HK1196018B

HK1196018B - N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate

Info

Publication number: HK1196018B
Application number: HK14108902.4A
Authority: HK
Inventors: W．施瓦布; A．比克曼; K．弗格特利; D．哈格; A.伦德; A．格瓦嫩博格; B.凯尔; J.雷泽
Original assignee: Aic316 Gmbh
Priority date: 2011-09-26
Filing date: 2012-09-26
Publication date: 2017-09-22

Description

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

Technical Field

The present invention relates to an improved synthesis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and its mesylate monohydrate using boronic acid derivatives or cyclopentylborane (borolane) reagents while avoiding toxic organotin compounds; and to the monohydrate of the mesylate salt of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide, which salt shows increased long-term stability and release kinetics (releasekinetics) from pharmaceutical compositions.

Background

A method for the synthesis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide is known from EP1244641B1, and WO2006/103011a1 discloses the use of an acidic component comprising methanesulfonic acid to formulate tablets containing micronized N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

Disclosure of Invention

It is an object of the present invention to provide an improved synthesis of the compound N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and stable salts showing increased long term stability and improved release kinetics from pharmaceutical formulations, as well as pharmaceutical formulations comprising said salts and having improved release kinetics.

The object of the invention is achieved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are apparent from the dependent claims, the description, the figures and the embodiments of the application.

Detailed description of the preferred embodiments

The present invention relates to an improved and novel synthesis of the pharmaceutically active (pharmacologically active) compound N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and its mesylate salt. The improved synthesis starts from the same compounds as the old known synthesis in the prior art, but combines three reaction steps by using boronic acid derivatives or cyclopentylborane reagents. The improvement allows easier synthesis to be accomplished and also allows increased yields by avoiding two separation and purification steps.

The old known synthesis as described on page 21 of EP1244641B1 starts from 2-bromopyridine. In step 1, 2-trimethylstannylpyridine (2-trimethylstannylpyridinine) is prepared in yields of 45% to 50% (of theory). Subsequently, 2-trimethylstannylpyridine was reacted with ethyl (4-bromophenyl) acetate to obtain ethyl (4-pyridin-2-ylphenyl) acetate in a yield of 75%. In a third step, ethyl (4-pyridin-2-ylphenyl) acetate was saponified to (4-pyridin-2-ylphenyl) acetic acid in a yield of about 95% of theory. Thus, the prior art synthesis method as shown below:

comprising 3 steps with an overall yield of about 34%, said 3 steps comprising two separation and purification steps, which are time consuming and involve the use of solvents for the extraction and washing of the desired compound and configurations for the purification of said compound (arrangement).

The synthesis method of the invention is shown as follows:

the use of boronic acid derivatives or cyclopentylborane or cyclohexborane reagents to combine three discrete steps allows the synthesis of the key intermediate (4-pyridin-2-ylphenyl) acetic acid in a single stage with an overall yield of about 40% of the theoretical yield, thus avoiding the two separation and purification steps of the prior art synthesis methods.

As an additional benefit, the use of boron-containing reagents has the advantage over the use of toxic organotin compounds in that the resulting boric acid by-product can be easily removed by aqueous washing. In contrast, organotin compounds are not only a known problem in process waste streams, but are also noted to undesirably contaminate the resulting products of downstream synthesis. (4-pyridin-2-ylphenyl) acetic acid was reacted with 4-methyl-2- (methylamino) -1, 3-thiazole-5-sulfonamide to yield the final product, which was then converted to the well-defined (definite) mesylate monohydrate as shown below.

Accordingly, the present invention relates to a process for the synthesis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and its mesylate salt, said process being carried out according to the following steps:

step A: reacting a compound a of the general formula a:

wherein

R¹Represents a leaving group, and

R²represents an alkyl residue having 1 to 6 carbon atoms or a cycloalkyl residue having 3 to 6 carbon atoms,

with boric acid derivatives, cyclopentaneborane, cyclohexaneborane or diboronic acid reagents in the elimination of R¹-H or R¹-B(OR)₂And under conditions to form an intermediate boronic acid derivative of compound a,

wherein the preferred catalysts for the reaction are the reagent system palladium acetate with triethylamine and triphenylphosphine or PdCl₂(PPh₃)₂And the reaction product of the alcohol and triethylamine,

wherein the intermediate boronic acid derivative is subsequently reacted with a pyridine compound B of the following general formula B:

wherein

R³Represents a leaving group, and represents a leaving group,

under basic conditions to obtain (4-pyridin-2-ylphenyl) acetic acid as a basic solution of the corresponding carboxylate salt.

The resulting (4-pyridin-2-ylphenyl) acetic acid is purified by simple washing and clarifying filtration steps at different pH values, followed by a suitable adjustment of the pH value of an acidic aqueous solution of (4-pyridin-2-ylphenyl) acetic acid, preferably by using a suitable amount of base, to a value of 3.5 to 5.0, preferably 3.8 to 4.7, for precipitation or crystallization. No further purification of (4-pyridin-2-ylphenyl) acetic acid or any intermediate by e.g. recrystallization or chromatography is required, except for simple washing and filtration steps.

And B: (4-pyridin-2-ylphenyl) acetic acid obtained from step A is reacted with 4-methyl-2- (methylamino) -1, 3-thiazole-5-sulfonamide

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

thereafter N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide is most preferably converted (as step C) to the hitherto unknown monohydrate of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide. It is noted that the mesylate salt is disclosed in WO2006/103011a1, but no specific monomethanesulfonate salt monohydrate is disclosed that exhibits improved properties.

The process of the present invention for the synthesis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate can further comprise step D, which involves the preparation of a pharmaceutical composition of said methanesulfonic acid monohydrate:

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

The pharmaceutical compositions may be prepared by mixing or blending crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with at least one pharmaceutically acceptable carrier, excipient, solvent, and/or diluent.

