CA2939529A1

CA2939529A1 - N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate

Info

Publication number: CA2939529A1
Application number: CA2939529A
Authority: CA
Inventors: Alexander Birkmann; Alfons Grunenberg; Dieter Haag; Birgit D.I. Keil; Andreas Lender; Stephan Mass; Kerstin Paulus; Joachim Rehse; Kristian Ruepp; Wilfried Schwab; Kurt Vogtli
Original assignee: Aicuris GmbH and Co KG
Current assignee: Aic316 GmbH
Priority date: 2011-09-26
Filing date: 2012-09-26
Publication date: 2013-03-26
Anticipated expiration: 2032-09-26
Also published as: CA2939529C

Abstract

The present invention relates to an improved and shortened synthesis of N -[5-aminosulfonyI)-4-methyl-1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide and the mesylate monohydrate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds and to the mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl] -N-methyl-2-[4-(2-pyridinyl)phenyl]acet-amide which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions. Also the present invention relates to the crystalline mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl] acetamide in a definite particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl) phenyl]acetamide mesylate monohydrate having the afore-mentioned particle size distribution and specific surface area range.

Description

N-(5-(Aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyliacetamide mesylate monohydrate Specification The present invention relates to an improved synthesis of N-[5-(anninosulfony1)-4-methyl-1,3-thiazol-2-y1]-1\1-methyl-2-[4-(2-pyridinyl)phenyl]acetamide and the mesylate monohydrate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds and to the mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyl]acet-amide which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions.
Background of the invention Synthesis of Ni5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide is known from EP 1244641 B1, and the use of acidic components including methanesulfonic acid for the formulation of tablets containing micronized N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y9-N-methyl-

2-[4-(2-pyridinyl)phenyl]acetamide is disclosed by WO 2006/103011 Al.
It is the objective of the present invention to provide an improved synthesis for the compound N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridinyl) phenyl]acetamide and a stable salt which exhibits increased long term stability and improved release kinetics from pharmaceutical formulations as well as a pharmaceutical formulations comprising that salt with improved release kinetics.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
Description of the invention The present invention relates to an improved and novel synthesis of the pharmaceutically active compound N-15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide as well as its mesylate salt.
This improved synthesis starts from the same compounds as the older known synthesis of the state of the art but combines three reaction steps by the use of a boronic acid AIC-P03329CA01 Application doc derivatives or borolane reagent. This modification makes the complete synthesis easier by avoiding two separation and purification steps and is also able to increase the yield.
The older known synthesis as described in EP 1244641 B1 on page 21 starts from 2-bromopyridine. In step 1 the 2-trimethylstannanylpyridine is prepared in a 45 to 50% yield (of the theory).
The 2-trimethylstannanylpyridine is subsequently reacted with ethyl (4-bromophenyl)acetate in order to obtain the ethyl (4-pyridin-2-ylphenyl)acetate in a 75% yield.
In the third step the ethyl (4-pyridin-2-ylphenyl)acetate is saponified to the (4-pyridin-2-ylphenyl)acetic acid with about 95% yield of theory. Consequently, the state of the art synthesis as shown below Br ,E3r Step 1 Sn(C1-13)3 Step 2, 75% 401 \,-NI 45-50% \-,-N Step 3, NaOH / Et0H, 95% N
comprises 3 steps with an over all yield of about 34% including two separation and purification steps which take time and involve the use of solvents for extracting and washing the desired compounds as well as arrangements for purifying them.
The synthesis of the present invention as shown below H
cooc2H5 /
0¨B

+ Pd(OAc)2, PPh3, Et3 N

Br 0¨B
toluene, reflux 1 1 Step NaOH CI
40%

N
COOH

N
AIC-P03329CA01 Applicatton.doc

3 combines the three discrete steps by using boronic acid derivatives or borolane or a borinane reagent which allows for synthesis of the key intermediate (4-pyridin-2-ylphenyl)acetic acid in a single stage with an over all yield of about 40% of theory avoiding the two separation and purification steps of the state of the art synthesis.
As an added benefit, the use of boron containing reagents is advantageous over the use of the toxic organic tin compounds in that the resulting boric acid by-product can be easily removed by an aqueous wash. In contrast, organic tin compounds are not only a known problem in process waste streams, but are also noted for notoriously contaminating the resulting products of the down-stream synthesis.
The (4-pyridin-2-ylphenyl)acetic acid is reacted with 4-methy1-2-(methylamino)-1,3-thiazole-5-sulfonamide to the final product which is then converted to the definite mesylate monohydrate salt as shown below.

H¨N 40 N N
.---" I 10 + )---,,)-N
S.,CH3 THF
I
). ,--- ---....,--CH 1 0 S? ___________________________________________________________________ N N 0_ 0-.../..---s,, NMP
--,--S---ii NH2 Et0H

I
N N
-----=
140 0 S,? CH3 ./
I ,-----S
N,, 0 # "NH2 e H3c¨s03 ,,, H202o Thus the present invention is directed to a method for synthesizing 1115-(aminosulfony1)-4-methy1-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyl]acet-amide and the mesylate salt thereof according to the following steps:
Step A: Reacting compound A of the following general formula A*

A*
R1 1$1 A1C-P03329CA01Application.doc

4 wherein 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, with a boronic acid derivative, borolane, borinane or diboronic acid reagent under elimination of R1¨H or R1-B(OR)2 and formation of an intermediate boronic acid derivative of compound A, wherein preferred catalysts for the reaction are the reagent systems palladium acetate with triethylamine and triphenylphosphine or PdC12(PPh3)2 with triethylamine, wherein the intermediate boronic acid derivative is then reacted with the pyridine compound B of the following general formula B*
IN B*
wherein R3 represents a leaving group under basic conditions in order to obtain the (4-pyridin-2-ylphenyl)acetic acid as an alkaline solution of the corresponding carboxylate salt.
The resulting (4-pyridin-2-ylphenyl)acetic acid was purified by simple washings at different pH and clear filtration steps followed by precipitation or crystallization, preferably by properly adjusting the pH of an aqueous acidic solution of (4-pyridin-2-ylphenyl)acetic acid with an appropriate amount of base to 3.5 ¨ 5.0, preferably 3.8 ¨ 4.7. Beside the simple washing and filtration step, no further purification of the (4-pyridin-2-ylphenyl)acetic acid or any of the intermediates by, for instance, recrystallization or chromatography is required.
Step B: Reacting (4-pyridin-2-ylphenyl)acetic acid obtained from step A
with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide H¨N
oS
(-.)NF12 AIC-P03329CA01 Application doc in order to obtain N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyliacetamide of the formula NN
(10 --S
N 0-7/ 'NH2

5 The N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methy1-244-(2-pyridiny1)-phenyliacetamide is thereafter most preferably converted (as step C) to the so far unknown monohydrate of the mesylate salt of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyljacetamide. It has to be stated that a mesylate salt is disclosed in WO 2006/103011 Al but not the specific mono mesylate monohydrate salt which exhibits the improved properties.
The inventive method for synthesizing the N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridinyl)phenyll-acetamide methanesulfonic acid mono-hydrate may further comprise step D directed to the preparation of a pharmaceutical composition of said methanesulfonic acid monohydrate salt:
Step D: Preparing a pharmaceutical composition of the crystalline N-[5-(anninosulfony1)-4-methy1-1, 3-thiazol-2-yl]-N-methyl-244-(2-pyridi nyl)phenyll-acetamide methanesulfonic acid monohydrate with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.
Such a pharmaceutical composition can be prepared by admixing or blending the crystalline N[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-244-(2-pyridinyl) phenylFacetamide methanesulfonic acid monohydrate together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.
The inventive method may further comprise step E following the step D:
Step E: Adding acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir and/or famciclovir to the pharmaceutical composition of the crystalline N45-(aminosulfony1)-4-methyl-1,3-th iazol-2-y11-N-methy1-2[4-(2-pyrid inyl)phenylFacetam ide methanesulfonic acid monohydrate and at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.
A1C-P03329CA01Application.doc

6 Thus after step E a pharmaceutical composition containing acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir or famciclovir or a pharmaceutical composition containing acetylsalicylic acid and trifluridine or acetylsalicylic acid and idoxuridine or acetylsalicylic acid and foscarnet or acetylsalicylic acid and cidofovir or acetylsalicylic acid and ganciclovir or acetylsalicylic acid and aciclovir or acetylsalicylic acid and penciclovir or acetylsalicylic acid and valaciclovir or acetylsalicylic acid and famciclovir in combination with crystalline N-[5-(aminosulfony1)-4-methy1-1, 3-thiazol-2-A-N-methyl-2-[4-(2-pyrid inyl)pheny1]-acetamide methanesulfonic acid monohydrate together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent is obtained.
Consequently the present invention relates also to a pharmaceutical composition containing acetylsalicylic acid or aciclovir or penciclovir or acetylsalicylic acid and aciclovir or acetylsalicylic acid and penciclovir and crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)pheny1]-acetamide methanesulfonic acid monohydrate together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent. Some suppliers use the name acyclovir instead of aciclovir.
The term "leaving group" as used herein is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl-, BC, and I-, and sulfonate esters, such as para-toluenesulfonate ("tosylate", Ts0-), trifluoromethanesulfonate ("triflate", Tf0-, CF3S020-), benzenesulfonate ("besylate, C6H5S020-) or methanesulfonate ("mesylate", Ms0-).
General formula A* as shown below A*

covers all phenyl acetic acid esters having a leaving group on the phenyl residue in position 4.
Thus R1 preferably represents ¨F, ¨Cl, ¨Br, ¨I, ¨OMs, ¨0Tf and ¨0Ts. The group "¨OMs" refers to ¨0Mesylate, the group "¨OTf" refers to ¨0Triflate and the group "¨OTs" refers to ¨0Tosylate.
A1C-P03329CA01Application.doc

7 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, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -05H11, -C6H13, cyclo-C3H5, cyclo-C4H7, cyclo-05H9, cyclo-C6H1 1. More preferred are -CH3, -C2H5, -C3H7, -CH(CH3)2, -C41-19, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, and -05H11. Especially preferred are -CH3, -C2H5, -C3H7, and -CH(CH3)2.
Various borolanes and borinanes as well as the corresponding diboronic acid derivatives can be used in step A of the inventive synthesis disclosed herein.
Preferred are borolanes of the following general formula:
R'0 OR"
wherein R' and R" are independently of each other any substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms, or R' and R" can also form together with the boron atom a heterocyclic ring wherein R' and R" together form a substituted or unsubstituted, linear or branched alkylen group with 2 to 10 carbon atoms. Preferably R' and R"
represent independently of each other -CH3, -C2H5, -C3147, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, and -05H11. The cyclic borolanes are preferred.
The following borolanes, borinanes and diboronic acid derivatives are preferred:

z N \

Ra 9 Rf Ra,) '(-Rd 0 Rb Re Ru RC RC Rd Borolane Catecholboran Borinane Rd\ Ra ReRf Ra Rb R
Rb ,0C RC
BB
d R b--TRc Rb b --Ra Rd Ra Rf Diborolane Diborinane AIC-P03329CA01 Application.doc

8 wherein Ra, Rb, Rc, Rd, I-(¨e and Rf represent independently of each other a substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms. Preferred are the linear alkyl residues with 1 to 6 carbon atoms, and most preferred are -CH3, -C2H5, -C3H7 and -CH(CH3)2.
Especially preferred examples for the above borone containing compounds are 4,4,5,5-tetramethyl[1,3,2]dioxaborolane (pinacolborane), [1,3,2]dioxaborolane, [1,3,2]dioxaborinane, 5,5-dimethyl[1,3,2]dioxaborinane, 4,6,6-trimethyl[1,3,2]-dioxaborinane, 4,4,6,6-tetramethyl[1,3,2]-dioxaborinane, 4,4,5,5,6,6-hexamethyl[1,3,2]-dioxaborinane, diisopropoxyborane, hexahydrobenzo[1,3,2]di-oxaborole, 9,9-d imethy1-3,5-dioxa-4-bora-tricyclo-[6.1.1.62'6]decane, 6,9,9-trimethy1-3,5-dioxa-4-bora-tricyclo[6.1.1.62'6]decane, B2Pin2 (bis(pinacolato)diborane), bis(neopentylglycolato)diboron and catecholboran.
In step A this boronic acid derivative, borolane, borinane or diboronic acid reagent is reacted with a compound A of general formula A* in order to obtain an intermediate borolan or borinane reagent which is not isolated and purified. This reaction may be supported by the use of either catalysts prepared in situ by combination of palladium salts such as [Pd(OAc)2] and PdC12 with triphenylphosphine (PPh3), tri-ortho-tolylphosphine (P(o-To1)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 a variety of organic and inorganic bases such as triethylamine (Et3N), Na0Ac, KOAc, and K3PO4. For this reaction heating to temperature between 70 C and 150 C, preferably between 80 C and 130 C, more preferably between 90 C and 110 C is preferred. Moreover aprotic and preferably apolar solvents and preferably aromatic solvents such as benzene or toluene or xylenes are used.
This step A improves the state of the art synthesis by avoiding the use of toxic organic tin compounds which are a big problem in the purification of the waste streams as well as the actual product(s) of the reaction which are finally drugs for use in humans.
The intermediate boronic acid reagent is subsequently reacted with a pyridinyl compound of the general formula 6*, wherein R3 represents a leaving group.
Thus R3 represents -F, -Cl, -Br, -I, -OMs, -0Tf and -0Ts and preferably -Cl or -Br.
A1C-P03329CA01Applicabon.doc

9 The corresponding (4-pyridin-2-ylphenyl)acetic acid ester is in situ treated with an aqueous base in order to cleave the ester linkage. It could be advantageous to heat the reaction mixture during the coupling / saponification step to moderate temperature and preferably to temperature between 40 C and 90 C, more preferably between 45 C and 80 C, still more preferably between 50 C and 70 C
and most preferably between 55 C and 65 C.
After purification and isolation of the key intermediate (4-pyridin-2-ylphenyl)acetic acid, the (4-pyridin-2-ylphenyl)acetic acid was obtained in a yield of at least 40% of theory including only one isolation and purification step.
Further advantages of the present method are:
= Purification and Pd removal by successive washes of aqueous alkaline and acidic product solutions with organic solvents (toluene, MIBK, Et0Ac, MeTHF etc.).
= Additional Pd depletion by charcoal / Celite treatment.
= Crystallization is possible from either alkaline or acidic aqueous solutions by neutralization (at preferably 50-70 C) Thereafter the (4-pyridin-2-ylphenyl)acetic acid was reacted with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide of the formula H¨N
os which was prepared according to the synthesis disclosed in EP 1244641 B1 in order to obtain N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide of the formula NN

--S, N 0-'11 NH2 A1C-P03329CA01Application.doc In WO 01/47904 A the amide coupling reaction is described using HOBT (1-Hydroxy-1H-benzotriazole hydrate) in DMF which ¨ due to its explosive character ¨ generally causes problems during up-scaling.
In addition, during the optimization process the solvent DMF had been detected as cause for a variety of 5 by-products (from Vilsmaier type formylations).
Attempts for improved coupling conditions resulted surprisingly in the successful use of EDC x HCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) without HOBT in NMP/THF solvent combinations. Thus Step B of the above-

