Polymorph form of 2-amino (nitroaryl) thiazole derivative

(54) Title: PROCESS FOR THE SYNTHESIS OF 2-AMINOTIAZOLE COMPOUNDS AS KINASE INHIBITORS (51) Int. Cl .: C07D 417/04 (30) Unionist Priority: 13/02/2007 US 60 / 889,587 (73) (s): AB SCIENCE (72) Inventor (s): ALAIN MOUSSY; PHILIPPE REGINAULT; FRANÇOIS BELLAMY; ANNE LERMET (74) Attorney (s): MATOS E ASSOCIADOS (86) International Request: PCT EP2008051704 of 02/13/2008 (87) International Publication: WO

2008/098949 of 08/21/2008

<img file="BRPI0807626A2_D0001.tif" />

DESCRIPTIVE REPORT

Patent application for "PROCESS FOR THE SYNTHESIS OF 2-AMINOTIAZOLE COMPOUNDS AS KINASE INHIBITORS"

The present invention relates to an industrial process for the synthesis of pharmaceutical compounds that have the formula:

<img file="BRPI0807626A2_D0002.tif" />

which are useful as certain tyrosine kinase inhibitors and more particularly as c-kit and bcr-abl inhibitors. The R groups! and R₂, identical or different, each represents a hydrogen atom, halogen, an alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino group, a solubilizing group; m ranges from 0 to 5 and n ranges from 0 to 4; the group R₃ represents an aryl or heteroaryl group.

Fundamentals of the invention

Tyrosine kinases are receptor-type or non-receptor proteins that transfer ATP terminal phosphate to protein tyrosine residues, thereby activating or deactivating signal transduction pathways. These proteins are known to be involved in many cellular mechanisms, which in the event of disruption, lead to evils such as abnormal cell proliferation and migration as well as inflammation.

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To date, there are 58 known tyrosine kinase receptors. Included are well-known VEGF receptors (Kim et al., Nature 362, pp. 841-844, 1993), PDGF receptors, c-kit, Flt-3 and the FFK family. These receptors can transmit signals to other tyrosine kinases that include Src, Raf, Frk, Btk, Csk, Abl, Fes / Fps, Fak, Jak, Ack, etc.

Among tyrosine kinase receptors, the c-kit is of special interest. Indeed, the c-kit is a crucial receptor in the activation of mast cells, which has been shown to be directly or indirectly associated with several pathologies for which the Depositor deposited WO 03/004007,

WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO

03/002105, WO 03/039550, WO 03/035050, WO 03/035049, WO

03/0720090, WO 03/072106, WO 04/076693 and WO 2005/016323.

We found that mast cells present in patient tissues are implicated or contribute to the genesis of autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases (IBD), allergic diseases, osteoporosis, cancers such as solid tumors, leukemia and GIST, tumor angiogenesis, inflammatory diseases , interstitial cystitis, mastocytosis, graft versus host diseases, infection diseases, metabolic disorders, fibrosis, diabetes and CNS diseases. In these diseases, mast cells have been shown to participate in tissue destruction by releasing a cocktail of different proteases and mediators such as histamine, neutral proteases, lipid-derived mediators (prostaglandins, thromboxanes and leukotrienes) and various cytokines (IL-1, IL25 2 , IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MlP-la, ΜΙΡ-lb, MIP-2 and IFN-γ).

The c-kit receptor can also be constitutively activated by mutations that lead to abnormal cell proliferation and

3/26 development of diseases such as mostocytosis (D816V mutation), and several cancers such as GIST (c-kitA27, a deletion in the just-membrane).

In addition, 60% to 70% of patients presenting with AML have blasts that express the c-kit, the receptor for stem cell factor (FCT) (Broudy, 1997). FCT promotes the growth of hematopoietic parents, and act as a survival factor for AML blasts. In some cases (1 to 2%) of AML, a mutation in a conserved residue of the kinase domain (Kit816), which results in the constitutive activation of the c-kit, has been described (Beghini et al., 2000; Longley et al. , 2001). This function gain mutation (substitution of Asp for Val / Tyr) was identified in leukemic cell lines of mast cells and in samples derived from patients with mastocytosis (Longley etal., 1996).