The method of the present invention may further comprise a step E, after step D:

step E: to a pharmaceutical composition of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent is added acetylsalicylic acid, trifluridine (trifluridine), idoside, foscarnet (foscarnet), cidofovir (cidofovir), ganciclovir (ganciclovir), acyclovir (aciclovir), penciclovir (penciclovir), valacyclovir (valaciclovir) and/or famciclovir (famciclovir).

Thus, after step E a pharmaceutical composition is obtained containing acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir or famciclovir in combination with crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent, or 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 acyclovir, or, Or acetylsalicylic acid and penciclovir, or acetylsalicylic acid and valacyclovir, or acetylsalicylic acid and famciclovir in combination with crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent. Thus, the present invention also relates to a pharmaceutical composition comprising acetylsalicylic acid or acyclovir or penciclovir or acetylsalicylic acid and acyclovir or acetylsalicylic acid and penciclovir, and crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent. Some suppliers use the name acyclovir (acyclovir) instead of acyclovir (aciclovir).

The term "leaving group" as used herein is a molecular fragment that leaves with a pair of electrons upon cleavage of a heterogeneous bond. The leaving group may be an anion or a neutral molecule. Typical anionic leaving groups are halides, such as Cl^-、Br^-And I^-And sulfonates such as p-toluenesulfonate ("tosylate", TsO)^-) Trifluoromethanesulfonic acid radical ('trifluoromethanesulfonic acid radical', TfO)^-、CF₃SO₂O^-) Benzenesulfonate ("benzenesulfonate"), C₆H₅SO₂O^-) Or methanesulfonate ("methanesulfonate", MsO)^-）。

General formula A shown below

All phenylacetates having a leaving group at the 4-position of the phenyl residue are contemplated.

Thus, R¹Preferably represents-F, -Cl, -Br, -I, -OMs, -OTf and-OTs. The group "-OMs" means-O-mesylate, the group "-OTf" means-O-triflate and the group "-OTs" means-O-tosylate.

Radical R²Represents an alkyl residue having 1 to 6 carbon atoms or a cycloalkyl residue having 3 to 6 carbon atoms, and is preferably-CH₃、-C₂H₅、-C₃H₇、-CH(CH₃)₂、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃、-C₅H₁₁、-C₆H₁₃ring-C₃H₅ring-C₄H₇ring-C₅H₉ring-C₆H₁₁. More preferably-CH₃、-C₂H₅、-C₃H₇、-CH(CH₃)₂、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃and-C₅H₁₁. Particularly preferred is-CH₃、-C₂H₅、-C₃H₇and-CH (CH)₃)₂。

Various cyclopentylboranes and cyclohexaneboranes and corresponding diboronic acid derivatives may be used in step a of the synthetic methods of the invention disclosed herein. Preferred are cyclopentaneboranes of the general formula:

wherein

R 'and R' are each independently of the other any substituted or unsubstituted, linear or branched alkyl radical having from 1 to 10 carbon atoms or cycloalkyl having from 3 to 10 carbon atoms, or R 'and R' may also form together with the boron atom a heterocycle, where R 'and R' together form a substituted or unsubstituted, linear or branched alkylene radical having from 2 to 10 carbon atoms. Preferably R 'and R' independently of one another represent-CH₃、-C₂H₅、-C₃H₇、-CH(CH₃)₂、-C₄H₉、-CH₂-CH(CH₃)₂、-CH(CH₃)-C₂H₅、-C(CH₃)₃and-C₅H₁₁. Preferably cyclic cyclopentaneborane.

The following cyclopentylborane, cyclohexylborane and diboronic acid derivatives are preferred:

wherein R is^a、R^b、R^c、R^d、R^eAnd R^fIndependently of one another, represents a substituted or unsubstituted, linear or branched alkyl radical having from 1 to 10 carbon atoms or a cycloalkyl radical having from 3 to 10 carbon atoms. Preferably a straight chain alkyl residue having 1 to 6 carbon atoms, and most preferably-CH₃、-C₂H₅、-C₃H₇and-CH (CH)₃)₂。

A particularly preferred example of the above boron-containing compound is 4,4,5, 5-tetramethyl [1,3,2 ]]Dioxolane (pinacolborane)), [1,3,2]Dioxolane, [1,3,2 ] pentaborane]Dioxaborolan, 5-dimethyl [1,3,2 ]]Dioxaborolan, 4,6, 6-trimethyl [1,3,2 ]]Dioxaborolan, 4,6, 6-tetramethyl [1,3,2 ]]Dioxaborolane, 4,5,5,6, 6-hexamethyl [1,3,2 ] borane]Dioxaborolane, diisopropoxyborane, hexahydrobenzo [1,3,2 ] borane]Dioxaborole, 9-dimethyl-3, 5-dioxa-4-bora-tricyclo [6.1.1.6^2,6]Decane, 6,9, 9-trimethyl-3, 5-dioxa-4-bora-tricyclo [6.1.1.6^2,6]Decane, B₂Pin₂(bis (pinacolato) diborane), bis (neopentylglycolato) diboron and catecholborane.

In step a, the boronic acid derivative, cyclopentylborane, cyclohexylborane or diboronic acid reagent is reacted with compound a of general formula a to obtain the intermediate cyclopentylborane or cyclohexylborane reagent without isolation and purification. A variety of organic and inorganic bases may be present, such as triethylamine (Et)₃N), NaOAc, KOAc and K₃PO₄By combining palladium salts (such as [ Pd (OAc))₂]And PdCl₂) With triphenylphosphine (PPh)₃) Tri-o-tolylphosphine (P (o-Tol)₃) Tricyclohexylphosphine (PCy)₃) Tris-tert-butylphosphine, 1, 4-bis (diphenylphosphino) -butane (dppb) and 1,1' -bis (diphenylphosphino) -ferrocene (dppf) catalysts prepared in situ or preformed catalysts such as Pd (PPh)₃)₂Cl₂、Pd(PPh₃)₄Fibrecat1032 and Pd (dppf) Cl₂) To support this reaction. For the reaction, it is preferable to heat to a temperature of 70 ℃ to 150 ℃, preferably 80 ℃ to 130 ℃, more preferably 90 ℃ to 110 ℃. Furthermore, aprotic and preferably nonpolar solvents are used, and preferably aromatic solvents such as benzene or toluene or xylene are used.