10 mentioned method is preferably carried out with EDC x HCI as coupling agent (without HOBT) in THF / NMP solvent mixtures having a ratio of 10: 1 to 1:1.
The following re-crystallization from THF / water resulted in a depletion of Pd to < 5 ppm. A total yield of > 80% for coupling and recrystallization could be achieved.
Thus the present invention also relates to the compound N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyl]acetamide obtained according to the synthesis as disclosed herein.
This N15-(am inosulfony1)-4-methy1-1,3-thiazol-2-yli-N-methyl-214-(2-pyrid inyI)-phenyllacetamide was thereafter converted to the crystalline mesylate monohydrate salt which was not disclosed in the state of the art so far. A not stoichiometric -mesylate salt was already known in the state of the art, but not the definite and stoichiometric mono mesylate monohydrate salt having exactly one mol equivalent water and one mol equivalent mesylate per mol equivalent N-[5-(aminosulfonyI)-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide.
Thus the present invention relates to the compound N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenynacetannide methanesulfonic acid monohydrate and especially to crystalline Ni5-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)-phenyliacetamide methanesulfonic acid mono-hydrate as well as to crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate obtainable and obtained according to the synthesis as disclosed herein. The (aminosulfony1)-4-methy1-1, 3-thiazol-2-yll-N-methyl-244-(2-pyridiny1)-phenyl]acet-amide methanesulfonic acid monohydrate is substantially pure (purity above 96 weight-%, preferably > 98 weight-% and more preferably > 99 weight-%) and is the definite monohydrate, i.e. 1 mol N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyllacetamide methanesulfonic acid monohydrate AIC-P03329CA01 Application doc

11 contains 1 mol water and 1 mol mesylate anion in a regular crystalline structure as shown in Figures 2 and 3.
The crystalline mesylate monohydrate salt of N-[5-(aminosulfonyI)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide is formed from a supersaturated solution of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide and methanesulfonic acid by crystallization under controlled conditions. Preferred conditions for the crystallization are the addition of methanesulfonic acid at elevated temperatures, and preferably between 30 C and 90 C, more preferably between 35 C and 80 C, still more preferably between 40 C
and 70 C, still more preferably between 45 C and 60 C and most preferably at ¨ 55 C to the mixture of an organic solvent and water containing N-[5-(aminosu Ifony1)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid i nyl)phenyl]acet-amide yielding a supersaturated solution of the mesylate of N-[5-(aminosulfonyI)-4-methyl-13-thiazol-2-y1]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.
Organic solvents which are miscible or consolute with water are preferred such as Me0H, Et0H, n-PrOH, I-PrOH, acetonitrile, THF, acetone. Moreover it is preferred to add seed crystals of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate to this supersaturated mixture also at elevated temperatures like 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. Also moderate to slow stirring of this mixture and a slow cooling of this mixture to room temperature are preferred.
Furthermore it is preferred to add the methanesulfonic acid over 5 to 15 minutes at the elevated temperature and to keep the resulting mixture at this elevated temperature for 0.5 to 5 hour and more preferably 1 to 2 hours after completion of the addition of the methanesulfonic acid. The cooling to room temperature is performed within 1 to hour and preferably 2 to 3 hours and the mixture is thereafter slowly stirred for preferably another hour at room temperature. Then the crystals are filtered off, washed with alcohol/water and preferably dried under vacuum at a temperature between 20 C and 60 C, preferably starting at 20 C and ending at 60 C.
The crystalline mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-244-(2-pyridinyl)phenyl]acetamide exhibits increased long term stability properties and a desired or improved release kinetic especially from pharmaceutical compositions and thus allows the preparation of long term stable pharmaceutical compositions.
The long term stability of the crystalline mono mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-A1C-P03329CA01Application.doc

12 methyl-2-[4-(2-pyridinyl)phenyl]acetamide is superior in comparison to the free base form of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl].
Moreover the crystalline mono mesylate monohydrate salt of N45-(aminosulfony1)-methyl-1,3-thiazol-211]-N-methyl-244-(2-pyridinyl)phenyl]acetamide exhibits also polymorphic stability in comparison to the free base form or other salts as evident from Table 1. Polymorphism refers to the ability of a solid material to exist in more than one crystal structure or solid form.
Table 1: Thermal analysis and polymorphic stability (Methods used: DSC, TGA) Form TGA Thermal stability of hydrate DSC
1xHCI 2.1% labile loss of water before melting 1xMs0H 4.3% stable loss of water before melting 1xTs0H 5.9% labile loss of water before melting Free Base 8.8% labile loss of water before melting TGA: Thermogravimetric Analysis or Thermal Gravimetric Analysis DSC: Differential Scanning Calorimetry Form:
refers to the mono chloride salt, the mono mesylate salt, the mono tosylate salt and the free base of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenyllacetamide The free base form as well as the hydrochloride and tosylate salts form hydrates of low thermal and low polymorphic stability. Upon mild heating (about 50 C to 60 C), the water content is reduced which would make these salts and the free base form extremely difficult to handle and to process during production and formulation. In contrast the hydrate of the mono mesylate salt is thermally stable and polymorphic stable at much higher temperatures of considerably above 100 C as judged by TGA.
The free base of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyl]acetamide exists in four polymorphic forms and an amorphous form at room temperature. In addition, several solvates can be detected for the free base depending on the solvent.
The data currently available do not permit the identification of the thermodynamically most stable form because all batches synthesised according to prior art display more than one melting peak by differential scanning calorimetry. The physico-chemical properties of various salts (hydrochloride HCI, mesylate Ms0H, tosylate Ts0H) as well as of the free base have been investigated and compared (see Table 2).
AIC-P03329CA01 Application.doc

13 Table 2. Salt screening for 1µ145-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridiny1)-phenyl]acetamide. n.a. not applicable, n.d. not determined, HPLC
high pressure liquid chromatography, ++ very good/high + good/high, - bad/low, - - very bad/low.
Property lx 2x lx 2x lx 2x lx Free Determined HCI HCI Ms0H Ms0H Ts0H Ts0H PhCOOH base by Preparation Final + + + and processing crystallisation Stirring for Stability to one week at ++ ++ ++ n.a.
dissociation MOM
tern peratu re HPLC:
> 98%, Purity +
correct stoichiometry X-ray Crystallinity n.d. + n.d n.d n.d +
diffraction, microscopy Water Solubility solubility 39.4 n.d 138.3 n.d 50 n.d n.d 0.2 screening (mg/100 mL) Storage at Stability to ++ n.d. ++ n.d n.d n.d ++ 90 C
for one decomposition week Dihydrochloride (2xHCI), dimesylate (2xMs0H), ditosylate (2xTs0H) and benzoate (1xPhCOOH) salts of the free base of N45-(aminosulfony1)-4-methyl-1,3-thiazol-y11-N-methy1-214-(2-pyridiny1)-phenyljacetamide do not meet the criterion of stoichiometry. In addition, the hydrate of the monohydrochloride salt shows a decrease of crystallinity during storage.
Furthermore, the free base and the monotosylate form hydrates with low termal stability making them unsuitable for tabletting. These results are disclosed in Table 1 above, where the polymorphic instability of the hydrochloride salt, the tosylate salt and the free base form are discussed. Thus surprisingly only the inventive mono mesylate salt exhibited the required polymorphic and thermal stabiliy in order to allow manufacture, processing and formulation especially in a pharmaceutical scale.
One possibility to prepare the crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohyd rate was by dissolving the base in 10 vol ethanol/water (1:1), adding 1.15 equivalents of methanesulfonic acid at 50 ¨ 55 C during 5¨ 15 min, seeding with 0.5 mol % of final product, ageing for 1 ¨ 1.5 h at 50 C and cooling to 20¨ 25 C during 2.5h.
After further stirring for 1h, the crystalline mesylate monohydrate was isolated by filtration and dried in vacuo, resulting in a yield of > 95%. Using this procedure, N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acet-A1C-P03329CA01 Application.doc

14 amide methanesulfonic acid monohydrate in purity >99% containing < 2ppm residual Pd could be prepared reproducibly concerning yield and purity.
Further, the crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-214-(2-pyridiny1)-phenyllacetamide methanesulfonic acid monohydrate can be prepared in a defined and stable polymorphic form and in addition the co-precipitation of the less soluble free base form is avoided applying this process. Consequently the crystalline mesylate monohydrate of the present invention is free or substantially free of free base.
The inventive crystalline mesylate monohydrate salt further shows stability (as pure API and in pharmaceutical formulations) in long term stability studies, exhibits increased release kinetics from pharmaceutical compositions and leads to improved bioavailability.
As evident from figure 2 which shows the single-crystal X-ray structure analysis of the N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)pheny1]-acetamide methanesulfonic acid monohydrate, the salt is formed between the mesylate and the protonated pyridinyl ring. Moreover, exactly one mol equivalent water is incorporated into the crystal structure wherein the hydrogen atoms of the water molecule form hydrogen bridges with oxygen atoms of two different mesylate molecules. This well-defined position in the crystal lattice (see figure 3) is verified by the fact that water is released from the crystal only at high temperature, starting at 160 C. Thus the inventive compound is a definite mono mesylate and mono hydrtate of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]-acetamide.
The crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyliacetannide methanesulfonic acid monohydrate according to the invention is a useful compound for the preparation of a pharmaceutical composition for treatment and/or prophylaxis of herpes virus infections and/or prevention of transmission of a herpes virus or herpes viruses. Pharmacokinetic data derived from single and multiple dose applications in healthy volunteers exhibited favourable plasma concentration over time profiles with long lasting half lives indicative for an once daily dosing regimen or less frequent such as once weelky. The plasma concentrations in humans exceeded those reached in in vivo and in vitro experiments sufficient to effectively treat herpes simplex virus infections in various animal models and to prevent viral replication in cell culture.
A1C-P03329CA01Application.doc Surprisingly it was found that crystalline N45-(anninosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate is highly active against herpes viruses and infections caused by herpes viruses, mainly herpes simplex viruses.
Therefore the inventive crystalline N45-5 (aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyl]acet-amide methanesulfonic acid monohydrate is especially useful for the treatment and/or prophylaxis of diseases, which are caused by herpes simplex viruses, and/or prevention of transmission of a herpes virus or herpes viruses.
10 Infections with herpes simplex viruses (HSV, subtype 1 and 2) are categorized into one of several distinct disorders based on the site of infection. Orofacial herpes virus infection, the visible symptoms of which are colloquially called cold sores or fever blisters, infects the face and mouth. Orofacial herpes is the most common form of infection. Genital herpes is the second common form of a herpes simplex

15 virus infection. Although genital herpes is largely believed to be caused by HSV-2 only, genital HSV-1 infections are increasing. Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are also caused by herpes simplex viruses.
Further, the present invention relates to crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate in combination with an anti-inflammatory agent. Especially preferred is a combination of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate and acetylsalicylic acid.
Furthermore, the present invention relates to crystalline N45-(aminosulfony1)-methyl-1,3-thiazol-2-y11-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide methane-sulfonic acid monohydrate in combination with an anti-viral agent. The further anti-viral agent is preferably an antimetabolite and most preferably a nucleobase analogues, nucleotide analogues or nucleoside analogue drug.
It is further preferred if the further anti-viral agent is useful against herpes viruses and/or against transmission of a herpes virus or herpes viruses and is selected from the group of drugs comprising but not limited to or consisting of: trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir or penciclovir or the respective prod rugs valaciclovir or famciclovir. Most preferred is a combination of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-A1C-P03329CA01 Application doc

16 phenylFacetamide methanesulfonic acid monohydrate and aciclovir or penciclovir or the respective prodrugs valaciclovir and famciclovir.
The combination of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyljacetamide methanesulfonic acid monohydrate and a further active agent (like anti-inflammatory, immunomodulatory, or anti-viral agents, e.g. therapeutic vaccines, siRNAs, antisense oligonucleotides, nanoparticles or virus uptake inhibitors such as n-docosanol) may be administered simultaneously in one single pharmaceutical composition or in more than one pharmaceutical composition, wherein each composition comprises at least one active agent.
The inventive compound is preferably used for the production of a pharmaceutical composition containing crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-214-(2-pyridinyl)phenyliacetamide methanesulfonic acid monohydrate together with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.
The crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-214-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate used is free or substantially free of the free base form of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenyl]acetamide.
The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. Preferred preparations may be adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits.
The pharmaceutical compositions according to the invention preferably comprises 5 to 70% more preferably 10 to 30% by weight crystalline N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide methane-sulfonic acid monohydrate (all percentage data are percentages by weight based on the weight of the pharmaceutical preparations).
The pharmaceutical composition comprises usually 2 to 600 mg of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyl]acetamide methane-sulfonic acid monohydrate, preferably 5 to 500 mg, more preferably 10 to 300 mg and particularly preferably 20 to 200 mg based on a single dosage.
The pharmaceutical composition according to the invention optionally comprises one or more filler which are for example selected from the group consisting of:
A1C-P03329CA01Application.doc

17 microcrystalline cellulose, fiber cellulose, calcium phosphates and mannitol.
Preferably according to the invention microcrystalline cellulose and mannitol is used.
The pharmaceutical composition expediently comprises 20 to 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 auxiliary which is for example selected from the group consisting of starch, pre-gelatinized starch, starch glycolates, cross-linked polyvinylpyrrolidone, sodium carboxymethylcellulose (=croscarmellose sodium) and other salts of carboxyrnethylcellulose. A mixture of two disintegration agents can also be used. According to the invention the use of croscarmellose sodium is preferred.
The pharmaceutical composition expediently comprises 3 to 35%, preferably 5 to 30% and particularly preferably 5 to 10% of the disintegration auxiliary(ies). The pharmaceutical preparation 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.
The pharmaceutical composition of the invention may comprise a flow agent which could be colloidas anhydrous silica or talcum powder. According to the invention the use of Colloidas anhydrous silica is particularly preferred. The flow agent is expediently used in an amount of 0.3 to 2.0%, particularly preferably from 0.4 to 1.5% and most preferably from 0.5 to 1%.
A particularly preferred pharmaceutical composition of the invention comprises:
5% ¨ 30% crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-(2-pyridinyl)phenyl]acetamide methane-sulfonic acid monohydrate, 5% ¨ 10%
croscarmellose-sodium, 0.5 ¨ 0.7% magnesium stearate, 40% ¨ 70% micro-crystalline cellulose, 10% ¨ 20% mannitol and 0.5% ¨ 1% colloidal anhydrous silica.
The pharmaceutical compositions according to the invention can be administered to a patient in need thereof once daily at a once daily dose of about 20 to 750 mg of crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyliacetamide methanesulfonic acid monohyd rate.
The pharmaceutical compositions according to the invention can also be administered to a patient in need thereof thrice daily, twice daily, once daily, thrice weekly, twice weekly, or once weekly. The administration on a thrice weekly, twice weekly, or once weekly basis is preferred and especially preferred is a once weekly AIC-P03329CA01 Application doc