In addition, we studied around 300 patients affected by systemic mastocytosis and demonstrated that the mutation in Kit816 is expressed in approximately 60% of cases. In this regard, we deposit WO 04/076693, which refers to the adapted treatment of different forms of mastocytosis that depend on the presence or absence of the mutation in Kit816.

Thus, we recently proposed to seek the c-kit to extinguish the mast cells responsible for these diseases. In this regard, we discovered new potent and selective c-kit inhibitors, which are the 2- (3aminoaryl) amino-4-aryl-thiazoles described in our PCT publication WO 2004/014903.

The synthesis of substituted 2-aminothiazole is known in the literature. In the following publications, the general synthesis of these compounds is usually obtained using a two-stage scheme, including the bromination of the initial ketones (A) (G. Crank and R. Kahn, Austr. J. Chem,

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38 (3), 447 - 458 (1985)), followed by the cyclocondensation of intermediate abromoketones (C) with thiourea (B) by reflux in ethanol or methanol (M. Maziere et al, Bull. Soc. Chim. France, 1000- 1003 (1963); JD Spivack, US Patent 3299087).

Layout 1

THE _rThe

THE

Bromination

<img file="BRPI0807626A2_D0003.tif" />

However, when R is an electron removal group such as nitro functionality, the cycloaddition yield is no more than

65% (SP Singh et al, Indian J. Chem. Sect. B, 29 (6), 533-538, (1990)).

This disadvantage is probably due to the instability of nitroariltiouréia, which leads to the formation of both impure and highly reactive by-products, when it reacts in the presence of a base.

Λ

It is evident from the discussion above that this methodology applied to nitroariltiouréia has synthetic disadvantages related to one or more of the following aspects: yield, scalability for syntheses and multi-gram purifications. Our goal was to develop an industrially applicable process, in which good returns are obtained involving simple industrial operations.

We found that the reaction of acetylated nitroarylthiourea with abromocetoaryl at room temperature in methanol and in the presence of a

5/26 base such as potassium carbonate results in the desired thiazole after 3 to 6 hours with excellent yield (90 to 97%).

In addition, pure thiazoles were obtained by simple filtration after adding water to the reaction mixture.

Therefore, the present invention offers a new and industrial process for the synthesis of 2-amino (nitroaryl) thiazole in good yield by reacting a stable acetylated nitroarthiourea with α-bromocetoaryl under moderate conditions.

description

The invention is concerned with a process for the preparation of a compound of formula (I):

<img file="BRPI0807626A2_D0004.tif" />

or a salt, or a solvate thereof, in which:

- Ri and R₂ independently selected from hydrogen, halogens, a linear or branched alkyl group, cycloalkyl containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy, cyano, dialkylamino, and a solubilizing group, m goes from 0 to 5 and from 0 to 4,

- R₃ is one of the following:

6/26 (i) an aryl group such as phenyl or a substituted variant thereof containing any combination, in any ring position, of one or more substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(ii) a heteroaryl group such as a 2, 3, or 4 pyridyl group, which may additionally contain any combination of one or more substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy;

(iii) an aromatic heterocyclic group with a five-membered ring such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5 thiazolyl, which may additionally comprise one or more substituents such as halogens, group alkyl containing 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

comprising the steps of:

a) cyclization at room temperature of a compound (IV):

-ÇrYr

N0₂ (IV) with an Int4 intermediate of the formula:

THE

R₃^

Br Int4 where Ra can be methyl, trifluormethyl, isopropyl, or an optionally substituted phenyl, and R₂, R3 and n are as defined above, to form a compound of a formula (III):

Ί / 26

<img file="BRPI0807626A2_D0005.tif" />

in which R₂, R₃ and n are as defined above;

b) reduction of the nitro group of said compound (III) to form a compound of the formula (II):

(R2) n

NH₂ (II) in which R₂, R₃ and n are as defined above;

c) coupling an aprotic solvent of a compound of the formula (II) with a compound of the formula

<img file="BRPI0807626A2_D0006.tif" />

(Ri) m (Int5) in which Rb is a hydroxyl or alkoxy or halogen group and Ri in are as defined above, to form a compound of formula (I).