Said step a improves the prior art synthesis methods by avoiding the use of toxic organotin compounds, which are a big problem in the purification of waste streams and the actual reaction products eventually used as human pharmaceuticals.

Subsequently, reacting the intermediate boronic acid reagent with a pyridyl compound of the general formula B, wherein R³Represents a leaving group. Thus R³represents-F, -Cl, -Br, -I, -OMs, -OTf and-OTs, and is preferably-Cl or-Br.

The corresponding (4-pyridin-2-ylphenyl) acetate was treated in situ with aqueous base to cleave the ester linkage. The following are beneficial: during the coupling/saponification step, the reaction mixture is heated to an intermediate temperature and preferably to a temperature of from 40 ℃ to 90 ℃, more preferably from 45 ℃ to 80 ℃, even more preferably from 50 ℃ to 70 ℃ and most preferably from 55 ℃ to 65 ℃.

After purification and isolation of the key intermediate (4-pyridin-2-ylphenyl) acetic acid, (4-pyridin-2-ylphenyl) acetic acid is obtained in a yield of at least 40% of the theoretical yield (comprising only one isolation and purification step).

The method of the invention has the following other advantages:

□ purification and Pd removal were performed by successively washing the basic aqueous product solution and the acidic aqueous product solution with an organic solvent (toluene, MIBK, EtOAc, MeTHF, etc.).

□ additional Pd was removed by charcoal/diatomaceous earth treatment.

□ can be crystallized from an aqueous alkaline or acidic solution by neutralization (preferably at 50 ℃ C. to 70 ℃ C.).

Thereafter, (4-pyridin-2-ylphenyl) acetic acid is reacted with 4-methyl-2- (methylamino) -1, 3-thiazole-5-sulfonamide of the formula:

the above compounds were prepared according to the synthesis disclosed in EP1244641B1, so as to obtain N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide of the formula:

in WO01/47904A, HOBT (1-hydroxy-1H-benzotriazole hydrate) in DMF, which generally causes problems during up-scaling due to its explosive nature, is used to describe amide coupling reactions. Furthermore, in the optimization process, the solvent DMF has been detected as a cause of the formation of various by-products (from the vilsmeier type formylation).

In an attempt to modify the coupling conditions, it was surprising that EDC × HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) in a solvent combination of NMP/THF could be successfully used without HOBT. Thus, step B of the above process is preferably carried out using a THF/NMP solvent mixture (ratio of 10:1 to 1: 1) containing EDC × HCl (without HOBT) as the coupling agent. Subsequent recrystallization from THF/water can scavenge Pd to less than 5 ppm. For coupling and recrystallization, overall yields of greater than 80% can be achieved.

Thus, the present invention also relates to the compound N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide obtained according to the synthetic method disclosed herein.

The N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide is then converted to a crystalline mesylate monohydrate, which has not been disclosed in the prior art. Non-stoichiometric methanesulfonate salts are known in the art, but this is not the case for a well-defined and stoichiometric monohydrate of the methanesulfonate salt, which has exactly 1 molar equivalent of water and 1 molar equivalent of methanesulfonate salt per mole equivalent of N- [5- (sulfamoyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridyl) phenyl ] acetamide.

Accordingly, the present invention relates to the compound N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and in particular to crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, and crystalline N- [5- (aminosulfonyl) -4-methyl-1 obtainable according to the synthetic methods disclosed herein and obtained according to the synthetic methods disclosed herein, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridyl) phenyl ] acetamide methanesulfonic acid monohydrate. N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamidomethanemethanesulfonic acid monohydrate is essentially pure (purity higher than 96% by weight, preferably higher than 98% by weight and more preferably higher than 99% by weight) and is a well-defined monohydrate in the form of a regular crystalline structure, that is, 1 mole of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate contained 1 mole of water and 1 mole of methanesulfonate anion, as shown in FIGS. 2 and 3.

Crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide mesylate monohydrate is formed from a supersaturated solution of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and methanesulfonic acid by crystallization under controlled conditions. Preferably the crystallization conditions are such that methanesulfonic acid is added to a mixture of an organic solvent containing N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide and water at elevated temperature and preferably at 30 ℃ to 90 ℃, more preferably at 35 ℃ to 80 ℃, even more preferably at 40 ℃ to 70 ℃, even more preferably at 45 ℃ to 60 ℃ and most preferably at 50 ℃ to 55 ℃, producing a supersaturated solution of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide mesylate. Organic solvents miscible with water (miscible) or co-soluble (consolute) are preferred, such as MeOH, EtOH, n-PrOH, i-PrOH, acetonitrile, THF, acetone. Furthermore, it is preferred that seed crystals of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate are also added to the supersaturated mixture at elevated temperature (e.g., 30 ℃ to 90 ℃, preferably 35 ℃ to 80 ℃, more preferably 40 ℃ to 70 ℃, even more preferably 45 ℃ to 60 ℃, and most preferably 50 ℃ to 55 ℃). It is also preferred that the mixture is stirred at moderate to slow speed and the mixture is allowed to cool slowly to room temperature. Furthermore, it is preferred to add the methanesulfonic acid at an elevated temperature over a period of 5 to 15 minutes and to keep the resulting mixture at said elevated temperature for a period of 0.5 to 5 hours and more preferably for a period of 1 to 2 hours after the addition of the methanesulfonic acid is complete. The mixture is cooled to room temperature within 1 hour to 5 hours and preferably within 2 hours to 3 hours and thereafter preferably slowly stirred at room temperature for a further 1 hour. The crystals are then filtered off, washed with ethanol/water and dried, preferably under vacuum, at a temperature of from 20 ℃ to 60 ℃ (preferably starting at 20 ℃ and ending at 60 ℃).

Crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide mesylate monohydrate exhibits increased long term stability, in particular ideal or improved release kinetics from pharmaceutical compositions and thus allows the preparation of long term stable pharmaceutical compositions. The long term stability of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide monomethanesulfonate monohydrate is superior compared to the free base form of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

In addition, crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide monomethanesulfonate monohydrate also exhibits polymorphic stability compared to the free base form or other salts, as can be seen in table 1. Polymorphism (Polymorphism) refers to the ability of a solid substance to exist in more than one crystal structure or solid form.

Table 1: thermal analysis and polycrystal stability (method used: DSC, TGA)

Form(s) of	TGA	Thermal stability of hydrates	DSC
				1×HCl	2.1%	Instability of the film	Water loss before melting
1×MsOH	4.3%	Stabilization	Water loss before melting
				1×TsOH	5.9%	Instability of the film	Water loss before melting
Free base	8.8%	Instability of the film	Water loss before melting

TGA: thermogravimetric analysis (Thermogravimetric analysis/thermal Gravimetric analysis)

DSC: differential scanning calorimetry (differential scanning calorimetry)

Form (a): refers to the monochloride salt, the monomethanesulfonate salt, the monotoluenesulfonate salt and the free base of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

The free base form and the hydrochloride and tosylate salts form hydrates with low caloric and low polymorphic stability. After moderate heating (about 50 ℃ to 60 ℃), the water content decreases, thereby making these salt and free base forms extremely difficult to handle and process during production and formulation. In contrast, the hydrate of the monomethanesulfonate salt may be thermally and polycrystalliy stable at temperatures significantly well above 100 ℃, as determined by TGA.

The free base of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide exists in four polymorphic forms and one amorphous form at room temperature. Furthermore, depending on the solvent, several solvates of the free base can be detected. The data available at present do not allow the identification of the thermodynamically most stable form, since all batches synthesized according to the prior art show more than one melting peak as indicated by differential scanning calorimetry. The physico-chemical properties of various salts (hydrochloride (HCl), mesylate (MsOH), tosylate (TsOH)) and free base have been studied and compared (see table 2).

TABLE 2 salt screen of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide. n.a., not applicable; n.d., not determined; HPLC, high pressure liquid chromatography; excellent/high; +, better/high; -poor/low; -, extremely poor/low.

Dihydrochloride (2 × HCl), dimesylate (2 × MsOH), xylenesulfonate (2 × TsOH) and benzoate (1 × PhCOOH) of N- [5- (sulfamoyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridyl) phenyl ] acetamide free base do not meet the stoichiometric criteria. In addition, the monohydrochloride hydrate exhibits reduced crystallinity during storage. In addition, the free base and the monotosylate form a less thermally stable hydrate, making it unsuitable for tableting. These results are disclosed in table 1 above, where the polymorphic instability of the hydrochloride, tosylate and free base forms are discussed. Thus, surprisingly, only the monomethanesulfonate salt of the present invention exhibits the desired polymorphic and thermal stability, allowing for manufacturing, processing and formulation, particularly on a pharmaceutical scale.

One possible method for preparing crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate is to dissolve the base in ethanol/water (1: 1) in a volume of 10 times its volume, add 1.15 equivalents of methanesulfonic acid at 50 ℃ to 55 ℃ over 5 to 15 minutes, seed the final product with 0.5 mol%, age at 50 ℃ for 1 to 1.5 hours, and cool to 20 ℃ to 25 ℃ over 2.5 hours.

After stirring for another 1 hour, the crystalline mesylate monohydrate was isolated by filtration and dried in vacuo to give a yield of > 95%. By using this method, N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with a purity of more than 99% and containing less than 2ppm residual Pd can be reproducibly prepared in terms of yield and purity.

In addition, crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate can be prepared in a well-defined and stable polymorphic form, and in addition, the use of this process avoids the less soluble free base form coprecipitation. Thus, the crystalline mesylate monohydrate salt of the invention is free or substantially free of free base.

The crystalline mesylate monohydrate salt of the invention also shows stability in long term stability studies (as pure API and in pharmaceutical formulations), increased release kinetics from pharmaceutical compositions, and results in improved bioavailability.

From figure 2, which shows a single crystal X-ray structural analysis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, it is evident that a salt is formed between the methanesulfonate group and the protonated pyridyl ring. In addition, exactly 1 molar equivalent of water is incorporated into the crystal structure, where the hydrogen atoms of a water molecule form hydrogen bridges with the oxygen atoms of two different methanesulfonate molecules. This well-defined position in the lattice (see fig. 3) is verified by the fact that water is released from the crystal only at high temperatures (starting at 160 ℃). Thus, the compounds of the present invention are the definite monomethanesulfonates and monohydrate of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

The crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate according to the present invention is a useful compound for the preparation of a pharmaceutical composition for the treatment and/or prevention of herpes virus infections and/or for the prevention of the transmission of one or more herpes viruses. Pharmacokinetic data obtained for single and multiple dose administrations to healthy volunteers showed favorable plasma concentration profiles over time, indicating a long-acting half-life for once-daily dosing regimens or less frequent dosing regimens, such as once weekly. Plasma concentrations in humans exceed the following two concentrations: concentrations sufficient to effectively treat herpes simplex virus infection in a variety of animal models, and concentrations that prevent viral replication in cell culture, have been achieved in vivo and in vitro experiments.