18 administration, i.e. an administration one time a week of a pharmaceutical composition containing between 400 mg to 600 mg of the inventive N-[5-(am inosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyI)-phenyl]acet-amide methanesulfonic acid monohydrate. Moreover it is preferred to start the administration of the mesylate monohydrate of the present invention with a high loading dose, for instance, with an initial single dose of 400 mg to 800 mg and to continue the administration with a lower dose of 100 mg to 150 mg per day or per week over the period of treatment.
Furthermore, the present invention also includes pharmaceutical compositions for the preferred parenteral application. Further ways of administration are dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application. The administered pharmaceutical compositions contain in addition to typical vehicles and/or diluents crystalline N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyliacetamide methanesulfonic acid monohydrate as active ingredient.
Further preferred are topical formulations of crystalline N[5-(aminosulfony1)-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyllacetamide methane-sulfonic acid monohydrate for dermal or transdermal application. Preferred topical formulations are skin creams, skin lotions, emulsions, gels, suspensions, ointments, oils, lip sticks and balms.
The formulation may be added any conventional carriers, adjuvants and optionally other ingredients.
Preferred auxiliaries originate from the group comprising or consisting of: preservatives, antioxidants, stabilizers, solubilizers and odors.
Ointments, pastes, creams and gels may include at least one conventional carriers, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
Solutions and emulsions may include conventional carriers such as solvents, solubilizing agents and emulsifiers, e.g. water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances. Suspensions may include conventional carriers such as liquid diluents, for example water, ethanol or propylene glycol, suspending AIC-P03329CA01 Application doc

19 agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, bentonite, agar-agar and tragacanth or mixtures of these substances.
An inventive composition may contain lipid particles in which crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyliacet-amide methanesulfonic acid monohydrate is transported. The formulation of the pharmaceutical composition may also contain adjuvants, which are usually used in this type of composition, such as thickeners, emollients, humectants, surfactants, emulsifiers, preservatives, anti-foaming, perfumes, waxes, lanolin, propellants and dyes.
The inventive pharmaceutical composition may also be present as an alcoholic gel which comprises crystalline N145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-214-(2-pyridiny1)-phenyliacetamide methanesulfonic acid monohydrate and one or more lower alcohols or lower polyols, such as ethanol, propylene glycol or glycerol, and a thickening agent, such as siliceous earth. The oily-alcoholic gels also comprise natural or synthetic oil or wax.
Gels may also contain organic thickeners, such as Gum arabic, xanthan gum, sodium alginate, cellulose derivatives, preferably methylcellulose, hydroxymethylcellulose, hYdroxyethyl-cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or inorganic thickeners, such as aluminum silicates such as bentonite or a mixture of polyethylene glycol and polyethylene glycol stearate or distearate.
An inventive pharmaceutical composition may contain the following preservatives:
phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid.
As pharmaceutically acceptable carrier, excipient and/or diluents can be used carriers such as preferably an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules); suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate; lubricants such as boric acid, sodium benzoate, sodium acetate, A1C-P03329CA01Application.doc sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine; disintegrating agents (disintegrates) such as starch, 5 methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked micro-crystalline celluloses such as sodium croscararnellose, alginates such as alginic 10 acid and sodium alginate, clays such as bentonites, and effervescent mixtures;
coloring agents, sweetening agents, flavoring agents, preservatives; glidents are for example silicon dioxide and talc; suitable adsorbent 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, starches 15 derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques

20 disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description.
Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention.
It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention.
Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
AIC-P03329CA01 Application doc

21 EXAMPLES
Definition: As used herein, the term "1 vol." refers to 1 L per kg of the respective starting material (1 vol. = 1 L per kg of the respective material or starting material).
Example 1: Synthesis of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methy1-2-[4-(2-pyridiny1)-phenyl]acetamide methanesulfonate monohydrate Step 1 (Suzuki-Miyaura coupling and saponification) The inertized reactor is charged with bis(triphenylphosphine)palladium(II) chloride (0.010 eq.) and reinertized. Then, toluene (1.65 vol.) is added. After heating to 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 prior to dosing pinacol borane (1.30 eq.) over a period of 60-90 min.
Stirring at 90-95 C is continued for at least 2 more h before 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 to 55-60 C. Stirring at this temperature is continued for at least 4 h before conversion is checked by HPLC. Once conversion is deemed complete, the reaction mixture is concentrated at about 300 mbar until 0.8 vol. of distillate have 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 addition of 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 min at 20 C before the solids are removed by filtration. The reactor and the filter cake are rinsed successively with water and the combined filtrate is transferred back into 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 packed with Celite at the bottom and activated charcoal on top. The Celite/charcoal plug was washed once more with pre-heated water (0.5 vol., 55 C) and the combined filtrate was charged back into the reactor. At 20 C, the pH was adjusted to ¨3.0 by addition of 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 prior to being cooled to 20 C. After additional stirring A1C-P03329CA01Application.doc

22 for at least 1 h at this temperature, the product was filtered, washed twice with water, pre-dried in a flow of N2 and finally dried in vacuo at 50-65 C.
Typical yield: 38-42%.
Step 2 (amide coupling) The reactor is charged with product from step 1 (1.00 eq.) and 4-methy1-2-(methylamino)-1,3-thiazole-5-sulfonamide (1.02 eq.). THF (7.08 vol.) and NMP
(1.11 vol.) are added. The resulting suspension is cooled to 0 C prior to adding 1-ethy1-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.23 eq.) in 4 equal portions over a period of > 90 min. After at least 2 more h at 0 C, the reaction mixture is warmed to 20 C. At this temperature, stirring is continued for additional 2 h before conversion is checked by HPLC. Then, at 10-15 C about 2% (0.2 vol.) of the reaction mixture are added to water (12.3 vol) within at least 5 min.
The resulting thin suspension is stirred at 10-15 C for at least 1 h prior to dosage of the remaining bulk of the reaction mixture over > 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 steady flow of N2 until deemed sufficiently dry (LOD <45 %
w/w; LOD: Loss on drying).
The feed reactor is charged with the crude product, THF (8.15 vol.), and water (up to 1.17 vol. depending on LOD of crude product). The resulting suspension is heated to 60-65 C and stirred for 1 h at this temperature. An almost clear solution is obtained which is subjected to polish filtration using a heatable lense filter heated to 60 C. The feed reactor, the transfer lines and the filter are successively rinsed with a mixture of THF (0.44 vol.) and purified water (0.06 vol.) at 60-65 C.
The combined filtrate is collected in a separate reactor and heated to 50-55 C.
To the reactor content, water (3.23 vol.) is dosed over at least 30 min.
Stirring at 50-55 C is continued for 1-1.5 h before another portion of water (8.93 vol.) is slowly added within 2 h. After stirring for 1-1.5 hat 50 C, the resulting suspension is cooled to 5 C over 2.5 h and stirred for further 0.5 h. Then, the solids are filtered off, washed with water (3 x 2.96 vol.) and pre-dried on the nutsche filter in a steady flow of N2. Final drying is accomplished in vacuo at 50-65 C using a conical drier. Typical yield: 78-83%.
Step 3 (Salt Formation) The reactor is charged with product from step 2 (1.00 eq.), ethanol (4.96 vol.) and water (4.96 vol.). After heating the resulting suspension to 50-55 C, methanesulfonic acid (1.15 eq.) is added within < 15 min. Complete dissolution of starting materials is typically observed at the very end of addition.
Immediately A1C-P03329CA01Application.doc

23 within the next 5 min, stirring is reduced to the minimum acceptable rate and the reaction mixture is seeded with N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridiny1)-phenyllacetamide methanesulfonate monohydrate (0.005 eq.) which was prepared in the desired polymorphic form in a preceding experiment. Slow stirring at 50-55 C is continued for 60-90 min prior to cooling to 20-25 C during > 2.5 h. After stirring for 1 more h, the solids are filtered off, washed with ethanol/water 5:2 VN (3.10 vol.), pre-dried in a nitrogen flow and transferred into a conical drier for final drying in vacuo at 20-60 C.
Typical yield: >95%.
Example 2:
Tablet comprising 60 mg of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenynacetamide (calculated as free base form) according to the invention as micronized active compound, content of active compound about 59% (based on an unvarnished tablet):
crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate, 77.0 mg Avicel PH 101 118.0 mg Lactose, fine 40.0 mg Ac-Di-Sol 20.0 mg Polyinylpyrrolidone 25 10.0 mg Magnesium stearate 2.0 mg Example 3:
Ointment comprising 30 mg of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide (calculated as free base form) according to the invention as micronized active compound crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-244-(2-pyridiny1)-phenyl]acetamide nnethanesulfonic acid monohydrate, micronized 38.4 mg zinc oxide 60.0 mg talcum 60.0 mg glycerol 120.0 mg AIC-P03329CA01 Application doc

24 propyleneglycole 40.0 mg sterile water 80.0 mg Example 4:
Gel comprising 40 mg of N145-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide (calculated as free base form) according to the invention as micronized active compound.
crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate, micronized 51.2 mg solution of sodium hydroxide 30.0 mg 1,2-propandiol 80.0 mg glycerol 20.0 mg polyacrylic acid 60.0 mg sterile water 280.0 mg Example 5:
Gel comprising 40 mg of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-[4-(2-pyridiny1)-phenyl]acetamide (calculated as free base form) according to the invention as micronized active compound.
crystalline N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-214-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate, micronized 51.2 mg 1,2-propandiol 80.0 mg glycerol 20.0 mg polyacrylic acid 60.0 mg sterile water 280.0 mg Example 6:
Tablet comprising 50 mg of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide (calculated as free base form) according to the invention as micronized active compound, content of active compound about 59% (based on an unvarnished tablet):
A1C-P03329CA01Application.doc crystalline N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-yl]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate, micronized 64.00 mg Polyinylpyrrolidone 25 3.50 mg 5 Microcrystalline cellulose 20.00 mg Croscamellose sodium 10.00 mg Magnesium stearate 0.85 mg optionally HPMC film coating 3.00 mg Example 7:
Crystal structure of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate Formula C19H24N407S3, M = 516.62, F(000) = 540, colorless 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, a = 86.130(3) , p = 72.104(3) , y =
68.253(4) , V = 1153.68(15) A3, Dcalc. = 1.487 Mg m-3. The crystal was measured on a Nonius KappaCCD diffractometer at 293K using graphite-monochromated Mo Ka-radiation with A = 0.71073 A, Ornax = 30.065 . Minimal/maximal transmission 0.95/0.99, p = 0.370 mm-1. The COLLECT suite has been used for datacollection and integration.
From a total of 43492 reflections, 6761 were independent (merging r = 0.026). From these, 4955 were considered as observed (1>3.0a(I)) and were used to refine 298 parameters. The structure was solved by direct methods using the program SIR92.
Least-squares refinement against F was carried out on all non-hydrogen atoms using the program CRYSTALS. R = 0.0313 (observed data), wR = 0.0432 (all data), GOF = 1.0736.
Minimal/maximal residual electron density = -0.28/0.33 e k3. Chebychev polynomial weights were used to complete the refinement.
Single-crystal structure parameters for N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate are shown in Figure 1 A.
Characteristic peaks of batch BXR3NC1 obtained by X-ray powder diffraction analysis are shown in Table 3.
A1C-P03329CA01Application.doc Table 3: Characteristic peaks of batch BXR3NC1 obtained by X-ray powder diffraction analysis (Cu Kalpha irradiation).
Angle d value (2-Theta ) (Angstrom) 6.5 13.7 12.9 6.8 16.8 5.29 18.9 4.70 19.3 4.61 19.5 4.56 20.0 4.44 22.4 3.97 22.6 3.94 23.2 3.84 23.8 3.74 .

25.5 3.49 25.9 3.43 28.8 3.10 30.5 2.93 32.7 2.74 35.7 2.51 The 2-Theta values are rounded to 1 decimal place due to a normal deviation of +1-0.1 Example 8:
The exposure of rats to 1\145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FNI-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in a repeated dose 13-week toxicity study performed with the free base N145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide (free base) was compared to the exposures observed in a 26-week repeated dose toxicity study performed with the mesylate monohydrate. In both studies, the test items were administered as 0.5%
(w/v) tylose suspensions, and the concentrations were adjusted to the equivalents of free base 1\115-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyljacetamide.
Exposures were comparable after administration of 10, 50 and 250 mg/kg/day both after administration of the first dose (days 1, 2; Table 4), as well as after repeated dose administration for 13 weeks (Table 5). There was an indication of a possibly higher exposure after a dose of 10 mg/kg/day.
Of note was the observation that exposures after administration of N145-(aminosulfony1)-4-methyl-A1C-P03329CA01Apphcation doc 1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenylJacetamide mesylate monohydrate were higher, after doses of 50 and 250 mg/kg/day (adjusted to the equivalents of free base), as compared to exposures after administration of the free base.
The extent of exposure increased by up to 2.7-fold for Cmax and 4-fold for AUC. It is concluded that N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate gave rise to higher exposures as compared to those observed following administration of equimolecular doses (50 and 250 mg/kg/day) of free base equivalents of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-214-(2-pyridinyl)phenyliacetamide.
Such a major increase in the extent of exposure is thus indicative of the mesylate salts improved physicochemical properties giving rise to a more favourable dissolution profile with concomitant increase in systemic exposure relative to that observed following administration of the freebase.
This enhancement in exposure, following administration of the mesylate salt, therefore means that a higher exposure to the active ingredient is achieved giving rise to a greater efficacy and higher viral resistance barrier, both regarded as an essential feature for the treatment of viral infections. The enhancement of both efficacy and resistance barrier are judged to be prime features associated with the mesylate salt formulation Table 4: Comparison of exposures in the 13-week toxicity (free base) and the