In a preferred embodiment, in step (c) compound (II) is treated with 3.0 equivalents of Lewis acid and is added to a solution of 1.0 equivalent of ester (Int5). In addition, Lewis acid is trimethyl aluminum.

In yet another preferred embodiment, in step (c) a solution of 1.0 equivalent of chloride acid (Int5) is added to a solution of 0.8 equivalent of the compound of formula II. Here, the reaction is carried out in basic condition and the base can be, for example, triethylamine.

In still other preferred embodiments, in step (c), 1.0 equivalent of the compound of formula II is coupled to 1.1 equivalent of benzoic acid (lnt5 / This reaction is carried out using an agent

8/26 activator, such as the Mukaiyama Reagent (2-Chloro-1-methylpyridinium iodide).

In step (a), the reaction mixture is diluted with water and the precipitated product is isolated by filtration.

In step (b) of the method as described above, the compound (II) obtained by reducing the corresponding nitro compound is obtained by hydrogenation. Hydrogenation can be carried out with a catalyst such as Raney Nickel and the reaction is carried out in a polar protic solvent such as methanol or ethanol.

In step (b), the reaction mixture is diluted with water and the precipitated product is isolated by filtration.

In yet another preferred embodiment, in step (a), cyclization is performed in basic condition and at a temperature between 20 to 30 ° C. The base can be potassium carbonate and the reaction is carried out in a polar protic solvent such as methanol or ethanol.

The method described above may further comprise the step of preparing a compound of the formula (IV), comprising the reaction of an Intl intermediate of the formula:

(R₂) n-

<img file="BRPI0807626A2_D0007.tif" />

nh₂

Intl with an lnt2 of the formula:

Ck .Ra Π

Int2 and an lnt3 of the NH formula₄SCN, where Ra, R? and n are as defined above.

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Preferably, the reaction is carried out in an aprotic solvent such as acetone. In addition, the reaction mixture is advantageously diluted with water and the precipitated product is isolated by filtration.

Unless otherwise specified, the terms used here below are defined as follows:

As used here, an "aryl group" means a monocyclic or polycyclic-aromatic radical that comprises carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused functions such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more substituents.

In one embodiment, the aryl group is a monocyclic ring, where the ring comprises 6 carbon atoms, referred to here as "aryl (C6)".

As used herein, the term "alkyl group" means a saturated straight or branched chain non-cyclic hydrocarbon containing from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, nhepty, n-octyl, n-nonyl and n-decyl; while saturated branched chain alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4methylpentyl, 2-methylhexyl, 3-methylexyl, 4 -methylexil, 5-methylexyl, 2,3dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylexil, 2,4dimethylexyl, 2,5-dimethylexyl, 2,2-dimethylpentyl, 2,2-dimethylexyl , 3,3 dimethylpentyl, 3,3-dimethylexil, 4,4-dimethylexil, 2-ethylpentyl, 3-ethylpentyl, 2-ethylpyl, 3-ethylexil, 4-ethylexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2methyl-4-ethylpentyl, 2-methyl-2-ethylexyl, 2-methyl-3-ethylexyl, 2-methyl-4-ethylexyl, 2,2-diethylpentyl, 3,3-diethylexil, 2,2-diethylexil, 3,3-diethylexil, and others. The

10/26 alkyl groups included in compounds of this invention can be optionally substituted with one or more substituents.

As used here, the term "alkoxy" refers to an alkyl group that is linked to another organic function by an oxygen atom. Examples of alkoxy groups include methoxy, isopropoxy, ethoxy, tert-butoxy, and others. The alkoxy groups can be optionally substituted with one or more substituents.