Surprisingly, it was found that crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate has a high activity against herpes viruses and infections caused by herpes viruses, mainly herpes simplex viruses. Accordingly, the crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate of the present invention is particularly useful for the treatment and/or prevention of diseases caused by herpes simplex virus and/or for the prevention of herpes virus transmission.

Infection with herpes simplex virus (HSV, subtype 1 and subtype 2) is classified as one of a number of conditions, depending on the site of infection. Orofacial herpes virus infections (the visible symptoms of which are commonly referred to as cold sores (coldforms) or fever blisters (febrile)) infect the face and mouth. Orofacial herpes is the most common form of infection. Genital herpes is the second most common form of herpes simplex virus infection. While it is believed that genital herpes is caused primarily by HSV-2 alone, genital HSV-1 infection is increasing. Herpes simplex viruses may also cause other disorders such as herpes whitlow, traumatic herpes, ocular herpes (keratitis), encephalitis of herpes infections of the brain, Morarett's meningitis, neonatal herpes and possibly leading to Bell's palsy (Bell ' spalsy).

In addition, the present invention relates to a combination of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and an anti-inflammatory agent. Particularly preferred is the combination of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with acetylsalicylic acid.

Furthermore, the present invention relates to a combination of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and an antiviral agent. The additional antiviral agent is preferably an antimetabolite and most preferably a nucleobase (nucleobase) analogue, nucleotide analogue or nucleoside analogue drug. If the additional antiviral agent is suitable for combating herpesviruses and/or herpesvirus transmission and is comprised of or selected from the group comprising, but not limited to: trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir or penciclovir or valacyclovir prodrugs or famciclovir prodrugs are more preferred. Most preferred is the combination of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with acyclovir or penciclovir or the prodrug valacyclovir and the prodrug famciclovir.

The combination of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and another active agent (such as an anti-inflammatory, immunomodulatory or antiviral agent, e.g. a therapeutic vaccine, siRNA, antisense oligonucleotide, nanoparticle or viral uptake inhibitor, such as N-docosanol) can be administered simultaneously in a single pharmaceutical composition or in more than one pharmaceutical composition, wherein each composition comprises at least one active agent.

The compounds of the present invention are preferably used in the manufacture of pharmaceutical compositions containing crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate and at least one pharmaceutically acceptable carrier, excipient, solvent and/or diluent. The crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate employed is free or substantially free of the free base form of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

The pharmaceutical compositions of the present invention may be prepared in a known manner at suitable dosage concentrations in conventional solid or liquid carriers or diluents and conventional pharmaceutical adjuvants. Preferably the formulation may be adapted for oral administration. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro-and nano-formulations, powders and deposits.

The pharmaceutical composition according to the present invention preferably comprises from 5 to 70% by weight, more preferably from 10 to 30% by weight, of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate (all percentage data are weight percentages based on the weight of the pharmaceutical formulation). The pharmaceutical compositions typically comprise from 2 mg to 600 mg of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, preferably from 5 mg to 500 mg, more preferably from 10 mg to 300 mg and especially preferably from 20 mg to 200 mg, in a single dose. The pharmaceutical composition according to the invention optionally comprises one or more fillers, for example selected from the following: microcrystalline cellulose, calcium phosphates, and mannitol. According to the invention, preference is given to using microcrystalline cellulose and mannitol. The pharmaceutical composition suitably comprises from 20% to 80%, preferably from 40% to 80%, especially preferably from 45% to 70% microcrystalline cellulose and from 1% to 40%, preferably from 5% to 30%, especially preferably from 10% to 20% mannitol. The pharmaceutical preparation according to the invention may comprise at least one disintegration aid, for example selected from the following disintegration aids: starch, pregelatinized starch, starch glycolate, crospovidone, sodium carboxymethylcellulose (= croscarmellose sodium), and other salts of carboxymethylcellulose. Mixtures of two disintegrants may also be used. According to the invention, croscarmellose sodium is preferably used. The pharmaceutical composition suitably comprises from 3% to 35%, preferably from 5% to 30% and especially preferably from 5% to 10% of a disintegration aid. The pharmaceutical formulation of the present invention may comprise at least one lubricant selected from the group consisting of fatty acids and salts thereof. According to the invention, magnesium stearate is particularly preferably used.

The pharmaceutical compositions of the invention may include a glidant, which may be colloidal anhydrous silicon dioxide or talc. According to the invention, it is particularly preferred to use colloidal anhydrous silica. The amount of glidant used is suitably from 0.3% to 2.0%, especially preferably from 0.4% to 1.5%, and most preferably from 0.5% to 1%.

Particularly preferred pharmaceutical compositions of the invention comprise: 5% to 30% crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, 5% to 10% croscarmellose sodium, 0.5% to 0.7% magnesium stearate, 40% to 70% microcrystalline cellulose, 10% to 20% mannitol, and 0.5% to 1% colloidal anhydrous silicon dioxide.

The pharmaceutical composition according to the present invention may be administered to a patient in need thereof in a once daily dose of about 20 mg to 750 mg of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methane sulfonic acid monohydrate, and once daily. The pharmaceutical composition according to the invention may also be administered to a patient in need thereof three times daily, twice daily, once daily, three times weekly, twice weekly or once weekly. Preferably on a three-weekly, twice-weekly or once-weekly basis, and particularly preferably once-weekly, i.e. once-weekly, administration of a pharmaceutical composition containing 400 to 600 mg of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate according to the invention. Furthermore, it is preferred to start administration of the mesylate monohydrate salt of the invention at a high loading dose, e.g. an initial single dose of 400 mg to 800 mg and to continue administration at a lower dose of 100 mg to 150 mg daily or weekly during treatment.

Furthermore, the invention also comprises a pharmaceutical composition for preferably parenteral administration. Other modes of administration are dermal, intradermal, intragastric, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, buccal, transdermal (percutan), rectal, subcutaneous, sublingual, topical or transdermal (transdermal) administration. In addition to typical vehicles and/or diluents, the administered pharmaceutical compositions contain crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide-methanesulfonic acid monohydrate as active ingredient.

