 m2 / g, in healthy volunteers (n = 12 per dose).

[0125] The abbreviations used in Table 10 are defined below.

[0126] Dependent: measurement of plasma concentration immediately before dosing on day 21 (at the end of the steady state dosing interval); AUCT, that is, the AUC in constant state (area under the curve) within the 24-hour dosing interval, Cmax, ss refers to the maximum analyte concentration observed in the constant state. Cav is defined as the mean plasma concentration during the dosing interval of the monohydrate salt of N - [5 - (aminosulfonyl) - 4-methyl -1,3-thiazol -2-yl] –N methyl -2 - [4 - (2-Pyridinyl) phenyl] acetamide in constant state, R-AUC refers to the accumulation rate of AUC, that is AUCT / AUC0-24h, day1, R -Cmax refers to the accumulation ratio of Cmax, that is, Cmax, ss / Cmax, day1; t1 / 2z as defined as above.

Table 10:

Dose [mg]

Cmín [ng / mL] AUCT [ng · h / mL] Cmax, ss [ng / mL] Cav [ng / mL] R - AUC R - Cmax T1 / 2z [h]

5

187 2059 301 213 5.2 5.0 82.6

25

832 23430 1358 977 5.3 5.3 68.6

100

3743 108800 6358 4540 5.1 5.3 59.8

[0127] For the three doses applied, there was a proportional increase in the dose for all exposure measurements in constant state (Cpendiente, AUCT, Cmax, ss, and Cav) (see Table 10).

[0128] Therefore, the AUC and Cmax, the accumulation ratio R of all applied doses was very similar to a factor of 5 (see Table 10).

[0129] The time to reach Cmax, ss was similar for the three doses (0.5 to 4.5 h). The fluctuation of peak - minimum point in constant state ranged between 59 and 64%.

[0130] Half-life elimination was in the same range as after single dose application with 82.6 h (5 mg), 68.6 h (25 mg), and 59.8 h (100 mg) . The apparent total clearance (CL / F) was estimated to be similar for all doses investigated (0.99 to 1.08 L / h).

[0131] Summary of the results of Example 7: Under steady-state conditions, an increase in the dose of the monohydrate salt of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2 - il] -N-methyl-2 - [4 - (2 pyridinyl) phenyl] acetamide in the formulation according to example 2, Table 2, in which the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d ( 0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) from 200 to 350 µm with a specific particle area of less than 0.3 m2 /

E12762305

09-16-2014

fifteen

25

35

Four. Five

55

g, resulted in a proportional increase in exposure to N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide. In general, steady state plasma concentrations are expected approximately five times greater than after the administration of a single dose of the same dose of this being a reflection of the half-life and the dosage range. The interindividual variability of the exposure in constant state was quite low as revealed by a low coefficient of variation, for example, for minimum concentrations or "minimum point" and maximum and minimum fluctuations. The elimination rate and terminal half-lives in the steady state was comparable to the situation of a single dose.

[0132] These results clearly demonstrate that the use of the monohydrate salt of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2 -pridinyl) phenyl] -acetamide, in which the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0 , 9) from 70 to 400 µm with a specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) from 100 to 175 µm, d (0.9) of 200 to 350 mm, with a specific surface area of particles smaller than 0.3 m2 / g in the formulations as described above, one dose once a day (or even less frequent administration) It is sufficient to reach an adequate plasma concentration for the treatment of viral diseases, for example, infection with one or some herpes viruses. In addition, in a human test, it has been shown that administration of a dose greater than 400 mg to 600 mg and preferably about 500 mg of the mesylate monohydrate salt of the present invention is also sufficient to achieve an adequate plasma concentration. for the treatment of viral infections diseases, for example, infection by one or some herpes viruses.

Description of the figures

[0133]

Figure 1

shows the superposition of x-ray diffractions of powders obtained after

granulation experiments; from top to bottom:

N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl - mesylate monohydrate

2 - [4 - (2-pyridinyl) phenyl] acetamide

N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl]

acetamide (free base),

N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl]

acetamide, free base granulation using 1 equivalent methanesulfonic acid according to

WO 2006/103011, example 5; the bottom curve shows the granulation matrix in

White.

A 1: 1 mixture (weight: weight) of free base and diffraction mesylate monohydrate was analyzed

X-ray of powders as a calibration of the ratio of free base to salt. The relationship was calculated

based on the integration and shows the granulation mix that has a content of the

8 to 12 percent mesylate monohydrate form.

Figure 2

shows the superposition of the x-ray diffraction spectra of granulation powders of

a mixture of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl

- 1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide with mono acid

methanesulfonic acid from N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2

-pyridinyl) phenyl] acetamide after closed storage at 40 ° C for four

weeks (above), after storage closed at 40 ° C for four days (medium) and of

the initial sample, that is, the mixture of mono-methanesulfonic acid monohydrate of N - [5

(aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide

with N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N - mono methanesulfonic acid

methyl - 2 - [4 - (2-pyridinyl) phenyl] acetamide.

Figure 3

shows microscopy images of

A) free base form,

B) crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4 -

methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide and

C) the spontaneous crystallized material after the addition of methanesulfonic acid.

Figure 4

shows the x-ray structure of N - [5 - mono methanesulfonic acid monohydrate

(aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide

with indicated hydrogen bridges. It shows that the nitrogen atom in the ring of

pyridinyl (lower right) is protonated and a hydrogen bridge is formed between the

hydrogen, which protonates the pyridinyl ring nitrogen and an oxygen from the mesylate anion, and forms

another hydrogen bridge between another oxygen of the mesylate anion and the hydrogen of the molecule

water while the other hydrogen in the water molecule forms a hydrogen bridge with the

oxygen from the other anion mesylate.