As used herein, the term "heteroaryl" or similar terms means a monocyclic or polycyclic heteroaromatic ring that comprises ring members of carbon atoms and one or more ring members of hetero atoms (such as, for example, oxygen, sulfur or nitrogen) . Typically, a heteroaryl group has about 1 to 5 ring members of hetero atoms and about 1 to 14 ring members of carbon atoms. Representative heteroaryl groups include pyridyl, 1-oxo-pyridil, furanyl, benzo [1,3, dioxolyl, benzo [1,4, dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridine, zinc pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzotiadiazolil, tincazidyl, quinazolinyl, purinyl, pyrrolo [2,3] pyrimidinyl, pyrazolo [3,4] pyrimidinyl, imidazo [1,2-a] pyridyl, and benzo (b) thienyl. A heteroatom can be replaced with a protecting group known to those skilled in the art, for example, hydrogen in a nitrogen can be replaced with a tert-butoxycarbonyl group. The heteroaryl groups can be optionally substituted with one or more substituents. In addition, the ring members of nitrogen or sulfur heteroatoms can be oxidized. In one embodiment, the heteroaromatic ring is selected from 5 to 8-membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic ring or

11/26 heteroaryl to another group can be on a carbon atom or on a heteroatom of the heteroaromatic or heteroaryl rings.

The term "heterocycle", as used here, refers collectively to heterocycloalkyl groups and heteroaryl groups.

As used here, the term "heterocycloalkyl" means a monocyclic or polycyclic group containing at least one heteroatom selected from O, N or S, and having at least 2 to 11 carbon atoms, which can be saturated or unsaturated, but not it's aromatic. Examples of heterocycloalkyl groups include, but are not limited to: piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopirrolidinil, 4-piperidonyl, pyrrolidinyl, hidantoinil, valerolactamil, oxiranyl, oxetanyl, tetraidropiranil, tetraidrotiopyranyl, tetrahydropyrindinil, tetraidropirimidinil sulfone tetraidrotiopiranil, tetraidrotiopiranil sulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothienyl, and tetrahydro1,1-dioxothienyl. Typically, monocyclic heterocycloalkyl groups have 3 to 7 members. Preferred 3- to 7-membered monocyclic heterocycloalkyl groups are those having 5 or 6 ring atoms. A heteroatom can be replaced with a protecting group known to those skilled in the art, for example, the hydrogen in a nitrogen can be replaced by a tert-butoxycarbonyl group. In addition, heterocycloalkyl groups can optionally be substituted with one or more substituents. In addition, the point of attachment of a heterocyclic ring to another group can be on a carbon atom or on a hetero-atom of a heterocyclic ring. Only stable isomers of such substituted heterocyclic groups are provided for in this definition.

As used herein, the term "substituent" or "substituted" means that a hydrogen radical in a compound or group is replaced by any desired group that is substantially stable to

12/26 reaction conditions in an unprotected manner or when protecting yourself using a protective group. Examples of preferred substituents are those found in the exemplary compounds and modalities disclosed herein, as well as halogens (chlorine, iodine, bromine or fluorine); alkyl; alkene; alkine; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyan; starch; phosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-0); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which can be fused or unfused monocyclic or polycyclic (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); or a heterocycloalkyl, which can be fused or unfused monocyclic or polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), fused or unfused monocyclic or polycyclic aryl, or heteroaryl (eg, phenfl, nafty , pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzim, benzim or benzofuranyl); amino (primary, secondary or tertiary); CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂; ONLY₂NH₂; OCHF₂; CF₃; OCF₃; and such functions can also optionally be replaced by a fused ring or bridge structure, for example, -OCH₂THE-. These substituents can also be optionally substituted with a substituent selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a substituent selected from the group consisting of an alkyl, an alkene, an alkaline, a cycloalkyl, a cycloalkene, a heterocycloalkyl, an aryl, a heteroaryl , an arylalkyl, a heteroarylalkyl, a haloalkyl, C (O) NRR¹², -NR¹³COLOR¹⁴, a halo, -OR¹³, cyano, nitro, haloalkoxy, C (O) R¹³, -NRⁿR¹², -SR¹³, -C (O) OR¹³, -THE COLOR¹³, -NR^l3C (O) NRⁿR¹², OC (O) NRR¹², -NR¹³C (O) OR¹⁴, -S (O) rR¹³, -NR¹³S (O) rR¹⁴, -OS (O) rR¹⁴, S (O) rNR''R¹², -O, -S, and -NR¹³, where r is equal to 1 or 2; R¹¹ and R¹², for each