More preferably, the topical formulation of crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate for dermal or transdermal administration. Preferred topical formulations are skin creams, skin lotions, emulsions, gels, suspensions, ointments, oils, lipsticks and balms.

Any conventional carrier, adjuvant and optionally other ingredients may be added to the formulation. Preferably the adjuvant is derived from the group comprising or consisting of: preservatives, antioxidants, stabilizers, solubilizers and odorants.

Ointments, pastes, creams and gels may comprise at least one conventional carrier, 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 contain conventional carriers such as solvents, solubilizers and emulsifiers, for example water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, olive, castor and sesame oils), glycerol fatty acid esters, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances. Suspensions may contain conventional carriers such as liquid diluents (e.g. water, ethanol or propylene glycol), suspending agents (e.g. ethoxylated isostearyl alcohols, polyethylene oxides and polyethylene oxide sorbitan esters), microcrystalline cellulose, bentonite, agar-agar and tragacanth, or mixtures of these substances.

The compositions of the present invention may contain lipid particles that transport crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate. The formulation of the pharmaceutical composition may also contain adjuvants commonly used in compositions of this type, such as thickening agents, emollients, moisturizers, surfactants, emulsifiers, preservatives, anti-foaming agents, fragrances, waxes, lanolin, propellants and dyes.

The pharmaceutical compositions of the present invention may also be in the form of an alcoholic gel comprising crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide 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 diatomaceous earth). Oily-alcoholic gels also include natural or synthetic oils or waxes. The gel may also contain organic thickeners (such as gum arabic (Gumarabic), xanthan gum, sodium alginate, cellulose derivatives, preferably methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose) or inorganic thickeners (such as aluminium silicates (such as bentonite) or mixtures of polyethylene glycol and polyethylene glycol stearate or polyethylene glycol distearate).

The pharmaceutical composition of the present invention may contain the following preservatives: phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid.

As pharmaceutically acceptable carriers, excipients and/or diluents that may be used, the carrier is preferably such as an inert carrier, e.g. lactose, starch, sucrose, cellulose, magnesium stearate, calcium hydrogen phosphate, calcium sulfate, talc, mannitol, ethanol (liquid filled capsules); suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia (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, seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate, cellulosic materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, 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 waxes and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and D, L-leucine; disintegrants (disintegrates) such as starch, methylcellulose, guar gum, modified starches (such as sodium carboxymethyl starch), natural and synthetic gums (such as locust bean gum, karaya gum, guar gum, tragacanth gum and agar), cellulose derivatives (such as methylcellulose and sodium carboxymethyl cellulose), microcrystalline and cross-linked microcrystalline celluloses (such as cross-linked sodium carboxymethyl cellulose), alginates (such as alginic acid and sodium alginate), clays (such as bentonite), and effervescent mixtures; coloring agents, sweetening agents, flavoring agents, preservatives; glidants are, for example, silicon dioxide and talc; suitable adsorbents are clay, alumina; suitable diluents are parenteral water or water/propylene glycol solutions, juices, sugars (such as lactose, sucrose, mannitol and sorbitol), starches (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.

Other modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description of the invention. Accordingly, this description of the invention 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. Other 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 ordinarily 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.

Examples

Defining: as used herein, the term "1 volume" refers to 1 liter per kilogram of the respective starting material (1 volume =1 liter per kilogram of the respective material or starting material).

Example 1: synthesis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonate monohydrate

Step 1 (Suzuki-Miyauraboupling) and saponification)

Bis (triphenylphosphine) palladium (II) chloride (0.010 eq) was charged to the inerted reactor and inerted again. Toluene (1.65 vol) was then added. After heating to 40 ℃, triethylamine (3.00 eq) was added. A solution of ethyl-4-bromophenyl acetate (1.00 eq) in toluene (0.82 vol) was added. The resulting suspension was heated to 90 ℃ to 95 ℃, followed by the addition of pinacolborane (1.30 equivalents) over 60 to 90 minutes. Stirring was continued for at least 2 hours at 90 ℃ to 95 ℃ and the conversion was checked by HPLC. After cooling to 10 ℃, 2-chloropyridine (1.00 eq) was charged to the reaction mixture. Next, 30% NaOH (6.00 equivalents) was added, followed by heating to 55 ℃ to 60 ℃. Stirring was continued at this temperature for at least 4 hours, followed by checking for conversion by HPLC. After the conversion was deemed complete, the reaction mixture was concentrated at about 300 mbar until 0.8 volume of distillate was collected. The reaction mixture was diluted with water (2.72 vol), cooled to 20 ℃ and the phases separated. The organic layer was discarded while the pH of the aqueous layer was adjusted to pH1 by the addition of 33% HCl at 20 ℃. MIBK (2.30 vol) and celite (165 g/kg) were added and the resulting mixture was stirred at 20 ℃ for at least 15 minutes, followed by removal of solids by filtration. The reactor and filter cake were successively flushed with water and the combined filtrate was transferred back to the reactor. The phases were separated and the aqueous layer was washed 2 more times with MIBK. After dilution with water, the acidic product aqueous solution was heated to 55 ℃ and filtered through a small column packed with celite at the bottom and activated carbon at the top. The celite/charcoal column was washed once more with pre-heated water (0.5 vol, 55 ℃), and the combined filtrate was charged back into the reactor. The pH was adjusted to about 3.0 by addition of 30% NaOH at 20 ℃, followed by heating the product solution to 60 ℃. Further NaOH was added to adjust the pH to 4.1 to 4.3. The resulting suspension was stirred at 60 ℃ for 1 to 1.5 hours and subsequently cooled to 20 ℃. After stirring at this temperature for at least 1 hour more, the product is filtered, washed twice with water, pre-dried in a stream of nitrogen and final dried in vacuo at 50 ℃ to 65 ℃. Typical yields are: 38% to 42%.