26-week toxicity (mesylate salt) studies in rats after one administration. M
male, F
female. Cmõ is the maximal observed analyte concentration; AUC(0_24) is defined as the area under the analyte vs. time concentration up to 24 hours post dosing;
calculated by linear up/In down summation Free base Mesylate monohydrate Exposure ratio 13-week toxicity 26-week toxicity study 26-wts/13-wts.
study (13-wts) (26-wts) day 1 day 1 Dose [mg/kg/day] Gender Cmax AUC(0.24) Cmax AUC(0_24) Cmax AU C (0-24) [ng/ml] [ngxh/ml] [ng/ml] [ngxh/ml]
10 M 13300 87900 16935 118752 1.3 1.4 50 M 30600 248000 70324 633522 2.3 2.6 250 M 53900 567000 133776 1982721 2.5 3.5 10 F 15300 159000 17237 175125 1.1 1.1 50 _ F 35300 409000 77824 912978 2.2 2.2 250 F 68900 966000 146142 2473155 2.1 2.6 AIC-P03329CA01 Application doc Table 5: Comparison of exposures in the 13-week toxicity (free base) and the week toxicity (mesylate monohydrate salt) studies in rats in week 13. M male, F
female. Cmax is the maximal observed analyte concentration; AUC(0_24) is defined as the area under the analyte vs. time concentration up to 24 hours post dosing;
calculated by linear up/In down summation Free base Mesylate monohydrate Exposure ratio 13-week toxicity 26-week toxicity study 26-wts/13-wts study (13-wts) (26-wts) week 13 week 13 Dose [mg/kg/day] Gender Cmax AUC(0-24) Cmax AUC(0.24) Cmax AUC(0-24) [ng/m1] [ngxh/ml] [ng/ml] _ [ngxh/m1]
M 15000 133000 21840 227165 1.5 1.7 2.5 2.9 2.7 4.2 1.0 1.5 2.6 2.6 3584983 _ 2.6 3.1 AIC-P03329CA01 Application.doc Description of figures Figure 1 shows A) the single-crystal structure parameters for N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyliacetamide methanesulfonic acid monohydrate (batch BXR3NC1), B) the X-ray powder diffraction spectrum of N-[5-(aminosulfonyI)-4-methyl-1, 3-thiazol-2-yll-N-methyl-2-[4-(2-pyridinyl)p henyl]acetamide methanesulfonic acid monohydrate (batch BXR3NC1) as calculated from single crystal data, and C) an overlay of the X-ray powder diffraction spectra of N-[5-(am inosulfony1)-4-methy1-1, 3-thiazol-2-yl]-N-methy1-244-(2-pyridinyl)phenylJacetamide methanesulfonic acid monohydrate of batch BXR3NC1 as measaured (blue line) and as calculated (red line).
D) Measured X-ray powder pattern of batch BXR3NC1 Figure 2 shows the X-ray structure of the N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate with indicated hydrogen bridges.
It is shown that the nitrogen atom of the pyridinyl ring (right side bottom) is protonated and that a hydrogen bridge is formed between the hydrogen, which protonates the pyridinyl ring nitrogen, and one oxygen of the mesylate anion, and that another hydrogen bridge is formed between another oxygen of the mesylate anion and the hydrogen of the water molecule while the other hydrogen of the water molecule forms a hydrogen bridge with the oxygen of another mesylate anion.
Figure 3 shows the single-crystal X-ray structure analysis of the N45-(amino-sulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyllacet-amide methanesulfonic acid monohydrate as packing within the crystal. It is shown that the phenylpyridinyl ring systems are oriented in planes, which are parallel to each other.
AIC-P03329CA01 Application doc N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyliacetamide mesylate monohydrate having a specific particle size distribution range and a specific surface area range for use in pharmaceutical formulations.

Specification The present invention relates to the crystalline mono mesylate monohydrate salt of N-[5-(aminosu Ifony1)-4-methy1-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyl)phenyll-10 acetamide in a definite particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyliacetamide mono mesylate monohydrate having the afore-15 mentioned particle size distribution and specific surface area range.
Background of the invention Synthesis of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyllacetamide is known from EP 1244641 B1 , and the use of acidic 20 components including methanesulfonic acid for the formulation of tablets containing micronized N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-[4-(2-pyridinyl)phenyl]acetamide is disclosed by WO 2006/103011 Al.
It is the objective of the present invention to provide a specific form of a salt of the 25 compound N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenynacetamide which exhibits improved properties in regard to stability and bioavailability and thus makes this specific form of the salt preferable for the manufacturing of pharmaceutical compositions and to provide pharmaceutical compositions containing such a specific salt so that these pharmaceutical 30 compositions exhibit improved properties in regard to stability and bioavailability of the contained specific form of a salt of the compound N45-(aminosulfony1)-4-methyl-1, 3-thiazol-2-y1FN-methyl-2[4-(2-pyrid inyl)phenyliacetam ide.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects, and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
AIC-P03329CA01 Application doc Description of the invention At room temperature, there are four polymorphic forms and an amorphous form of the free base of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide. In addition, several solvates can be detected for the free base of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyliacetamide depending on the solvent. Based on the existence of the afore-mentioned forms of the free base of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyl]acetamide at room temperature, no conclusion on thermic stability can be drawn.
Hence, the free base of N-[5-(aminosulfony1)-4-methy1-1, 3-th iazol-2-y1]-N-methyl-244-(2-pyrid inyI)-phenyl]acet-amide is not suitable for a long-term stable formulation, because long-term properties of the free base of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyliacetamide cannot be determined. In addition, the low solubility is responsible for unfavourable drug release and resorption properties compared to the mesylate monohydrate salt.
Surprisingly it was found that the mesylate monohydrate salt of N45-(am inosu Ifony1)-4-methy1-1, 3-th iazol-2-yll-N-methyl-244-(2-pyrid inyl)phenyl]acet-amide overcomes all drawbacks of the free base or other salts if that mesylate monohydrate salt has a specific PSD (particle size distribution), PSR
(particle size range) and SSA (specific surface area).
Thus the present invention relates to crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyllacetannide mono methanesulfonic acid monohydrate of the following formula / Ol N. ...N CH3 0 sõ........e I
--S
N 0---7/ 'NH2 H3C S03 * H20 wherein the N-[5-(am inosu Ifony1)-4-methy1-1, 3-th iazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate particles have a particle size range from 1 to 500 pm, a particle size distribution which is AIC-P03329CA01 Application.doc defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm and a specific surface area of less than 1.0 m2/g.
The synthesis of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-INI-methyl-244-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate is shown below 0¨B

C0002H5 Pd(OAc)2, PPh3, Et3 N
0 +
Br O¨B
toluene, reflux 1 Step NaOH
40%

A
COOH

N

H¨N N N
CH

=

NMP ¨S

Et0H

N N
CH3 1 0 S-õ?

H3c¨s03 * H20 AIC-P03329CA01 Application.doc The above synthesis uses a boronic acid derivative, a borolane or a borinane reagent which is reacted with ethyl-4-bromophenylacetate in order to obtain the key intermediate (4-pyridin-2-ylphenyl) acetic acid in a single stage with an over all yield of about 40% of theory. The (4-pyridin-2-ylphenyl)acetic acid is reacted with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide to the N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-244-(2-pyridinyl)phenyllacetamide (which is also named as "free base" herein) which is then converted to the definite mono mesylate monohydrate salt (also named herein as "mesylate monohydrate" or "mesylate monohydrate salt") exhibiting a specific PSD, PSR and SSA. The single reaction steps for the synthesis of the N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyljacetamide mesylate monohyd rate are summarized below.
Step A: Reacting compound A of the following general formula A*

A*

wherein 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, with a boronic acid derivative, borolane, borinane or diboronic acid reagent under elimination of R1¨H or R1-B(OR)2 and formation of an intermediate boronic acid derivative of compound A, wherein preferred catalysts for the reaction are the reagent systems palladium acetate with triethylamine and with triphenylphosphine or PdC12(PPh3)2 with triethylamine, wherein the intermediate boronic acid derivative is then reacted with the pyridine compound B of the following general formula B*

B*
wherein AIC-P03329CA01 Application doc R3 represents a leaving group under basic conditions in order to obtain the (4-pyridin-2-ylphenyl)acetic acid as an alkaline solution of the corresponding carboxylate salt.
The resulting (4-pyridin-2-ylphenyl)acetic acid was purified by simple washings at different pH and filtration steps followed by precipitation or crystallization, preferably by properly adjusting the pH of an aqueous acidic solution of (4-pyridin-2-ylphenyl)acetic acid with an appropriate amount of base to 3.5 - 5.0, preferably 3.8 - 4.7. Beside the simple washing and filtration step, no further purification of the (4-pyridin-2-ylphenyl)acetic acid or any of the intermediates by, for instance, recrystallization or chromatography is required.
Step B: Reacting (4-pyridin-2-ylphenyl)acetic acid obtained from step A with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide /
H¨N
)_-_-,-..N
S/)-----"CH3 0-7----s in order to obtain N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide of the formula I
N m -_.-.-- ri 01 0 Si /
I
N-The N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide is thereafter most preferably converted (as step C) to the so far unknown monohydrate of the mesylate salt of N45-(arninosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-214-(2-pyridinyl)phenyllacetamide.
The obtained N-[5-(am ino-sulfonyI)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyl)phenyl]acet-AIC-P03329CA01 Application doc amide mesylate monohydrate is then formulated as particles having a particle size in the range from 1 pm to 500 pm and a particle size distribution defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm and a specific surface area of the particles less than 1.0 m2/g, and more preferably a 5 PSD defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a SSA of the particles less than 0.3 m2/g.
In the above synthesis, the term "leaving group" as used herein is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
10 Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI, BC, and I-, and sulfonate esters, such as para-toluenesulfonate ("tosylate", Ts0-), trifluoromethanesulfonate ("triflate", T10-, CF3S020-), benzenesulfonate ("besylate, C6I-15S020-) or methanesulfonate ("mesylate", Ms0-).
General formula A* as shown below A*
R1 *
covers all phenyl acetic acid esters having a leaving group on the phenyl residue in position 4.
Thus R1 preferably represents ¨F, ¨Cl, ¨Br, ¨I, ¨OMs, ¨0Tf and ¨0Ts. The group "¨OMs" refers to ¨0Mesylate, the group "¨OTf' refers to ¨0Triflate and the group "¨OTs" refers to ¨0Tosylate.
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, ¨05H11, ¨C6H13, cyclo-C3H5, cyclo-C4H7, cyclo-05H9, cyclo-C6H1 1. More preferred are ¨CH3, ¨C2H5, ¨C3H7, ¨CH(CH3)2, ¨C4H9, ¨CH2¨CH(CH3)2, ¨CH(CH3)¨
C2H5, ¨C(CH3)3, and ¨05H1 1. Especially preferred are ¨CH3, ¨C2H5, ¨C3H7, and ¨CH(CH3)2.
Various boronic acid derivatives, borolanes and borinanes as well as the corresponding diboronic acid derivatives can be used in step A of the inventive A1C-P03329CA01Application.doc synthesis disclosed herein. Preferred are borolanes of the following general formula:
Id I
R10- -OR"
wherein R' and R" are independently of each other any substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms, or R' and R" can also form together with the boron atom a heterocyclic ring wherein R' and R" together form a substituted or unsubstituted, linear or branched alkylen group with 2 to 10 carbon atoms. Preferably R' and R"
represent independently of each other -CH3, -C2H5, -C3H7, -CH(CH3)2, -C4H9, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, and -05H11. The cyclic borolanes are preferred.
The following borolanes, borinanes and diboronic acid derivatives are preferred:
H H

\ , 0B, 0/B NO 41 B¨H Ra Rf Rai., Ru RcRd 0 Rb Re Rc Rd Borolane Catecholboran Borinane Rd\ Ra R
f a ve R
b Rc \---q /0,Z_Rb R 0\ 0 Rc mb B-13\
Rc B Bz ----1<: d rµ ----.
o---\---Rc Rb 0/
Rai/6 Rd \c$ R5 Ra Rf Diborolane Diborinane wherein Ra, Rb, Rc, Rd, Re and Rf represent independently of each other a substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms. Preferred are the linear alkyl residues with 1 to 6 carbon atoms, and most preferred are -CH3, -C2H5, -C3H7 and -CH(CH3)2.
AIC-P03329CA01 Application doc Especially preferred examples for the above borone containing compounds are 4,4,5,5-tetramethyl[1,3,2]dioxaborolane (pinacolborane), [1,3,2]dioxaborolane, [1,3,2]dioxaborinane, 5,5-dimethyl[1,3,2]dioxaborinane, 4,6,6-trimethyl[1,3,2]-dioxaborinane, 4,4,6,6-tetramethyl[1,3,2]-dioxaborinane, 4,4,5,5,6,6-hexamethyl[1,3,2]-dioxaborinane, diisopropoxyborane, hexahydrobenzo[1,3,2]di-oxaborole, 9,9-d imethy1-3,5-d ioxa-4-bora-tricyclo-[6.1.1.625]deca ne, 6,9,9-trimethy1-3,5-dioxa-4-bora-tricyclo[6.1.1.62'6]decane, B2Pin2 (bis(pinacolato)diborane), bis(nepentyl glycolato)diboron and catecholboran.
In step A this boronic acid derivative, borolane, borinane or diboronic acid reagent is reacted with a compound A of general formula A* in order to obtain an intermediate borolan or borinane reagent which is not isolated and purified.
This reaction may be supported by the use of either catalysts prepared in situ by combination of palladium salts such as [Pd(OAc)2] and PdC12 with triphenylphosphine (PPh3), tri-ortho-tolylphosphine (P(o-To1)3), tricyclohexylphosphine (PCY3), tri-tert-butylphosphine, 1,4-Bis-(diphenylphosphino)-butane (dppb), and 1,I-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 a variety of organic and inorganic bases such as triethylamine (Et3N), Na0Ac, KOAc, and K3PO4. For this reaction heating to temperature between 70 C and 150 C, preferably between 80 C and 130 C, more preferably between 90 C and 110 C is used. Moreover aprotic and preferably apolar solvents and preferably aromatic solvents such as benzene or toluene or xylenes are used.
The intermediate boronic acid reagent is subsequently reacted with a pyridinyl compound of the general formula B*, wherein R3 represents a leaving group.
Thus R3 represents ¨F, ¨Cl, ¨Br, ¨I, ¨OMs, ¨0Tf and ¨0Ts and preferably ¨Cl or -Br.
The corresponding (4-pyridin-2-ylphenyl)acetic acid ester is in situ treated with a aqueous base in order to cleave the ester linkage. It could be advantageous to heat the reaction mixture during the coupling / saponification step to moderate temperature and preferably to temperature between 40 C and 90 C, more preferably between 45 C and 80 C, still more preferably between 50 C and 70 C
and most preferably between 55 C and 65 C.
AIC-P03329CA01 Application doc After purification and isolation of the key intermediate (4-pyridin-2-ylphenyl)acetic acid, the (4-pyridin-2-ylphenyl)acetic acid was obtained in a yield of about 40% of theory including only one isolation and purification step.
Thereafter the (4-pyridin-2-ylphenyl)acetic acid was reacted with 4-methy1-2-(methylamino)-1,3-thiazole-5-sulfonamide of the formula H¨N

which was prepared according to the synthesis disclosed in EP 1244641 B1 in order to obtain N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyllacetamide of the formula N Al CH3 1 0 Sõ?