Occurrence, are, independently, H, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkaline, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl , an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl; or R¹¹ and R¹² together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; and R¹³ and R¹⁴ are, for each occurrence, independently, H, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkene, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

The term "solubilizing group" means any group that can be substantially ionized and that allows the compound to be soluble in a desired solvent, such as, for example, water or a solvent containing water. In addition, the solubilizing group may be one that increases the lipophilicity of the compound or the complex. Typically, the solubilizing group is selected from the alkyl group substituted with one or more heteroatoms, such as N, O, S, each optionally substituted with an alkyl group independently substituted with alkoxy, amino, alkylamino, dialkylamino, carboxyl, cyano, or replaced with cycloheteroalkyl or heteroaryl, or a phosphate, sulfate, or carboxylic acid.

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For example, “solubilizing group” refers to one of the following:

an alkyl, cycloalkyl, aryl, heteroaryl group that comprises at least one nitrogen or oxygen heteroatom, or that is replaced by at least one amino group or an oxo group.

an amino group that can be a saturated cyclic amino group that can be replaced by a group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl.

One of the structures from (a) to (i) shown below, where the wavy lines and arrows correspond to the points of connection to the nuclear structure of formula I.

<img file="BRPI0807626A2_D0008.tif" />

The term "cycloalkyl" means a saturated cyclic alkyl radical containing 3 to 10 carbon atoms. Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. The

15/26 cycloalkyl groups can be optionally substituted with one or more substituted.

The term "halogen" means -F, -Cl, -Br or -I.

In a particular embodiment, the invention offers a process for the synthesis of optionally substituted 2- (3-aminoaryl) amino-4-aryl-thiazoles having formula I.

<img file="BRPI0807626A2_D0009.tif" />

in which:

Ri and R₂ independently selected from 10 hydrogen, halogens, a linear or branched alkyl group, a cycloalkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing group.

m ranges from 0 to 5 and n from 0 to 4.

R₃ is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof containing any combination, in any ring position, of one or more substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy ;

(ii) a heteroaryl group such as a 2, 3, or 420 pyridyl group, which may additionally comprise any combination of one or

16/26 more substituents such as halogens, alkyl groups containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy;

(iii) an aromatic heterocyclic group with a five-membered ring such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5 thiazolyl, which may additionally comprise one or more substituents such as halogens, group alkyl containing 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

One aspect of the invention is a method for the preparation of 2 (3-aminoaryl) amino-4-aryl-thiazoles (I) or a pharmaceutically acceptable salt shown in scheme II, comprising:

a) The reaction of a nitro aniline (Intí), acyl chloride (Int 2) and ammonium thiocyanate (Int3) in a suitable solvent to form (IV), where:

Ra can be methyl, trifluormethyl, isopropyl or an optionally substituted phenyl,

R₂ independently selected from hydrogen, halogen, a linear or branched alkyl group, cycloalkyl containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing group, n goes from 0 to 4;

b) The reaction of a bromine ketone (Int4) with thiourea (IV) protected in a suitable solvent and using suitable bases.

The R substituent₃ in (Int4) and in compounds (III), (II) and (I) shown in scheme II below is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof having any combination, in any ring position, of one or

17/26 plus substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, cyano and alkoxy;

(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally contain any combination of one or more substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy;

(iii) an aromatic heterocyclic group with a five-membered ring such as, for example, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally contain one or more substituents such as halogens , alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

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Scheme II

<img file="BRPI0807626A2_D0010.tif" />

<img file="BRPI0807626A2_D0011.tif" />

<img file="BRPI0807626A2_D0012.tif" />

I

c) The reduction of the nitro group of compound (III) to the corresponding amine (II) 5 in a suitable solvent;

d) The reaction of aniline (II) with (Int 5) using a suitable coupling procedure in a suitable solvent.