Step 2 (amide coupling)

The product of step 1 (1.00 eq) and 4-methyl-2- (methylamino) -1, 3-thiazole-5-sulfonamide (1.02 eq) were charged to a reactor. THF (7.08 vol) and NMP (1.11 vol) were added. The resulting suspension was allowed to cool to 0 ℃ and then 4 equal parts of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.23 eq) were added over a period of more than 90 minutes. After a further at least 2 hours at 0 ℃ the reaction mixture was warmed to 20 ℃. Stirring was continued at this temperature for a further 2 hours, after which the conversion was checked by HPLC. Next, about 2% (0.2 vol) of the reaction mixture was added to water (12.3 vol) at10 ℃ to 15 ℃ over at least 5 minutes. The resulting thin suspension was stirred at10 ℃ to 15 ℃ for at least 1 hour, followed by addition of the remaining majority of the reaction mixture over more than 4 hours. Stirring is continued for at least 0.5 h at10 ℃ to 15 ℃ and the solid is subsequently filtered off, washed with water and dried on a suction filter in a steady stream of nitrogen until drying is deemed sufficient (LOD <45% (weight/weight); LOD: loss on drying).

The feed reactor was charged with the crude product, THF (8.15 volumes) and water (up to 1.17 volumes, depending on the LOD of the crude product). The resulting suspension was heated to 60 ℃ to 65 ℃ and stirred at this temperature for 1 hour. An almost clear solution was obtained, which was subjected to microfiltration (polishfiltration) using a heatable lens filter (lensefilter) heated to 60 ℃. The feed reactor, transfer lines and filters were successively flushed with a mixture of THF (0.44 vol) and pure water (0.06 vol) at 60 ℃ to 65 ℃. The combined filtrates were collected in separate reactors and heated to 50 ℃ to 55 ℃. Water (3.23 volumes) was added to the reactor contents over at least 30 minutes. Stirring was continued for 1 to 1.5 hours at 50 to 55 ℃ followed by slow addition of another portion of water (8.93 vol) over 2 hours. After stirring at 50 ℃ for 1 to 1.5 hours, the resulting suspension was cooled to 5 ℃ over 2.5 hours and stirred for a further 0.5 hour. The solid is then filtered off, washed with water (3 times 2.96 volumes each) and pre-dried on a suction filter under a steady stream of nitrogen. Final drying was achieved using a conical dryer in vacuo at 50 ℃ to 65 ℃. Typical yields are: 78% to 83%.

Step 3 (salt formation)

The product from step 2 (1.00 eq), ethanol (4.96 vol) and water (4.96 vol) were charged to the reactor. After heating the resulting suspension to 50 ℃ to 55 ℃, methanesulfonic acid (1.15 equivalents) was added in less than 15 minutes. Complete dissolution of the starting material is usually observed at the end of the complete addition. Immediately following this, stirring was decelerated to a minimum acceptable rate and the reaction mixture was seeded with N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonate monohydrate (0.005 equivalents) in the form of the desired polymorph prepared in the previous experiment. Slow stirring was continued at 50 ℃ to 55 ℃ for 60 to 90 minutes followed by cooling to 20 ℃ to 25 ℃ over a period of more than 2.5 hours. After stirring for another 1 hour, the solid was filtered off, washed with ethanol/water 5:2 (v/v) (3.10 v), pre-dried in nitrogen stream and transferred to a conical dryer for final drying in vacuo at 20 ℃ to 60 ℃.

Typical yields are: is more than 95 percent.

Example 2:

tablets containing 60 mg of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide according to the invention (calculated as free base) as micronized active compound,

active compound content about 59% (based on uncoated (unwarnish) tablets):

example 3:

ointment comprising 30 mg of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide according to the invention (calculated as free base) as micronized active compound

Crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, micronized 38.4 mg

Example 4:

a gel comprising 40 mg of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide according to the invention (calculated as free base) as micronized active compound.

Crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, micronized 51.2 mg

Example 5:

Example 6:

tablet comprising 50 mg of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide according to the invention (calculated as free base) as micronized active compound,

active compound content about 59% (based on uncoated tablets):

crystalline N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate, micronized 64.00 mg

Example 7:

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

Chemical formula C₁₉H₂₄N₄O₇S₃，M=516.62，F(000)=540，

Colorless flakes having a size of 0.02 × 0.13.13 0.13 × 0.15.15 cubic millimeters, triclinic, space group P-1, Z =2, a =9.4908(7) angstroms, b =9.5545(7) angstroms, c =14.4137(9) angstroms, α =86.130(3) °, β =72.104(3) °, γ =68.253(4) °, V =1153.68(15) cubic angstroms, D_calc.=1.487 mg/cubic meter. graphite-Monochromatic MoK at 293K with a Nonius kappa CCD diffractometer_αRadiation (λ =0.71073 angstrom, θ)_max=30.065 °) to measure crystals. Minimum/maximum transmission 0.95/0.99, μ =0.370 mm^-1. Data collection and integration were performed using a COLLECT suite. Of a total of 43492 reflections, 6761 were independent (combined r = 0.026). Of these independent reflections, it is believed that 4955 reflections (I) are observed>3.0 σ (I)) and used to correct 298 parameters. The structure is resolved by direct methods using the program SIR 92. The least squares correction for F was performed for all non-hydrogen atoms using the program CRYSTALS. R =0.0313 (observed data), wR =0.0432 (all data), GOF = 1.0736. Minimum/maximum residual electron density = -0.28/0.33 electrons/cubic angstrom. The correction is done using Chebychev polynomial weighting.

The single crystal structural parameters of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate are shown in fig. 1A.

Characteristic peaks of batch BXR3NC1 obtained from X-ray powder diffraction analysis are shown in table 3.

Table 3: analysis by X-ray powder diffraction (CuK)_αRadiation) of the characteristic peaks of batch BXR3NC1 obtained.

Angle of rotation	d value of 17->
		（2-θ°）	(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

Since the normal deviation is +/-0.1 deg., the 2-theta value is rounded to 1 decimal place

Example 8:

the exposure of rats to N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide in a repeat dose 13 week toxicity study using the free base N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide (free base) was compared to the exposure observed in a 26 week repeat dose toxicity study using the mesylate monohydrate. In both studies, the test substance was applied as a 0.5% (weight/volume) tyler cellulose (tylose) suspension and the concentration was adjusted for the equivalent of the free base N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide.

After administration of the first dose (day 1, day 2; table 4) and after 13 weeks of repeated dose administration (table 5), the exposures after 10 mg/kg/day, 50 mg/kg/day and 250 mg/kg/day of administration can be compared. After a dose of 10 mg/kg/day, it was shown that there may be higher exposure. It should be noted that N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl was observed after administration of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl) after 50 mg/kg/day and 250 mg/kg/day doses (adjusted for free base equivalents) compared to the exposure after administration of free base]-N-methyl-2- [4- (2-pyridyl) phenyl]The exposure after acetamide mesylate monohydrate was higher. The exposure increased up to 2.7 times (for C)_max) And 4 fold (for AUC). The following conclusions were made: with administration of an equimolecular dose (50 mg/kg/day and 250 mg/kg/day) of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl]-N-methyl-2- [4- (2-pyridyl) phenyl]N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] amide free base equivalent weight]-N-methyl-2- [4- (2-pyridyl) phenyl]Acetamide mesylate monohydrate caused higher exposure. Thus, this significant increase in the extent of exposure indicates that the mesylate salt improved the physicochemical properties leading to more favorable dissolution properties, with an increase in systemic exposure relative to that observed following administration of the free base.

Thus, said enhanced exposure after administration of the mesylate salt means that a higher exposure to the active ingredient is reached, resulting in a greater efficacy and a higher barrier to viral resistance, both of which are considered essential features for the treatment of viral infections. Both efficacy and resistance barriers are enhanced for the main features believed to be associated with the mesylate formulation.

Table 4: rats were compared for exposure after the first administration in the 13 week toxicity (free base) study and the 26 week toxicity (mesylate) study. M, male; f, female. C_maxMaximum observed analyte concentration; AUC_(0-24)Defined as the area under the analyte concentration versus time up to 24 hours after administration; by linearityCalculation by ascending/natural logarithmic descending summation method (linear/exponential)

Table 5: rats were compared for exposure at week 13 in the 13 week toxicity (free base) study with the 13 th week toxicity (methanesulfonic acid monohydrate) study in the 26 week toxicity study. M, male; f, female. C_maxMaximum observed analyte concentration; AUC_(0-24)Defined as the area under the analyte concentration versus time curve up to 24 hours after dosing; calculation by linear rise/natural logarithmic fall summation

Drawings

FIG. 1 shows

A) Single crystal structural parameters of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate (batch BXR3NC 1);

B) an X-ray powder diffraction pattern (calculated from single crystal data) of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate (batch BXR3NC 1); and

C) overlay of measured X-ray powder diffraction pattern (blue line) of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamidomethane sulfonic acid monohydrate of batch BXR3NC1 with calculated X-ray powder diffraction pattern (red line) of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamidomethane sulfonic acid monohydrate;

D) measured X-ray powder plot of batch BXR3NC 1.

FIG. 2 shows the X-ray structure of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate with indicated hydrogen bridge. It is shown that the nitrogen atom of the pyridyl ring (lower right) is protonated and that one hydrogen bridge is formed between the hydrogen protonating the pyridyl ring nitrogen and one oxygen of the methanesulfonate anion and that another hydrogen bridge is formed between another oxygen of the methanesulfonate anion and the hydrogen of a water molecule, and that another hydrogen of a water molecule forms a hydrogen bridge with the oxygen of another methanesulfonate anion.

FIG. 3 shows single crystal X-ray structural analysis of N- [5- (aminosulfonyl) -4-methyl-1, 3-thiazol-2-yl ] -N-methyl-2- [4- (2-pyridinyl) phenyl ] acetamide methanesulfonic acid monohydrate when encapsulated in a crystal. The phenyl pyridyl ring systems are shown oriented in planes parallel to each other.

Claims

1. A process for the synthesis of 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 a compound A of the general formula A

Wherein

R¹To representA leaving group, and

with a boronic acid derivative, cyclopentylborane, cyclohexylborane or diboronic acid reagent selected from:

wherein R ', R', R^a、R^b、R^c、R^d、R^eAnd R^fIndependently of one another, represents a substituted or unsubstituted, linear or branched alkyl radical having from 1 to 10 carbon atoms or a cycloalkyl radical having from 3 to 10 carbon atoms,

to form the corresponding intermediate of the compound A,

wherein said intermediate is then reacted with a pyridine compound B of the general formula B:

wherein

R³Represents a leaving group, and represents a leaving group,

reacting under alkaline conditions to obtain (4-pyridin-2-ylphenyl) acetic acid directly, followed by purification;

and B:

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

2. the method of 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. the method of claim 1, wherein R¹And R³Independently of one another, from the group consisting of-F, -Cl, -Br, -I, -OMs, -OTf and-OTs.

4. The process as claimed in claim 1, wherein for the preparation of intermediates of the compound A, the reagents palladium acetate, triethylamine and triphenylphosphine or PdCl are used₂(PPh₃)₂And triethylamine.

5. The process of claim 1, wherein step B is carried out in a THF/NMP solvent mixture with EDC x HCl as coupling agent.

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

7. The method of any one of claims 1 to 6, further comprising step D:

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