This N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-2-[4-(2-pyridiny1)-phenyl]acetamide was thereafter converted to the crystalline mesylate monohydrate salt, wherein the typical particle size range is from 1 to 500 pm and the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm and wherein the crystalline particles have a specific surface area of less than 1.0 m2/g, and more preferably the PSD is defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm and the SSA of the particles is less than 0.3 m2/g.
The parameter d(0.1) refers to the mesh size of a single notional sieve allowing 10% of the total of all particles of the sample to pass. Thus d(0.1) = 2 ¨ 100 pm means that the upper limit of the particle size range defining the 10% of smallest AIC-P03329CA01 Application doc particles in the sample is between 2 pm to 100 pm. Thus 10% of the total particles have a particle size of not more than d(0.1) meaning in this case that they have a maximum size of 2 pm to 100 pm.
Accordingly the parameter d(0.5) refers to the mesh size of a single notional sieve allowing 50% of the total of all particles of the sample to pass. Thus d(0.5) = 30 -210 pm means that the upper limit of the particle size range defining the notional half of the sample containing the smaller particles is between 30 pm to 210 pm.
Thus 50% of the total of all particles have a particle size of not more than d(0.5) meaning in this case that they have a maximum size of 30 pm to 210 pm.
Accordingly the parameter d(0.9) refers to the mesh size of a single notional sieve allowing 90% of the total of all particles of the sample to pass i.e. only 10%
of the sample is retained. Thus d(0.9) = 70 - 400 pm means that the lower limit of the particle size range defining the 10% of largest particles in the sample is between 70 pm to 400 pm. Thus 90% of all particles have a particle size of not more than d(0.9) meaning in this case that they have a maximum size of 70 pm to 400 pm.
It is furthermore preferred that the particle size of the crystalline N-[5-(amino-sulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-214-(2-pyridiny1)-phenylJacetannide mesylate monohydrate particles is within the range of 1 pm to 500 pm, preferably in the range of 1.5 pm to 450 pm and more preferably in the range of 2 pm to pm. Thus, the particle size range (PSR) of the mesylate monohydrate is from 1.0 pm to 500 pm, preferably from 1.5 pm to 450 pm, more preferably from 2.0 pm to 400 pm, still more preferably from 2.5 pm to 300 pm and most preferably from 3.0 pm to 250 pm. If the PSR is not mentioned at all or if reference to the PSR is made without stating a definite value, it shall be referred to a particle size range from 1 to 500 pm.
Moreover it is preferred that the particle size distribution of the crystalline N-[5-(amino-su Ifony1)-4-methy1-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid iny1)-phenyllacet-amide mesylate monohydrate particles is characterized by d(0.1) from 4 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm, more preferably d(0.1) from 6 to 95 pm, d(0.5) from 50 to 200 pm and d(0.9) from 100 to 390 pm, still more preferably d(0.1) from 7 to 90 pm, d(0.5) from 70 to 190 pm and d(0.9) from 130 to 380 pm, still more preferably d(0.1) from 8 to 85 pm, d(0.5) from 80 to 185 pm and d(0.9) from 160 to 370 pm, still more preferably d(0.1) from 9 to pm, d(0.5) from 90 to 180 pm and d(0.9) from 180 to 360 pm, still more preferably d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm and d(0.9) from 200 to 350 pm and most preferably d(0.1) from 11 to 70 pm, d(0.5) from 110 to 170 pm and d(0.9) from 220 to 340 pm.
A1C-P03329CA01Application.doc Furthermore 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, still more preferably less than 0.8 m2/g, still more preferably less than 0.7 m2/g, still more preferably less than 0.6 m2/g, still more preferably less than 0.5 m2/g, still more preferably less 5 than 0.4 m2/g and most preferably the SSA of the particles is less than 0.3 m2/g.
As used herein the term "mesylate monohydrate", or "crystalline mesylate monohydrate", or "methanesulfonic acid monohydrate", or "crystalline methanesulfonic acid monohydrate", or "N45-(amino-sulfony1)-4-methyl-1,3-10 thiazol-2-yll-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mesylate monohydrate", Or "N-[5-(amino-sulfony1)-4-methyl-1,3-thiazol-2-yl]-N-methy1-214-(2-pyridiny1)-phenyl]acetamide methanesulfonic acid monohydrate" refers to the crystalline N-[5-(amino-sulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyll-acetamide mono methanesulfonic acid monohydrate having the PSD, PSR and 15 SSA as defined herein.
The crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-244-(2-pyridiny1)-phenyllacetamide mono methanesulfonic acid monohydrate according to the invention is preferably combined with and used in combination with 20 acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, valaciclovir, famciclovir and/or valganciclovir.
Especially preferred are combinations with acetylsalicylic acid or aciclovir or penciclovir or acetylsalicylic acid and aciclovir or acetylsalicylic acid and penciclovir.
25 The inventive mesylate monohydrate or the afore-mentioned drug combinations 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 herpes simplex viruses.
The crystalline N45-(amino-sulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mesylate monohydrate obtainable according to the above disclosed synthesis is then used to prepare a pharmaceutical composition, wherein the N45-(amino-sulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-244-(2-pyridinyl)phenyllacetamide mesylate monohydrate has the particle size distribution (PSD), specific surface area (SSA) and particle size range (PSR) as defined herein.
To this pharmaceutical composition acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir, and/or their AIC-P03329CA01 Applcation.doc respective prodrugs valaciclovir, famciclovir and/or valganciclovir might be added.
Some suppliers use the name acyclovir instead of aciclovir.
Moreover, these pharmaceutical compositions are preferably solid pharmaceutical compositions without solvents, diluents, or liquids exhibiting solubilising properties for the active pharmaceutical ingredient so that the particles are not dissolved and remain unaltered in regard to their particle size distribution, particle size range and specific surface area.
In W02006/103011A a wet granulation process for tablet preparation is described for the base form using diverse acids including methanesulfonic acid. In a series of crystallization experiments starting from N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridiny1)-phenyliacetamide and benzoic acid, lactic acid, and sulphuric acid, a crystalline salt (apparently occurring in different polymorphic forms) could only be isolated with sulphuric acid.
Nevertheless, using sulphuric acid in the wet granulation process resulted in a tablet exhibiting unfavourable dissolution properties (see Table 3 of W02006/103011A).
Repeating the wet granulation process (cf. example 5 of W02006/103011A) using 1 equivalent methanesulfonic as acidic component resulted in a granulate, which contained a mixture of crystalline free base and mesylate monohydrate salt (ca 90:10, detectable by comparison of the X-ray powder diffraction spectra, which did not change significantly over 4 weeks at 40 C (see Figure 1*). This mesylate /