Rb can be a hydroxyl, alkoxy or halogen group.

Ri is independently selected from hydrogen, 10 halogen, a straight or branched alkyl group, cycloalkyl containing

19/26 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing group.

m ranges from 0 to 5.

In yet another particular embodiment, the method shown in scheme II is used to synthesize the compound of formula V, or a pharmaceutically acceptable salt thereof,

<img file="BRPI0807626A2_D0013.tif" />

(V) in which:

Ri is independently selected from hydrogen, halogen, a straight or branched alkyl group, cycloalkyl containing 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing group;

m ranges from 0 to 5.

The compound (VIII) can be prepared by adding nitroaniline (intla) to a solution of ammonium thiocyanate and acetyl chloride in an aprotic solvent, preferably acetone.

Compound (VII) is obtained by cyclizing compound (VIII) with bromoketone (Int4a) in basic condition, preferably with potassium carbonate in a polar protic solvent such as methanol.

The compound (VII) is reduced to form the compound (VI). Preferably, the reduction reaction is carried out with a catalyst, such as a reactivated Raney nickel. The reduction can be carried out in an alcoholic or polar aprotic solvent, such as THF. According to a

20/26 modality, the reaction is carried out in the presence of hydrogen. The reaction can also be carried out under phase transfer hydrogenation conditions.

Scheme III

<img file="BRPI0807626A2_D0014.tif" />

Int4a

<img file="BRPI0807626A2_D0015.tif" />

Compound (V) is obtained using different conditions:

i) Since Rb is an alkoxy group, the ester (Int5á) being coupled with (VI) using trimethyl aluminum as an activating agent in an aprotic solvent such as dichloromethane or toluene.

/ 26 ii) Since Rb is a halogen such as a chloride, acid chloride (Int5à) being coupled with (VI) in basic condition using preferably triethylamine in an aprotic solvent such as dichloromethane.

iii) Since Rb is a hydroxyl group, with the carboxylic acid (Int5a) being coupled with (VI) using activating agents such as Mukaiyama's reagent or HOBt / EDCI in aprotic solvent, preferably DMF.

The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed as limiting the scope of the invention.

Example 1 1-Acetyl-3- (2-methyl-5-nitro-phenyl) -thiourea

In a reactor, ammonium thiocyanate (25 kg, 328.43 mol), acetyl chloride (24 kg, 337.53 mol), acetone (225 1) and 2-methyl5-nitroaniline (Intl) (42 kg, 276, 04 mol). The temperature was maintained at 25 ± 10 ° C for approximately 4 hours. Water (413 1) was added and the reaction mixture was stirred for approximately 1 hour. The filtered precipitate was washed with water and diisopropylether. The product was then dried in a dish dryer at 45 - 50 ° C.

Yield = 84% 'H NMR (DMSO-4₆): δ = 12.37 (1H, s); 11.68 (1H, s); 8.68 (1H, d, 7 = 2.5 Hz); 8.06 (1H, dd, 7 = 8.4, 2.5 Hz); 7.58 (1H, d, 7 = 8.4 Hz); 2.33 (3H, s); 2.18 (3H, s).

MS (ES⁺) m / z = 254.1 (M + H)⁺; (ES ') m / z = 252.3 (MH)'.

Mp = 205 ° C.

Example 2 (2-Methyl-5-nitro-phenyl) - (4-pyridin-3-yl-thiazol-2-yl) -amine

In a reactor, methanol (1,120 1), potassium carbonate (287 kg, 2,076.70 mol) and l-acetyl-3- (2-methyl-5-nitro-phenyl) 22/26 thiourea (67 kg, 264.53 mol). 2-bromo-1-pyridin-3-yl-ethanone (Int4) (52 Kg, 259.96 mol) was then added and the temperature maintained at 25 - 30 ° C for 4 hours. Water (692 l) was then added to the reaction mixture and the precipitate filtered, washed with water and diisopropylether. The product was then dried in a dish dryer at 45 - 50 ° C.