Figure 5

shows the X-ray diffraction spectrum of powders of a film-coated tablet

with 5 mg of N - [5 - (aminosulfonyl) -4-methyl - mono methanesulfonic acid monohydrate

1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide, in which the distribution of

particle size is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to

E12762305

09-16-2014

5 10 15 20 25 30

Figure 6 Figure 7 Figure 8 Figure 9 210 µm and d (0.9) from 70 to 400 µm with specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) of 200 to 350 µm with specific surface area of particles smaller than 0.3 m2 / g, one placebo tablet and N - [5 - (aminosulfonyl) mono methanesulfonic acid monohydrate - 4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide after 24 months at 25 ° C. shows the X-ray diffraction spectrum of powders of a film-coated tablet with 25 mg of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide, in which the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0 , 5) 100 to 175 µm, d (0.9) of 200 to 350 µm with specific surface area of particles smaller than 0.3 m2 / g, one placebo tablet and N - [5 - mono methanesulfonic acid monohydrate. (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamities after 24 months at 25 ° C shows the ray diffraction spectrum X of powders of one tablet r film-coated with 100 mg of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) methanesulfonic acid monohydrate ) phenyl] acetamide, wherein the particle size distribution is preferably determined by d (0.1) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 at 400 µm with specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d (0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9 ) from 200 to 350 µm with a specific surface area of particles smaller than 0.3 m2 / g, a placebo tablet and N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazole mono-methanesulfonic acid monohydrate - 2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide after 24 months at 25 ° C. shows the dissolution curves of the six different tablets according to Table 7. shows the relationship between the individual doses (5 mg -600 mg) of tablets containing mono-methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) - 4 - methyl-1,3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide, in which the particle size distribution is preferably determined by d (0.1 ) from 2 to 100 µm, d (0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm with specific surface area of particles smaller than 1.0 m2 / g, and more preferably defined by d ( 0.1) from 10 to 75 µm, d (0.5) 100 to 175 µm, d (0.9) from 200 to 350 µm with specific surface area of particles smaller than 0.3 m2 / g, and the AUC∞ , measured as N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) phenyl] acetamide.

35

40

Four. Five

fifty

55

Claims (14)

5 fifteen 25 35 Four. Five 55 65 E12762305 09-16-2014 Claims 1. Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) - phenyl] acetamide of the following formula image 1 in which the mono- methane sulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide have a particle size range of 1 to 500 µm, with a particle size distribution defined by d (0.1) of 2 to 100 µm, d (0.5) of 30 to 210 µm and d (0.9) from 70 to 400 µm and a specific surface area less than 1.0 m2 / g. 2. Crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) - phenyl] acetamide according to claim 1, wherein the mono- methane sulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl - 2 - [4 - (2-pyridinyl) -phenyl] acetamide have a particle size range of 2 µm to 400 µm.

3.

Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide according to any of the preceding claims, wherein the mono- methane sulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide have a particle size distribution defined by d (0.1) of 10 to 75 µm, d (0.5) of 100 to 175 µm, d (0 , 9) from 200 to 350 µm.

Four.

Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide according to any of the preceding claims, wherein the mono- methane sulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide have a specific surface area of less than 0.3 m2 / g.

5.

Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide according to any of the preceding claims in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir, famciclovir and / or valganciclovir.

6.

Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] Acetamide according to any of the preceding claims for use in the treatment and / or prophylaxis of infectious diseases and / or the prevention of transmission of an infectious disease.

7.

Crystalline form of mono methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide according to claim 6, wherein the infectious disease is an infection caused by the herpes simplex virus.

8.

Pharmaceutical composition containing particles of the crystalline form of mono- methanesulfonic acid monohydrate of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - ( 2-Pyridinyl) phenyl] acetamide, in which the monohydrate particles of N - [5 - (aminosulfonyl) - 4 - methyl - 1, 3 - thiazol - 2 - yl] - N - methyl - 2 - mono methanesulfonic acid monohydrate [4 - (2-pyridinyl) -phenyl] acetamide have a particle size range of 1 to 500 µm, with a particle size distribution defined by d (0.1) of 2 to 100 µm, d ( 0.5) from 30 to 210 µm and d (0.9) from 70 to 400 µm and a specific surface area less than 1.0 m2 / g together with at least one pharmaceutically acceptable carrier, excipient, solvent and / or diluent.

9.

Pharmaceutical composition according to claim 8, wherein the monomethanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-Pyridinyl) phenyl] acetamide have a particle size range of 2 µm to 400 µm.

10.

Pharmaceutical composition according to claim 8 or 9, wherein the mono- methane sulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] -N-methyl-2 - [4 - (2-pyridinyl) -phenyl] acetamide have a particle size distribution defined by d (0.1) of 10 to 75 µm, d (0.5) of 100 to 175 µm, d ( 0.9) from 200 to 350 µm.

27 E12762305 09-16-2014 11. Pharmaceutical composition according to any one of claims 8 to 10, wherein the mono- methanesulfonic acid monohydrate particles of N - [5 - (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl] - N - methyl - 2 - [4 - (2-pyridinyl) -phenyl] acetamide have a specific surface area of less than 0.3 m2 / g. 5 12. Pharmaceutical composition according to any one of claims 8 to 11 in combination with acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir, famciclovir and / or valganciclovir. 13. Pharmaceutical composition according to any one of claims 8 to 11 for use in the treatment and / or prophylaxis of infectious diseases and / or prevention of transmission of an infectious disease. 14. Pharmaceutical composition for use according to claim 13, wherein the infectious disease is a Herpes simplex virus infection. fifteen 15. Pharmaceutical composition for use according to claims 13 or 14, wherein the pharmaceutical composition is administered three times a day, twice a day, once a day, three times a week, twice a week, or once per week twenty 25 30 35 40 Four. Five fifty 55 28