free base mixture had been found unsuitable for a tablet formulation, because of low solubility and dissolution behaviour, the occurrence of at least four polymorphic forms and the additional risk of further interconversion between base and salt form under long term storage (also depending on the water content and hygroscopicity of the tablet mixture). Thus is was very surprising that a definite mesylate monohydrate salt of N-[5-(anninosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide could be obtained and that this definite mesylate monohydrate salt of N45-(anninosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyl]acetamide with the characteristic PSR, PSD and SSA as disclosed herein overcame all problems of the state of the art and provided the opportunity to prepare stable, long term stable, and pharmacologically applicable pharmaceutical compositions which showed clear advantages for solid formulations.
For the purpose of tabletting, the flowability of a mixture of N-[5-(aminosulfonyI)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-2[4-(2-pyrid iny1)-phenyljacetamide mono methanesulfonic acid monohydrate having the PSR, PSD and SSA as defined AIC-P03329CA01 Application doc herein with usual pharmaceutical ingredients is improved with larger particles and narrower particle size distribution.
As particle size decreases, several interparticulate forces such as mechanical interlocking, hydrogen bonding, electrostatic, and van der Waals forces can predominate over gravity. These forces act in the surface of the particles and smaller particles have larger surface area in relation to their mass than larger ones. In addition, these varying results may be due to differences in the flowability measurement set-ups, humidity of the air, and/or particle properties such as original particle size. A broad particle size distribution induces segregation that influences tabletting force, tablet weigh and the content uniformity of the tablets. Broad particle size distribution causes more segregation problems during tabletting than a granule batch with smaller size distribution within a defined range.
Thus due to various possible particle size ranges, particle size distributions and specific surface areas adjustable by various techniques, it was unforeseeable for the skilled person that the ranges for PSD, SSA and PSR as defined herein are the most suitable for preparing pharmaceutical compositions.
The narrow particle size distribution of the crystalline form of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate, e.g. for a given mean particle size, they have fewer large and small particles, is advantageous for direct compression as a method of tablet manufacturing.
The resulting particle size distribution of the crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the PSR, PSD and SSA is as defined herein and preferably wherein the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, has physical characteristics, which are particularly adapted to be able to allow manufacturing by direct compression without a wet or dry granulation step.
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 preferred at least 99 v/v% of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acet-A1C-P03329CA01 Application doc amide mono methanesulfonic acid monohydrate particles fall in a particle size range of from 2 to 400 pm.
Moreover it is preferred that 40 v/v /0 N-[5-(aminosulfony1)-4-methy1-1, 3-th iazol-2-y1]-N-methyl-244-(2-pyrid inyI)-phenyl]acetamide methane-sulfonic acid monohydrate particles fall in a particle size range of from 2 ¨ 250 pm.
It was surprisingly found that by using crystalline form of N-[5-(aminosulfonyI)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyliacetamide mono methanesulfonic acid monohydrate in particulate form, wherein the PSR, PSD and SSA is as defined herein and preferably wherein the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g in the final blend shows improved free-flowing and cohesive powder characteristics and displays cohesive briquetting and dry granulation behaviour, which effects are significant for efficient and robust direct compression.
If too many crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyliacetamide mono methanesulfonic acid monohydrate particles are present whose particle size is lower than about 4 pm, picking and sticking tend to be caused in the later processing. If too many crystalline N-[5-(aminosulfonyI)-4-methyl-1, 3-th iazol-2-y1]-N-methy1-2[4-(2-pyridiny1)-phenylJacetamide mono methanesulfonic acid monohydrate particles are present whose particle size is larger than about 400 pm, the compressibility becomes too poor. Therefore, it is observed that at least 65 V/0/0/0 of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyllacetamide mono methanesulfonic acid monohydrate fall in a particle size range of from 2 to 400 pm, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g. When processing crystalline N-[5-(am inosu Ifony1)-4-methyl-1,3-th iazol-2-y1]-N-methyl-2[4-(2-pyrid iny1)-phenyliacet-amide mono methanesulfonic acid monohydrate, its particle size distribution remains substantially unchanged, typically it remains totally unchanged. In view of improved overall characteristics, it is preferred that at least 65 v/v%, more preferably at least 70 v/v%, even more preferably at least 80 v/0/0, even more preferably at least 85 v/0/0, even more preferably at least 90 v/0/0, even more AIC-P03329CA01 Apphcation.doc preferably at least 95 v/v% and most preferred at least 99 v/v% of crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-A-N-methyl-244-(2-pyridiny1)-phenyl]acetannide mono methanesulfonic acid monohydrate particles have the PSR, PSD and SSA as defined herein and more preferably fall in a particle size range of from 2 to 400 pm, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and still more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g.
A further advantage of the tablets according to the invention is that the tablet will have an optimised dissolution rate based on its particle size distribution of the crystalline form of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyliacetamide mono methanesulfonic acid monohydrate which has the PSD, PSR and SSA as defined herein and thus, the drug may be absorbed into the blood stream much faster compared to N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridiny1)-phenyl]acetamide or salts thereof.
Furthermore, the surprising dispersion times obtained with 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.
The crystalline mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyl]acetamide, wherein the PSR, PSD
and SSA is as defined herein, exhibits increased long term stability properties and a desired release kinetic and long term stability from pharmaceutical compositions, which is superior to other salts of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1FN-methyl-244-(2-pyridinyl)phenyl]acetamide, which are known in the state of the art including also other mesylate salts.
As evident from Figure 4* that shows the single-crystal X-ray structure analysis of the N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenylFacetamide mono methanesulfonic acid monohydrate, the salt is formed between the mesylate and the protonated pyridinyl ring. Moreover, exactly one mol equivalent methanesulfonic acid and one mol equivalent water is incorporated into the crystal structure, wherein the hydrogen atoms of the water molecule form hydrogen bridges with oxygen atoms of two different mesylate molecules.
A1C-P03329CA01Applicatton.doc Preferred conditions for the crystallization of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate are preparing a suspension of the base in about 10 vol. (vol.
=
L/kg of free base) ethanol / water (1:1), adding 1.15 equivalents of 5 methanesulfonic acid at 50¨ 55 C during < 15 min, seeding with 0.5 mol %
of final product, ageing for 1-1.5 h at 50 C and cooling to 20¨ 25 C during 2.5 h.
After further stirring for 1 h, the final product can be isolated by filtration and drying in vacuo, resulting in a yield of > 95 %.
Using this procedure, N45-(amino-sulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-2-[4-(2-pyridiny1)-phenyl]acetamide 10 methane-sulfonic acid monohydrate having the PSR, PSD and SSA is as defined and preferably having a particle size range of from 2 to 400 pm, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 15 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g in purity >99% containing <2 ppm residual Pd could be prepared reproducibly concerning yield, purity, polymorphic form, PSD, PSR and SSA from a supersaturated solution of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyllacetamide by crystalliza-20 tion under controlled conditions as described below.
Spontaneous crystallization from an over-saturated solution results in a co-precipitation of free base. To simulate this process, a sample of N-[5-(amino-sulfony1)-4-methy1-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]
acetamide 25 mono methanesulfonic acid monohydrate was dissolved in a mixture of ethanol and water (1:1) at 50 C an then cooled down and stirred at 0 C for ca 5 h.
Samples of the precipitate were taken for microscopy exhibiting mainly small needles (Figure 3A*) in contrast to the mesylate monohydrate, which crystallizes as prisms (Figure 3B*).
By investigating isolated needles applying 1H NMR
30 (nuclear magnetic resonance) no mesylate could be detected, thus exhibiting the existence of mainly free base form. Keeping a suspension of this precipitate at 0 C or room temperature shows slow growth of the prisms consuming the needles (Figure 3C*), which argues for a very slow conversion to the mesylate salt form.
This experiment demonstrates the importance of selection of well-defined 35 crystallization conditions.
To obtain N45-(amino-sulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenyl] acetamide mono methanesulfonic acid monohydrate in the AIC-P03329CA01 Application doc desired PSD, PSR and SSA, also moderate to slow stirring of this mixture and a flat cooling ramp of this mixture to room temperature are preferred.
Furthermore it is preferred to add the methanesulfonic acid over 5 ¨ 15 minutes at elevated temperature and to keep the resulting mixture at this elevated temperature for 1 to 2 hours after completion of the addition of methanesulfonic acid. The cooling to room temperature is performed within 2 to 3 hours and the mixture is thereafter slowly stirred for another hour at room temperature. Then the crystals are filtered off, washed with alcohol/water and dried under vacuum at a temperature between 20 C and 60 C, preferably starting at 20 C and ending at 60 C.
A modified way to obtain N-[5-(amino-sulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)phenyl] acetamide mono methanesulfonic acid monohydrate in the desired PSD, PSR and SSA applies the following conditions for the crystallization.
Methanesulfonic acid is added at elevated temperatures, and preferably between 30 C and 90 C, more preferably between 35 C and 80 C, still 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 N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenylFacetamide yielding a supersaturated solution of the mesylate of N-[5-(am inosu Ifony1)-4-methy1-1, 3-thiazol-2-y1j-N-methyl-214-(2-pyrid inyl)p henylj-acetamide.
Organic solvents which are miscible or consolute with water are preferred such as Me0H, Et0H, n-PrOH, I-PrOH, acetonitrile, THF, acetone.
Moreover it is preferred to add seed crystals of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenylJacetamide mono methane-sulfonic acid monohydrate to this supersaturated mixture also at elevated temperatures like 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. Also moderate to slow stirring of this mixture and a slow cooling of this mixture to room temperature are preferred. Furthermore it is preferred to add the methanesulfonic acid over 5 to 15 30 minutes at the elevated temperature and to keep the resulting mixture at this elevated temperature for 0.5 to 5 hour and more preferably 1 to 2 hours after completion of the addition of the methanesulfonic acid.
The cooling to room temperature is performed within 1 to 5 hour and preferably 2 to 3 hours and the mixture is thereafter slowly stirred for preferably another hour at room temperature.
Then the crystals are filtered off, washed with alcohol/water and preferably dried under vacuum at a temperature between 20 C and 60 C, preferably starting at 20 C
and ending at 60 C
AIC-P03329CA01 Application doc The crystalline N-[5-(aminosulfonyI)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyI)-phenyl]acetamide mono methanesulfonic acid monohydrate with the PSD, PSR and SSA as defined herein, exhibits optimised release kinetics from pharmaceutical compositions and improved bioavailability. Furthermore, storage properties, especially the long-term stability of the active pharmaceutical ingredient (API) as well as of the pharmaceutical formulations are excellent. X-ray powder diffraction spectra of film coated tablets (strengths 5 mg, 25 mg, 100 mg, powdered for measurement in comparison to placebo) after 24 months at room temperature revealed no change in crystallinity (see Figures 5* to 7*).
Compared to the mesylate salt of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyl)phenyl]acetamide, the monohydrate of the mesylate salt of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-2-[4-(2-pyridiny1)-phenyl]acetamide, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles 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 greater thermostability of up to 170 C. A clear advantage of the N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyllacetamide mesylate monohydrate, wherein the PSD, PSR and SSA are as defined herein, is its proven long-term stability.
Therefore, the inventive N45-, (arninosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyl]acet-amide mesylate monohydrate, which is characterized by the PSD, PSR and SSA
as disclosed herein, is better suited for the preparation of long-term stable tablets compared to the free base N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyliacetamide.
The crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridiny1)-phenyllacetamide mono methanesulfonic acid monohydrate according to the invention is a useful compound for treatment and/or prophylaxis of infectious diseases and/or prevention of transmission of infectious diseases.
The crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methy1-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate is highly active against herpesviruses and infections caused by herpesviruses and/or transmission of a herpes virus or herpes viruses.
Therefore, the inventive AIC-P03329CA01 Application doc crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate is especially useful for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of diseases, which are caused by herpesviruses or caused by the transmission of a herpes virus or herpes viruses.
The inventive mesylate monohydrate salt 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 a herpes virus or herpes viruses.
Infections with herpes simplex viruses (HSV, subtype 1 and 2) are categorized into one of several distinct disorders based on the site of infection. Orofacial herpes simplex infection, the visible symptoms of which are colloquially called cold sores or fever blisters, affects the face and mouth. Orofacial herpes is the most common form of infection. Genital herpes is the second common form of a herpes simplex infection. Although genital herpes is largely believed to be caused by HSV-2 only, genital HSV-1 infections are increasing.
Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are also caused by herpes simplex viruses.
The inventive mesylate monohydrate salt is thus useful for the treatment and/or prophylaxis of infections which are caused by herpes simplex viruses and/or for the prevention of transmission of herpes simplex viruses.
The mesylate monohydrate salt of the present invention can be combined and administered together with an anti-inflammatory agent such as acetylsalicylic acid and acetaminophen. Thus combinations of the inventive mesylate monohydrate with acetylsalicylic acid and/or acetaminophen as well as pharmaceutical compositions containing such a combination are preferred.
Furthermore, the inventive mesylate monohydrate can be combined and can be used in combination with an anti-viral agent. The anti-viral agent is preferably an antimetabolite and most preferably a nucleobase analogue, nucleotide analogue or nucleoside analogue drug. It is further preferred if the anti-viral agent is useful against herpesviruses and/or against transmission of a herpes virus or herpes viruses and is selected from the group of drugs comprising but not limited to or consisting of: trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir or penciclovir or the respective prodrugs valaciclovir, famciclovir or valganciclovir.
AIC-P03329CA01 Application doc The combination of the inventive mesylate monohydrate and a further active agent like an anti-inflammatory, immunomodulatory, or anti-viral agent, such as therapeutic vaccines, siRNAs, antisense oligonucleotides, nanoparticles or virus-uptake inhibitors such as n-docosanol, may be administered simultaneously in one single pharmaceutical composition or in more than one pharmaceutical composition, wherein each composition comprises at least one active agent.
The pharmaceutical compositions of the present invention can be prepared in a conventional solid and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. Preferred preparations may be adapted for oral application. These administration forms include, for example, pills, tablets, film tablets, coated tablets, sustained release formulations, and capsules.
The pharmaceutical compositions according to the invention preferably comprise to 70% by weight more preferably 10 to 30% by weight crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyllacet-amide mono methanesulfonic acid monohydrate (all percentage data are percentages by weight based on the weight of the pharmaceutical preparation), wherein the PSD, PSR and SSA is as defined herein. The pharmaceutical composition comprises usually 2 to 600 mg of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methy1-244-(2-pyridiny1)-phenylJacetamide mono methanesulfonic acid monohydrate, preferably 5 to 500 mg, more preferably 10 to 300 mg and particularly preferably 20 to 200 mg, wherein PSD, PSR and SSA is as disclosed above.
The pharmaceutical composition according to the invention optionally comprises one or more filler, 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 expediently comprises 20 to 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 auxiliary, which is, for example, selected from the group consisting of starch, pre-gelatinized starch, starch glycolates, cross-linked polyvinylpyrrolidone, sodium carboxymethylcellulose (= croscarmellose sodium) and other salts of carboxymethylcellulose. A mixture of two disintegration agents A1C-P03329CA01Application.doc can also be used. According to the invention, the use of croscarmellose sodium is preferred. The pharmaceutical composition expediently comprises 3 to 35%, preferably 5 to 30% and particularly preferably 5 to 10% of the disintegration auxiliary(ies). The pharmaceutical composition of the invention may comprise at 5 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.
The pharmaceutical composition of the invention may comprise a flow agent, which could be colloidas anhydrous silica or talcum powder. According to the 10 invention, the use of colloidas anhydrous silica is particularly preferred. The flow agent is expediently used in an amount of 0.3 to 2.0%, particularly preferably from 0.4 to 1.5% and most preferably from 0.5 to 1%.
A particularly preferred pharmaceutical composition of the invention comprises:
15 5% - 30% crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-214-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is as defined herein and preferably the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 20 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less 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 /0 colloidal anhydrous silica.
Further pharmaceutical compositions according to the invention preferably comprise 30 to 90% more preferably 50 to 70% by weight crystalline N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyrid inyI)-phenyl]acet-amide mono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA
is as defined herein and preferably the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g (all percentage data are percentages by weight based on the weight of the pharmaceutical preparations). The pharmaceutical composition comprises usually 20 to 750 mg of crystalline N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyllacetamide mono methanesulfonic acid A1C-P03329CA01Applicabon.doc monohydrate, wherein the PSD, PSR and SSA is as defined herein and preferably 50 to 500 mg and particularly preferably 50 to 250 mg based on a single dosage.
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 designation AvicelB, for example.
The pharmaceutical composition expediently comprises 1 to 20%, preferably 1 to 10%, particularly preferably 1 to 5% of the dry binder(s). The pharmaceutical preparation according to the invention may comprise at least one disintegration auxiliary which is for example selected from the group consisting of starch, pre-gelatinized starch, starch glycolates, cross-linked polyvinylpyrrolidone, sodium carboxy-methylcellulose (= croscarmellose sodium) and other salts of carboxy-methylcellulose. A mixture of two disintegration agents can also be used. The use of croscarmellose sodium and cross-linked polyvinylpyrrolidone or a mixture of the two is preferred. The pharmaceutical composition expediently comprises 3 to 35%, preferably 10 to 30% and particularly preferably 15 to 25% of the disintegration auxiliary(ies). The pharmaceutical preparation of the invention may comprise at least one lubricant selected from the group consisting of fatty acids and their salts. The use of magnesium stearate is particularly preferred.
A pharmaceutical composition for a tablet with 25 mg of the active pharmacologic ingredient (calculated as base form) comprises 32.3 mg of N-[5-(aminosulfonyI)-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyI)-phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is as defined herein and preferably the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, 60.9 mg of microcrystalline cellulose, 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 blend is 125.0 mg.
A further pharmaceutical composition for a tablet with 100 mg of the active pharmacologic ingredient comprises 129.0 mg of the inventive N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyliacet-AIC-P03329CA01 Application doc amide mono methanesulfonic acid monohydrate, 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 blend is 500.0 mg.
Furthermore, the present invention also includes pharmaceutical compositions for sublingual application, which preparations in addition to typical vehicles contain at least crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is as defined herein, as active ingredient.
An inventive pharmaceutical composition may contain the following preservatives:
phenoxyethanol, formaldehyde solution, parabens, pentanediol, or sorbic acid.
As pharmaceutically acceptable carrier, excipient and/or diluents can be used carriers such as preferably an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules); suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellu lose and hyd roxypropylmethyl-cellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate; lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine; disintegrating agents (disintegrates) such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxy-methylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures; coloring agents, sweetening agents, flavoring agents, preservatives; glidents are for example silicon dioxide and talc; suitable adsorbent are clay, aluminum oxide, AIC-P03329CA01 Application doc suitable diluents are water or water/propylene glycol solutions for parenteral injections, juice, sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples, which follow, represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
The pharmaceutical compositions according to the invention can be administered to a patient in need thereof at a once daily dose of about 20 to 750 mg of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridinyI)-phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is as defined herein and preferably the particle size distribution is defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, preferably 50 to 500 mg and particularly preferably 50 to mg based on a single dosage. The pharmaceutical compositions according to the invention can also be administered to a patient in need thereof thrice daily, twice daily, once daily, thrice weekly, twice weekly, or once weekly. The administration on a thrice weekly, twice weekly, or once weekly basis is preferred and especially preferred is a once weekly administration, i.e. an administration one time a week of a pharmaceutical composition containing between 400 mg to 500 mg of the inventive N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acet-amide mono methanesulfonic acid monohydrate. Moreover it is preferred to start the administration of the mesylate monohydrate of the present invention with a high loading dose, for instance, with an initial single dose of 400 mg to 800 mg and to continue the administration with a lower dose of mg to 150 mg per day or per week over the period of treatment.
AIC-P03329CA01 Application doc Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description.
Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention.
It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention.
Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
AIC-P03329CA01 Application doc EXAMPLES
5 Example 1*: Synthesis of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonate monohydrate having the inventive PSD, PSR and SSA
Step 1 (Suzuki-Miyaura coupling and saponification) 10 The inertized reactor is charged with bis(triphenylphosphine)palladium(II) chloride (0.010 eq.) and reinertized. Then, toluene (1.65 vol.) is added. After heating to 40 C, triethylannine (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 prior to dosing pinacol borane (1.30 eq.) over a period of 60-90 min.
15 Stirring at 90-95 C is continued for at least 2 more h before 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 to 55-C. Stirring at this temperature is continued for at least 4 h before conversion is checked by HPLC. Once conversion is deemed complete, the reaction mixture is 20 concentrated at about 300 mbar until 0.8 vol. (vol. refers to kg of starting material (= 1.00 eq) in the respective step, i.e. L/kg starting material) of distillate have 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 addition of 33% HCI at 20 C. MIBK (2.30 25 vol.) and Celite (165 g/kg) are added and the resulting mixture is stirred for at least 15 min at 20 C before the solids are removed by filtration. The reactor and the filter cake are rinsed successively with water and the combined filtrate is transferred back into the reactor. The phases are separated and the aqueous layer is washed twice more with MIBK. After dilution with water, the aqueous 30 acidic product solution was heated to 55 C and filtered through a plug packed with Celite at the bottom and activated charcoal on top. The Celite/charcoal plug was washed once more with pre-heated water (0.5 vol., 55 C) and the combined filtrate was charged back into the reactor. At 20 C, the pH was adjusted to -3.0 by addition of 30% NaOH before the product solution was heated to 60 C. More 35 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 prior to being cooled to 20 C. After additional stirring for at least 1 h at this temperature, the product was filtered, washed twice with A1C-P03329CA01Application.doc water, pre-dried in a flow of N2 and finally dried in vacuum at 50-65 C.
Typical yield: 38-41%.
Step 2 (amide coupling) The reactor is charged with product from step 1 (1.00 eq.) and 4-methy1-2-(methylamino)-1,3-thiazole-5-sulfonamide (1.02 eq.). THF (7.08 vol.) and NMP
(1.11 vol.) are added. The resulting suspension is cooled to 0 C prior to adding 1-ethy1-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.23 eq.) in 4 equal portions over a period of > 90 min. After at least 2 more h at 0 C, the reaction mixture is warmed to 20 C. At this temperature, stirring is continued for additional 2 h before conversion is checked by HPLC. Then, at 10-15 C about 2% (0.2 vol.) of the reaction mixture are added to water (12.3 vol.) within at least 5 min.
The resulting thin suspension is stirred at 10-15 C for at least 1 h prior to dosage of the remaining bulk of the reaction mixture over > 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 steady flow of N2 until deemed sufficiently dry (LOD <45 %
w/w; LOD: Loss on drying).
The feed reactor is charged with the crude product, THF (8.15 vol.), and water (up to 1.17 vol. depending on the loss on drying of crude product). The resulting suspension is heated to 60-65 C and stirred for 1 h at this temperature. An almost clear solution is obtained which is subjected to polish filtration using a heatable lense filter heated to 60 C. The feed reactor, the transfer lines and the filter are successively rinsed with a mixture of THF (0.44 vol.) and purified water (0.06 vol.) at 60-65 C. The combined filtrate is collected in a separate reactor and heated to 50-55 C. To the reactor content, water (3.23 vol.) is dosed over at least min.
Stirring at 50-55 C is continued for 1-1.5 h before another portion of water (8.93 vol.) is slowly added within 2 h. After stirring for 1-1.5 h at 50 C, the resulting suspension is cooled to 5 C over 2.5 h and stirred for further 0.5 h.
30 Then, the solids are filtered off, washed with water (3 x 2.96 vol.) and pre-dried on the nutsche filter in a steady flow of N2. Final drying is accomplished in vacuo at 50-65 C using a conical drier. Typical yield: 78-83%.
Step 3 (Salt Formation) The reactor is charged with product from step 2 (1.00 eq.), ethanol (4.96 vol.) and water (4.96 vol.).
After heating the resulting suspension to 50-55 C, methanesulfonic acid (1.15 eq.) is added within < 15 min. Complete dissolution of starting materials is typically observed at the very end of addition.
Immediately A1C-P03329CA01Application.doc within the next 5 min, stirring is reduced to the minimum acceptable rate and the reaction mixture is seeded with N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide methanesulfonate monohydrate (0.005 eq.) which was prepared in the desired polymorphic form in a preceding experiment. Slow stirring at 50-55 C is continued for 60 to 90 min prior to cooling down to 20 to 25 C during > 2.5 h. After stirring for 1 more h, the solids are filtered off, washed with ethanol/water 5:2 VN (3.10 vol.), pre-dried in a nitrogen flow and transferred into a conical drier for final drying in vacuo at 20 to 60 C.
Typical yield: >95%.
Particle Analysis and Detection A Malvern Mastersizer 2000 with a dispersion unit Malvern Hydro 2000S was used for liquid dispersion. Dispersing agent was SpanTM 80 used at a concentration of 0.1% (volume/volume) in n-heptane. Stirring rate was 2,500 rounds per minute.
Typically, a slurry of 50 milligrams of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyliacetamide mono methanesulfonic acid monohydrate was prepared in a vial containing 4 to 5 mL dispersant. Should any agglomerates have occurred, then these were converted to primary particles by ultrasonic treatment for 10 seconds. Those with ordinary skills in the art may recognise that ultrasonic treatment is common practice in converting agglomerates to smaller particles. Once the suspension had been generated, the suspension was transferred to the Malvern Mastersizer 2000 with a dispersion unit Hydro 2000S by pipetting, until an optimal concentration range had been reached. The optimal concentration range was assessed by the obscuration value displayed by the Malvern Mastersizer 2000. Typically, optimal obscuration values are in the range from about 10 to about 20 percent. Then, the measurement was performed with automatic subtraction of the background. Data were analysed automatically using the Fraunhofer diffraction equation. For microscopy, either the slurry used for particle size analysis or a new batch was used. The size of the observed particles was determined by means of the software analySIS start 5.0 (Olympus Soft Imaging Solutions GmbH). The procedure described above complies with USP 429 (light diffraction measurement of particle size) and Ph. Eur. 2.9.31 (particle size analysis by laser light diffraction).
In addition to particle size analysis by laser light diffraction, an optical investigation using a microscope was conducted. In case of release measurements, system suitability testing must be performed prior to dispersing, which is common practice for those skilled in the art.
AIC-P03329CA01 Application doc Example 2*:
The trials disclosed by example 2* were conducted in order to investigate the influence of the particle size distribution (PSD) of the active pharmaceutical ingredient (API) on the dissolution properties of the tablet cores.
The term "particle size distribution" of a powder, or granular material, or particles dispersed in fluid, as used within this application, is a list of values or a mathematical function that defines the relative amounts of particles present, sorted according to size. The d(0.1), d(0.5) and d(0.9) values indicate that 10%, 50%