Yield = 95% 'H NMR (DMSO-flfe): δ = 9.83 (1H, s); 9.60 (1H, d, 7 = 2.5 Hz); 9.18 (1H, d, 7 = 1.9 Hz); 8.53 (1H, dd, 7 = 4.6, 1.5 Hz); 8.27 (1H, dt, 7 = 8.0, 1.9 Hz); 7.80 (1H, dd, 7 = 8.2, 2.5 Hz); 7.66 (1H, s); 7.48 (2H, m); 2.44 (3H, s).

MS (ES⁺) m / z = 313.1 (M + H)⁺; (ES) m / z = 311.3 (MH) '.

Mp = 225 ° C.

Example 3

4-Methyl-N3- (4-pyridin-3-yl-thiazol-2-yl) -benzene-1,3-diamine

In a reactor, a mixture of (2-methyl-5-nitro-phenyl) - (4pyridin-3-yl-thiazol-2-yl) -amine (40 kg, 128.06 mol), Raney Nickel (2.7 Kg, 46.00 mol) and methanol (600 1), was heated to 40 - 45 ° C and hydrogenated under hydrogen pressure (5 Kg / cm²) for 2 hours. The reaction mixture was filtered and concentrated. Water was added to the residue with stirring. The product was then filtered and dried in a dish dryer at 45 - 50 ° C.

Yield = 85% 'H NMR (DMSO-7₆): δ = 9.20 (1H, s); 9.09 (1H, dd, 7 = 2.3, 0.76 Hz); 9.48 (1H, dd, 7 = 4.8, 1.7 Hz); 8.20 (1H, dt, 7 = 8.0, 2.1 Hz); 7.42 (1H, ddd, 7 = 7.8, 4.8, 0.8 Hz); 7.38 (1H, s); 7.09 (1H, d, 7 = 2.3 Hz); 6.85 (1H, d, 7 = 8.0 Hz); 6.29 (1H, dd, 7 = 8.0, 2.3 Hz); 4.95 (1H, s); 2.10 (3H, s).

MS (ES⁺) m / z = 283.1 (M + H)⁺; (ES ') m / z = 281.4.

Mp = 136 ° C.

Example 4

N- [4-Methyl-3- (4-pyridin-3-yl-thiazol-2-iamino) -phenyl] -benzamide derivatives

Method A

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In a reactor and under low nitrogen pressure, 4Methyl-N3- (4-pyridin-3-yl-thiazol-2-yl) -benzene-1,3-diamine (95 g, 336.45 mmol), dichloromethane are added (21). To this suspension, cooled to 5 ° C, a 2M / n-hexane solution of trimethyl aluminum (588 ml) was added in drops. The reaction mixture was brought gradually to 15 ° C, and kept for 2 hours under agitation. 4- (4-Methylpiperazin-1-ylmethyl) -benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 ml) was added for 10 minutes. After 1 hour of stirring at room temperature, the reaction mixture was heated to reflux for 20 hours and cooled to room temperature. This solution was transferred in drops through a cannula to a reactor containing 2N NaOH (2.1 l) cooled to 5 ° C. After stirring for 3 hours at room temperature, the precipitate was filtered through Celite. The solution was extracted with dichloromethane and the organic layer was washed with water and saturated sodium chloride solution, dried over MgSO₄ and concentrated in vacuo. The obtained brown solid was recrystallized from z'-Pr₂O to give 130.7 g (78%) of a beige powder.

Method B

Preparation of acid chloride

To a mixture of 4- (4-Methyl-piperazin-1-ylmethyl) -benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) were added at 18 - 28 ° C. The reaction mixture was stirred at 28 - 32 ° C for 1 hour.

Coupling of acid chloride with amino thiazole

To a cooled suspension (0 - 5 ° C) of 4-Methyl-N3- (4-pyridin-3-ylthiazol-2-yl) -benzene-1,3-diamine (0.8 eq) and thiethylamine (2, 2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) kept the temperature below 5 ° C. The reaction mixture was heated until

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- 30 ° C and stir at the same temperature for 10 hours. Methanol (2 vol) and water (5 vol) were added to the mixture and reactive stirred. After separating the layers, methanol (2 vol), dichloromethane (5 vol) and sodium hydroxide solution (10% aqueous, until the pH reached 9.5 - 10.0) were added to the aqueous layer and stirred by 10 minutes. The layers were separated. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50 - 55 ° C in a vacuum dish dryer.

Yield = 65 - 75%

Method C

To a solution of 4-methyl-N3- (4-pyridin-3-yl-thiazol-2-yl) -benzene1,3-diamine (1.0 eq) in DMF (20 vol) was added successively triethylamine (5 eq ), 2-chloro-1-methylpyridinium iodide (2 eq) and 4- (4 methyl-piperazin-1-ylmethyl) -benzoic acid (2 eq). The reaction mixture was stirred for 7 hours at room temperature. Then, the mixture was diluted with diethyl ether and washed with water and NaHCO₃ saturated aqueous, dried over Na₂SÜ4 and concentrated. The crude product was purified by column chromatography using 100% EtOAc elution to give a yellow solid.

Yield = 51% 'H NMR (CDCh): δ = 9.09 (1H, s, NH); 8.52 (1H, br s); 8.27 (1H, s); 8.13 (1H, s); 8.03 (1H, s); 7.85 (2H, d, J = 8.3 Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (1H, s); 3.56 (2H, s); 2.50 (8H, br s); 2.31 (6H, br s).

MS (CI) m / z = 499 (M + H)⁺.

A further aspect of the present invention relates to a particular polymorph of the N- [4-Methyl-3- (4pyridin-3-yl-thiazol-2-ylamino) -phenyl] -benzamide methanesulfonic acid salt of formula (IX) :

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<img file="BRPI0807626A2_D0016.tif" />

II ο

(SAW)

It is hereinafter referred to as the polymorphic form of (IX) which has the most advantageous properties with respect to processability, storage and formulation. For example, this form remains dry at 80% relative humidity and is thermodynamically stable at temperatures below 200 ° C.

The polymorph in this way is characterized by the X-ray diffraction pattern illustrated in Fig. 1, which comprises characteristic peaks at approximately 7.269; 9,120; 11,038; 13.704; 14,481; 15,483; 15,870; 16,718; 17.087; 17,473; 18,224; 19,248; 19,441; 19,940; 20,441; 21,469; 21,750; 22,111; 23,319; 23,763; 24,120; 24,681; 25,754; 26,777; 28,975; 29,609; 30,073 degrees Θ, and is also characterized by the differential scanning calorimetry (DSC) illustrated in Fig. 2, which has a single maximum value at approximately 237.49 ± 0.3 ° C.

The X-ray diffraction pattern is measured using a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) is measured using a Perking Elmer Precisely (Diamond DSC} ·

The polymorphic form can be obtained by treating 4- (4Methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) phenylj-benzamide with 1 , 0 to 1.2 equivalent of methanesulfonic acid, at a suitable temperature, preferably between 20 - 80 ° C.

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The reaction is carried out in a suitable solvent, especially a polar solvent such as methanol or ethanol, or a ketone such as acetone, or an ether such as diethyl ether or dioxane, or a mixture of these.

The invention is explained in an example given below which is offered by way of illustration only and therefore should not be construed as limiting the scope of the invention.

Preparation of the polymorphic form mentioned above of 4- (4-Methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -phenyl] benzamide methanesulfonate

4- (4-Methyl-piperazin-1-ylmethyl) -N- [4-methyl-3 - (4-p iridin-3 - 1-thiazol-2-ylamino) -phenyl] -benzamide (1.0 eq) was dissolved in ethanol (4.5 vol) at 65 - 70 ° C. Methanesulfonic acid (1.0 eq) was added slowly at the same temperature. The mixture was cooled to 25 - 30 ° C and maintained for 6 hours. The product was filtered and dried in a vacuum dish dryer at 55 - 60 ° C. Yield = 85 - 90%. Initial melting point (Pfi) = 236 ° C.