and 90% of the particles measured were less than or equal to the size stated.
For example, values of d(0.1)=52 , d(0.5)=129 and d(0.9)=257 mean that 10% of the particles were less than or equal to 52 pm, 50% were less than or equal to 129 pm and 90% were less than or equal to 257 pm (cf. Table 1*, trial batch number G05).
In order to study the dissolution properties of the tablet cores with different PSD of the inventive N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyljacetamide methane-sulfonic acid monohydrate, 100 mg and 25 mg (calculated as free base form) tablet cores containing the inventive N115-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acet-amide mono methanesulfonic acid monohydrate in an amount of 129 and 32.3 mg respectively were prepared.
Type and size of the tablet cores - 100 mg tablet core, diameter 11 mm - 25 mg tablet core, diameter 7 mm Equipments Blending: Bohle MC5 with glass tube Tabletting = Kilian rotary press with chamber feed shoe = Tooling 100 mg dose strength: 11r11 or 12r11 with break score on one site = Tooling 25 mg dose strength: 7r6 Analytics = Dissolution (1000 ml, 0.1 M HCI, paddle apparatus according to USP
apparatus 2, paddle speed 50 rounds per minute, n=6) A1C-P03329CA01Application.doc Compounds (API, active pharmaceutical ingredient) API: N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methy1-2-[4-(2-pyridiny1)-phenyl]acet-amide methane-sulfonic acid monohydrate, wherein at least 65 viv%
N-[5-(Aminosu Ifony1)-4-methy1-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyI)-pheny1]-acetamide mono methanesulfonic acid monohydrate particles fall in a particle size range of from 2 to 500 micrometer (pm).
G01, G02, G03, G04, G05 are five different tablet test batches of the N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyrid iny1)-phenyliacet-amide methane-sulfonic acid monohydrate, wherein the particle size is in a range from 1 to 400 pm with a particle size distribution of d(0.1), d(0.5) and d(0.9) shown by Table 1*.
Table I*: Particle size distribution (PSD) of different batches of N-[5-(am inosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridiny1)-phenyl]acet-amide methane-sulfonic acid monohydrate.
API batch Trial Specific number batch Particle size distribution surface number area d(0.1) d(0.5) d(0.9) [tun.1 [pm) [Pm]
BXR4FLS GUI 3 51 102 0.7 BXR3NC1 G02 43 118 254 0.1 G03 1 4 11 2.4 crude 1#1 M1 G04 22 66 143 0.2 IPC 1#1 NE-023932-batch-02-2010 G05 52 129 257 0.1 Preparation of final blends Five final blends (batches GO1 to 005) with the different API batches were prepared. The formulations of the cores (25 mg and 100 mg dose strength, calculated as free base form) are shown in Table 2*.
AIC-P03329CA01 Application doc Table 2*: Formulation 25 mg and 100 mg dose strength (calculated as free base form) Component mg per 25 mg tablet mg per 100 mg tablet N45-(aminosulfony1)-4-methyl-1,3- 32.3 (salt) 129.0 (salt) thiazol-2-y1]-N-methy1-2-[4-(2-pyridiny1)-phenyllacetamide mono methanesulfonic acid monohydrate Microcrystalline cellulose 60.9 243.4 Croscarmellose sodium 9.8 39.0 Mannitol 20.0 80.1 Silica, colloidal anhydrous 1.3 5.0 Magnesium stearate 0.9 3.5 Sum final blend 125.2 500.0 5 The final blends were prepared by sieving the raw materials using a 1.0 mm sieve.
N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyll-acetamide methane-sulfonic acid monohydrate, I. e. the API, wherein the particle size distribution is in a range from 1 to 400 pm, microcrystalline cellulose, croscarmellose sodium, mannitol and silica colloidal anhydrous were mixed for 10 minutes in a free fall blender. Magnesium stearate was added, and the blends were mixed for additional 5 minutes. No problems were observed during the process.
The bulk properties of batches GO1 to G05 are shown in Tables 3* and 4*.
Table 3*: Bulk properties of final blends Parameter GO1 G02 G03 G04 G05 Bulk density 0.413 0.435 0.385 0.403 0.440 [g/m1]
Tapped density 0.510 0.526 0.563 0.500 0.550 [g/m1]
Flowability [cot] 1.25 1.16 0.893 1.09 1.28 A significant difference in bulk density was seen for batch G03. This was the final blend, which contains the micronised API. Therefore, the bulk density was lower compared to the blends, which contain coarser API.
AIC-P03329CA01 Application doc Batch G03 also had the worst flowability of all final blends. This may also be explained by the use of micronised API.
Tabletting Final blends from batches GO1 to 004 and a part of final blend batch G05 were compressed as a 100 mg dose strength. The other part of the final blend batch G05 was compressed as a 25 mg dose strength.
During compression of the 100 mg dose strength batches 001, G02, 004 and 005, no further problems occurred.
Surprisingly, it was found that the tablet weight was fluctuating during compression of batch 003. Unexpectedly, problems with uniformity of weight occurred. In addition, the tablet mass was sticking to the tools.
It was obvious that both problems were caused by use of the micronised API. Therefore, it is advantageous to omit a micronisation step for tabletting, which will result in better handling and less production time.
Compression of the 25 mg dose strength batch 005 was done without problems.
The IPC (in process checks) data of batches GO1 ¨ 005 are shown in Tables 4*
and 5*.
Table 4*: IPC data 100 mg strength Parameter Nominal value 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] determine 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 <5 20-30 sec 15-25 sec 20-30 sec 20-25 sec 15-25 sec [min]
AIC-P03329CA01 Application.doc Table 5*: IPC data 25 mg strength Parameter Nominal value G05 Weight[mg] 122 - 128 127 Diameter [mm] 6.8 - 7.2 7.1 Height [mm] determine 3.6-3.7 Hardness [N] >50 56 Disintegration [min] <5 20-28 sec Analytics Tablets or capsules taken orally remain one of the most effective means of treatment available. The effectiveness of such dosage forms relies on the drug dissolving in the fluids of the gastrointestinal tract prior to absorption into the systemic circulation. The rate of dissolution of the tablet or capsule is therefore crucial.
Dissolution: The criteria for dissolution in media with a pH of 1 is 0=75 after 45 minutes.
Influence of particle size distribution on the dissolution:
Dissolution of cores from batches GO1 to G05 was performed. The dissolution results are shown in Figure 8* and Table 6*.
Table 6*: Dissolution results for batches GO1 ¨ G05 Average Min Max Average Min Max Average Min Max Batch [Vol rid [Vo] CY01 [%1 [ /01 r/01 rid GO1 100 mg 90 83 97 93 85 99 96 90 99 GO2 100 mg 82 80 84 90 88 91 91 90 94 003 100 mg 100 98 101 100 97 102 100 98 GO4 100 mg 99 97 100 100 98 102 101 101 GO5 100 mg 90 87 93 99 98 102 103 102 G05 25 mg 102 101 104 104 102 105 104 102 A1C-P03329CA01Application.doc The dissolution results of batches GO1 ¨ G05 are according to the specification.
There is no significant difference in the dissolution of cores, which contains finer or coarser API.
Content Uniformity (CU): Content uniformity of batches GO1 to G04 was tested.
The results are shown in Table 7*.
Table 7*: CU results of batches GO1 ¨ G04 Batch Assay mean (/o) Standard deviation Acceptance value GO1 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 All results comply with Ph.Eur. 2.9.40. Content uniformity of batch G03 is inferior compared to the content uniformity of the other batches. It is obvious that this is related to the problems during compression based on the micronized API.
CONCLUSIONS
The particle size distribution of the API has an influence on the bulk properties of the final blend and on the tabletting characteristics. Batch G03, which contains the micronized API, has a worse flowability. Therefore, problems with a uniform weight occurred during compression.
In addition, sticking problems were observed, and the CU results of the cores are not as good as the results of the cores with non-micronized API. By use of non-micronized API there was no influence of the particle size distribution, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, on uniformity of weight and CU obtained. The results do not show a marked influence of the particle size distribution on the dissolution of the cores as they are all within the predefined ranges.
A1C-P03329CA01Application.doc Example 3*:
Tablet comprising 60 mg of N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide (corresponding to 76.9 mg of crystalline N45-(aminosulfonyl)-4-methyl-1,3-thiazol-2-y1J-N-methyl-244-(2-pyridiny1)-phenyl]-acetamide mono methanesulfonic acid monohydrate according to the invention), wherein at least 65 v/v /0 are N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyljacetamide mono methanesulfonic acid monohydrate particles, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g;
content of active compound about 59% (based on an unvarnished tablet):
crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-244-(2-pyridiny1)-phenyliacetamide methane-sulfonic acid monohydrate 76.9 mg Avicel PH 101 118.0 mg lactose, fine 40.0 mg Ac-Di-Sol 20.0 mg polyinylpyrrolidone 25 10.0 mg magnesium stearate 2.0 mg total weight 266.9 mg Example 4:*:
Tablet comprising 50 mg of N-15-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-214-(2-pyridiny1)-phenyliacetamide (corresponding to 64 mg of crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-A-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate), wherein at least 65 v/v % are N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate particles, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g;
content of active compound about 59% (based on an unvarnished tablet):
AIC-P03329CA01 Applicabon doc crystalline 1145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-214-(2-pyridiny1)-phenyllacetamide methane-sulfonic acid monohydrate 64.0 mg polyinylpyrrolidone 25 3.5 mg microcrystalline cellulose 20.0 mg croscamellose sodium 10.0 mg magnesium stearate 0.9 mg optionally HPMC varnish 3.0 mg 10 total weight 101.4 mg Example 5*:
15 Crystal structure of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate Formula C191-124N407S3, M = 516.62, F(000) = 540, colorless plate, size 0.02 = 0.13 = 0.15 mm3, triclinic, space group P -1 , Z
= 2, a =
20 9.4908(7)A, b = 9.5545(7) A, c = 14.4137(9) A, a = 86.130(3) , 13. =
72.104(3) , y =
68.253(4) , V = 1153.68(15) A3, Dcalc. := 1.487 Mg=rn-3. The crystal was measured on a Nonius KappaCCD diffractometer at 293 K using graphite-monochromated Mo Ka-radiation with A = 0.71073 A, emax = 30.065 .
Minimal/maximal transmission 0.95/0.99, p = 0.370 mm-1. The COLLECT suite has been used for 25 data collection and integration. Of 43492 reflections in total, 6761 were independent (merging r = 0.026). From these, 4955 were considered observed (1>3.0a(I)) and were used to refine 298 parameters. The structure was solved by direct methods using the program SIR92. Least-squares refinement against F
was carried out on all non-hydrogen atoms using the program CRYSTALS. R =
30 0.0313 (observed data), wR = 0.0432 (all data), GOF = 1.0736.
Minimal/maximal residual electron density = -0.28/0.33 e k3. Chebychev polynomial weights were used to complete the refinement.
Table 8* shows single-crystal structure parameters for N-[5-(aminosulfonyI)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyl)phenyljacetamide mono methanesulfonic acid monohydrate.
A1C-P03329CA01Application.doc Table 8*: Single-crystal structure parameters for N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate.
Parameter Value formula C19H24N.407S3 formula weight 516.62 g/mol Z, calculated density 2, 1.487 Mgxm-3 F(000) 540 description and size of crystal Colourless plate, 0.02x0.13x0.15 mm3 absorption coefficient 0.370 mm-1 min/max transmission 0.95/0.99 temperature 293 K
radiation (wavelength) Mo Ka (X=0.7103 A) crystal system, space group Triclinic, P -1 a 9.4908 (7) A
b 9.5545(7) A
c 14.4137(9) A
a 86.130(3) i3 72.104(3) Y 68.253(4) V 1153.68(15) A3 min/max 0 2.426 /30.065 number of collected reflections 43492 number of independent reflections 6761 (merging r=0.026) number of observed reflections 4955 (1>3.0c5(1)) number of refined parameters 298 r 0.0313 (observed data with) rW 0.0432 (all data) goodness of fit 1.0736 residual electron density -0.28/0.33 eA-3 Example 6*:
Single-dose escalation and pharmacokinetics An advantage of the tablets according to the invention is that the tablet will have an optimised dissolution rate based on the particle size distribution of the AIC-P03329CA01 Application.doc crystalline form of 1145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridiny1)-phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, and thus, the drug may be absorbed into the blood stream much faster compared to N15-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridiny1)-phenyliacetamide as crystalline base form.
Furthermore, the surprising dispersion times obtained with 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.
Therefore, pharmacokinetic studies in human subjects were undertaken following both single and multiple dose administrations of the mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-244-(2-pyridinyl)pheny1]-acetamide, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g.
Single oral doses of the mesylate monohydrate salt of N-[5-(aminosulfony1)4-, methyl1,3thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl] acetamide using the formulations according to example 2*, Table 2*, were administered to six volunteers per dose step. The overall shape of the plasma concentrations vs.
time profiles were similar across all doses.
There was a rapid and continuous increase of plasma concentrations switching into a period of markedly slower absorption rate and evidence of a plateau effect in exposure. Thereafter, for all doses investigated, there was a decrease of concentrations starting after 4.0 to 4.5 hours post administration. This phase was followed by a phase of prolonged exposure, which was characterised by a long half-life, which is favourable for the treatment of infectious diseases. The mean terminal elimination half-life (t112,) ranged between 52 h and 85 h.
For doses from 5 mg to 480 mg there was a dose-proportional increase in AUC.
(AUC, area under curve); a single dose of 600 mg did not cause any further rise of exposure as shown by AUCcr. (see Figure 9*).
AIC-P03329CA01 Application doc Maximum plasma concentrations were linearly related to doses from 5 mg to 400 mg. At the higher dose up to 600 mg no further increase of exposure was obtained as shown by the both Cm. and AUC0¨. Median tmax ranged from 1.5 to 4.25 hours without any obvious relation to dose. A summary of single-dose pharmacokinetic parameters is shown in Table 9*.
Table 9*: Pharmacokinetic parameters after ascending single oral doses of mono mesylate monohydrate salt of N-[5-(aminosulfonyI)-4-methyl-1,3-thiazol-2-y1FN-methyl-2[4-(2-pyridinyl)phenyllacetamide in the formulations according to the formulation described on page 20 wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g.
In the following the abbreviations used in Table 9* are defined.
AUC0-.: Area under the analyte vs. time concentration from time of administration up to infinity, calculated as C a AUC0,. AUG, -last xz wherein AUC0-last .S i defined as the area under the analyte vs. time concentration up to time of the last qualifiable concentration, calculated by linear up/In down summation and Ciast is defined as last quantifiable observed analyte concentration.
A, is the apparent terminal elimination rate constant, determined by linear regression of terminal points of In-linear analyte concentration-time curve.
Cmax is the maximal observed analyte concentration and tmax is the time to reach Cmax;
t112, is defined as the apparent terminal elimination half-life, calculated as in(2) t1/2z = xz wherein Az is defined as above.
MRT: Mean Residence Time; calculated AUMC divided by AUC, wherein AUMC is the area under the first moment of the concentration-time curve from zero up to .0 with extrapolation of the terminal phase and AUG is the area under the AIC-P03329CA01 Application doc concentration-time curve from zero up to co with extrapolation of the terminal phase.
CL/F refers to the clearance after oral administration of a drug and Ae refers to the amount of drug excreted in the urine.
Table 9*:
dose parameter (means; n=6 volunteers/dose) [mg]
AUC0-. Cmax tmaxa t1/2z MRT CL/F A, [ng = h/mL] [ng/mL] [h] [h] [h] [L/h]
[c/o of dose]
5 5800 74 4.00 80 117 0.89 0 11670 170 1.50 85 116 0.87 0 18540 234 2.77 76 105 1.10 0 40 40680 608 3.50 72 94 1.00 0 80, males 87220 1306 2.50 74 94 0.94 0.16 (99790)b (1499)b 80, 96230 1999 4.00 58 77 0.85 0.31 females (90050)b (1853)b 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 a: for tma, the median is given, b: value normalized to body weight for a 70 kg subject;
Based on data for the 80 mg dose, women appeared to exhibit a higher exposure compared to males according to AUC. and C. (see Table 9*). However, normalization to body weight revealed that this apparent difference could be explained by the lower body weight of the female volunteers compared to males.
Therefore, a clinical relevance of any gender-related differences of pharmacokinetics should not be expected.
Summary of the results of Example 6*: For doses from 5 mg to 400 and 480 mg, respectively, there was a linear, i.e. dose-proportional, increase in AUC.
and Cmax with dose; higher doses do not further increase the exposure. The mean terminal elimination half-life (t112z) ranged between 52 h and 85 h.
No clinical relevant gender-related difference in exposure was detected for a single dose of 80 mg.
AIC-P03329CA01 Application.doc Example 7*:
5 Multiple-dose escalation and pharmacokinetics For the three doses of the mesylate monohydrate salt of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide in formulation according to example 1*, Table 2*, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) 10 from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, investigated (5, 25, and 100 mg; once per day oral administration, 20 days), the individual concentration-time curves of N-[5-(aminosulfonyI)-4-15 methyl-1,3-thiazol-2-yl]Nmethy1-244-(2-pyridinyl)phenyl]acetamide at day 1 (after the first administration) were very similar in their general shape and slope to those profiles obtained in the single dose escalation trial (see Example 6*). As for the single dose escalation trial presented in Example 6*, there were dose-proportional increases in AUCo-24h and Cmax at day 1.
During the 20-day treatment with administrations of the mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-214-(2-pyridiny1)-phenygacetamide, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, once daily, the attainment of steady-state conditions was demonstrated by virtually identical minimal or "trough" concentrations of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-yq-N-methyl-244-(2-pyridinyl)phenyllacetamide achieved between days 9 and 13.
At steady state, there was a low inter-individual variability of minimal or "trough"
concentrations with CVs (coefficient of variations) between 16.7 and 21.7%
(day 21). For all doses, the individual and mean concentration-time curves of N45-(am inosulfonyl)-4-methyl-1, 3-thiazol-2-y1]-N-methyl-244-(2-pyrid inyl)phenyl]acet-amide at day 21 were very similar in their shape and slope to those profiles obtained at day 1.
A1C-P03329CA01Application.doc Table 10* summarises the steady-state pharmacokinetics of N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-2-[4-(2-pyridinyl)phenyljacetamide.
Table 10*: Steady state pharmacokinetic parameters of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide at day 21 after daily administrations of 5, 25, or 100 mg of the mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyllacetamide in formulation according to example 2*, Table 2*, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, to healthy volunteers (n = 12 per dose).
In the following the abbreviations used in Table 10* are defined.
Ctrough: measured plasma concentration immediately before dosing at day 21 (at the end of the dosing interval at steady state); AUCT, i.e. the steady state AUC
(area under the curve) within the dosing interval of 24 hours, Cmax,ss refers to the maximal observed analyte concentration at steady state.
Cav is defined as average plasma concentration during the dosing interval the mono mesylate monohydrate salt of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methyl-(2-pyridinyl)phenyliacetamide at steady state, R-AUC refers to the accumulation ratio of the AUC, i.e. AUCT / AUC0-24h,dayl R-Cmax refers to accumulation ratio of Cm., i.e. Cmax,ss I Cmax, dayl ; t112z is defined as above Table 10*:
dose [mg] Ctrough AUCT Cmax,ss Cav R-AUC R-Cmax t1/2z [ng/mL] [ng = [ng/mL] [ng/mL] [h]
h/mL]
5 187 5094 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 For the three doses applied, there was a dose-proportional increase for all measures of exposure at steady state (Ctrough, AUCT, Cmax,ss, and Cav) (see Table 10*).
For both AUC and Cmax, the accumulation ratio R of all doses applied was very similar being approximately a factor of 5 (see Table 10*).
AIC-P03329CA01 Application.doc The time to reach Cmax,ss was similar for the three doses (0.5 ¨ 4.5 h). The peak-trough fluctuation at steady-state ranged between 59 and 64%.
Elimination half-life 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 ¨ 1.08 L/h).
Summary of the results of Example 7*: Under steady-state conditions, an increase in the dose of mesylate monohydrate salt of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyliacetamide in formulation according to example 2*, Table 2*, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, resulted in a proportional increase in exposure to N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-yl]-N-methy1-244-(2-pyridinyl)phenyl]acetamide. In general, plasma concentrations at steady state are to be expected to be approximately five times higher than after single dose administration of the same dose this being a reflection of the half-life and dosing interval. Inter-individual variability of steady state exposure was quite low as revealed by a low coefficient of variation, e.g. for minimal or "trough"
concentrations and peak-trough fluctuations.
Rate of elimination and terminal half-lives at steady-state were comparable to the single dose situation.
These results clearly demonstrate that using the mesylate monohydrate salt of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)pheny1]-acetamide, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g in the formulations as described above, a once daily dose (or even a less frequent administration) is sufficient for reaching an appropriate plasma concentration for the treatment of viral diseases, e.g. infection by a herpes virus or herpes viruses.
In a further human trial it has been shown that the administration of a higher dose of 400 mg to 600 mg and preferably about 500 mg of the mesylate monohydrate salt of the present invention is also sufficient for reaching an appropriate plasma A1C-P03329CA01Application doc concentration for the treatment of viral diseases, e.g. infection by a herpes virus or - herpes viruses.
, , A1C-P03329CA01Application.doc Description of figures Figure 1* shows the overlay of X-ray powder diffractions obtained after granulation experiments ; from top to bottom:
N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1)-N-methyl-244-(2-pyri-dinyl)phenyliacetamide mesylate monohydrate N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-244-(2-pyri-dinyl)phenyllacetamide (free base), N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methyl-244-(2-pyri-dinyl)phenyliacetamide, granulation of free base using 1 equivalent of methanesulfonic acid according to WO 2006/103011, example 5;
lowest curve shows blank granulation matrix.
A 1:1 (weight per weight) mixture of free base and mesylate monohydrate was analysed with X-ray powder diffraction as calibration of the ratio of free base to salt. The ratio was calculated based on integration and shows the granulation mixture having a content of the mesylate monohydrate form of 8 to 12 percent.
Figure 2* shows the overlay of X-ray powder diffraction spectra of granulations of a mixture of N45-(aminosulfony0-4-methyl-1,3-thiazol-2-y1]-N-methy1-214-(2-pyridinyl)phenyl]acetamide mono methanesulfonic i acid monohydrate with N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yq-N-methyl-244-(2-pyridinyl)phenyllacetamide mono methane-sulfonic acid after closed storage at 40 C for four weeks (top), after closed storage at 40 C for four days (middle) and of the initial sample, i.e. the mixture of N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyljacetamide mono methane-sulfonic acid monohydrate with N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyliacetamide mono methanesulfonic acid.
Figure 3* shows microscope pictures of A) free base form, B) crystalline N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y11-N-methy1-244-(2-pyridinyl)phenyl]acetamide mono methane-sulfonic acid monohydrate and AIC-P03329CA01 Application doc C) spontaneous crystallized material after addition of methanesulfonic acid.
Figure 4* shows the X-ray structure of the N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl)phenyl]acetamide mono 5 methanesulfonic acid monohydrate with indicated hydrogen bridges.
It is shown that the nitrogen atom in the pyridinyl ring (right side bottom) is protonated and that a hydrogen bridge is formed between the hydrogen, which protonates the pyridinyl ring nitrogen and one oxygen of the mesylate anion, and another hydrogen bridge is 10 formed between another oxygen of the mesylate anion and the hydrogen of the water molecule while the other hydrogen of the water molecule form a hydrogen bridge with the oxygen of another mesylate anion.
Figure 5* shows the X-ray powder diffraction spectra of a film-coated tablet 15 with 5 mg N145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-[4-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles 20 less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, a placebo tablet and of N145-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-244-(2-pyridinyl) 25 phenyljacetamide mono methanesulfonic acid monohydrate after 24 months at 25 C.
Figure 6* shows the X-ray powder diffraction spectra of a film-coated tablet with 25 mg N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1J-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid mono-30 hydrate, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific 35 surface area of the particles less than 0.3 m2/g, a placebo tablet and of 1145-(aminosulfony1)-4-methyl-1,3-thiazol-2-yli-N-methyl-244-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate after 24 months at 25 C
AIC-P03329CA01 Application.doc Figure 7* shows the X-ray powder diffraction spectra of a film-coated tablet with 100 mg N-[5-(aminosulfony1)-4-methyl-1,3-thiazol-2-yg-N-methy1-244-(2-pyridinyl)phenyliacetamide mono methanesulfonic acid mono-hydrate, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, a placebo tablet and of N-[5-(aminosulfony1)-4-methy1-1,3-thiazol-2-y1]-N-methy1-244-(2-pyridinyl)phenyliacetamide mono methanesulfonic acid monohydrate after 24 months at 25 C.
Figure 8* shows the dissolution curves of the six different tablets according to Table 7*.
Figure 9* shows the relationship between single doses (5 mg ¨ 600 mg) of tablets containing N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-yll-N-methyl-214-(2-pyridinyl)phenyliacetamide mono methanesulfonic acid monohydrate, wherein the particle size distribution is preferably defined by d(0.1) from 2 to 100 pm, d(0.5) from 30 to 210 pm and d(0.9) from 70 to 400 pm with a specific surface area of the particles less than 1.0 m2/g, and more preferably defined by d(0.1) from 10 to 75 pm, d(0.5) from 100 to 175 pm, d(0.9) from 200 to 350 pm with a specific surface area of the particles less than 0.3 m2/g, and AUC., measured as N45-(aminosulfony1)-4-methyl-1,3-thiazol-2-y1]-N-methyl-214-(2-pyridinyl)phenyqacetamide.
AIC-P03329CA01 Application doc

Claims

1. Method for synthesizing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide according to the following steps:
Step A:
Reacting compound A of the following general formula A*
wherein 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 with a boronic acid derivative, borolane, borinane or diboronic acid reagent under elimination of R1-H or R1-B(OR)2 and formation of an intermediate boronic acid derivative of compound A, wherein the intermediate boronic acid derivative is then reacted with the pyridine compound B of the following general formula B*
wherein R3 represents a leaving group under basic conditions in order to directly obtain (4-pyridin-2-ylphenyl)acetic acid which is then purified.
Step B:
Reacting (4-pyridin-2-ylphenyl)acetic acid obtained from step A with 4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide 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

2. Method according to claim 1 further comprising step C:
Converting N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide with methanesulfonic acid in a mixture of an organic solvent and water to crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide methanesulfonic acid monohydrate of the formula

3. Method according to claim 1, wherein R1 and R3 are independently of each other selected form ¨F, ¨CI, ¨Br, ¨I, ¨OMs, ¨OTf and ¨OTs.

4. Method according to claim 1, wherein the boronic acid derivative, borolane, borinane or diboronic acid reagent is selected from:
wherein R', R", R a, R b, R c, R d, R e and R f represent independently of each other a substituted or unsubstituted, linear or branched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with 3 to 10 carbon atoms.

5. Method according to claim 1, wherein for the preparation of the intermediate boronic acid derivative or borolane reagent, the reagents palladium acetate, triethylamine and triphenylphosphine or PdCl2(PPh3)2 and triethylamine are used.

6. Method according to claim 1, wherein Step B is carried out with EDC x HCI
as coupling agent in a THF / NMP solvent mixture.

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

8. Method according to any one of claims 1 ¨ 7 further comprising step D:
Preparing a pharmaceutical composition of the crystalline N-[5-(aminosuIfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide methanesulfonic acid monohydrate with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent.