Polymorph form of 2-amino (nitroaryl) thiazole derivative

attached.

DESCRIPTIVE REPORT

Patent application for “PROCESS FOR SYNTHESIS OF 2-AMINOTHIAZOLE COMPOUNDS AS KINASE INHIBITORS”

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

<img file="BRPI0807626B1_D0001.tif" />

which are useful as certain tyrosine kinase inhibitors and more particularly as c-kit and bcr-abl inhibitors. The R] and R groups₂, identical or different, each represent a hydrogen atom, halogen, an alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino group, a solubilizing group; m is from 0 to 5 and n is from 0 to 4; the R group₃ represents an aryl or heteroaryl group.

Fundamentals of the invention

Tyrosine kinases are receptor or non-receptor type proteins that transfer the terminal phosphate from ATP 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 such ailments as abnormal cell proliferation and migration as well as inflammation.

2/26

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

Among the receptor tyrosine kinases, the c-kit is of special interest. Indeed, c-kit is a crucial receptor in the activation of mast cells, which has been shown to be directly or indirectly associated with various pathologies for which the Applicant has filed 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 in 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, infectious 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, IL2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-oc, GM-CSF, MIP-1a, MIP-1b, 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 various cancers such as GIST (c-kitA27, a deletion in the juxta-membrane).

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

Furthermore, 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 have deposited WO 04/076693, which refers to the adapted treatment of the different forms of mastocytosis that depend on the presence or absence of the mutation in Kit816.

Thus, we recently proposed to search for the c-kit to extinguish the mast cells responsible for these evils. In this regard, we have 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 achieved using a two-stage scheme, including bromination of the starting ketones (A) (G. Crank and R. Kahn, Austr. J. Chem,

4/26

38(3), 447 - 458 (1985)), followed by cyclocondensation of intermediate abromoketones (C) with thiourea (B) by refluxing in ethanol or methanol (M. Maziere et al, Bull. Soc. Chim. France, 1000- 1003 (1963); JD Spivack, US Patent 3,299,087).

scheme 1

<img file="BRPI0807626B1_D0002.tif" />

However, when R is an electron-withdrawing group such as the nitro functionality, the cycloaddition yield is no more than 1065% (SP Singh et al, Indian J. Chem. Sect. B, 29 (6), 533-538 , (nineteen ninety)). This disadvantage is probably due to the instability of nitroarylthiourea, which leads to the formation of both impure and highly reactive by-products when it reacts in the presence of a base.

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

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

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

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

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

Description

The invention is directed to a process for the preparation of a compound of formula (I):

<img file="BRPI0807626B1_D0003.tif" />

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

R and R₂ are independently selected from hydrogen, halogens, a linear or branched alkyl group, cycloalkyl containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy, cyano, dialkylamino, and a solubilizing group, m ranges from 0 to 5 and n from 0 to 4,²⁰ - R3 is one of the following:

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

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

comprising the steps of:

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

Η HaV^NoV^NoV^Frog(RzlnZ ] HH

XX OS

AT THE₂(IV) with an Int4 intermediate of the formula:

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

7/26

<img file="BRPI0807626B1_D0004.tif" />

AT THE₂

<img file="BRPI0807626B1_D0005.tif" />

(ΠΙ) in which R₂, R₃ and en are as defined above;

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

HAV^Nov^No(R2X J Γ A^r3 ^NHtwo (Π) in which R₂, R₃ and en are as defined above;

c) coupling an aprotic solvent of a compound of formula (II) with a compound of formula Int5'.

Rb^o (^Ri)m (Int5) in which Rb is a hydroxyl or alkoxy or halogen group and R, 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 added to a solution of 1.0 equivalents of ester (Int5). Also, the Lewis acid is trimethylaluminium.

In yet another preferred embodiment, in step (c) a 1.0 equivalent solution of acid chloride (Int5) is added to a 0.8 equivalent solution of the compound of formula II. Here, the reaction is carried out under 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 (Int5). 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. The 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), the cyclization is carried out under basic condition and at a temperature between 20 to 30°C. The base may 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 formula (IV), comprising reacting an Intl intermediate of the formula:

<img file="BRPI0807626B1_D0006.tif" />

nh₂ at the₂

Intl with an Int2 of the formula:

<img file="BRPI0807626B1_D0007.tif" />

Int2 and an Int3 of the formula NH₄SCN, where Ra, R₂ and en are as defined above.

9/26

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

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

As used herein, an "aryl group" means a monocyclic or polycyclic-aromatic radical comprising 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 may 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 herein as "(C6)aryl".

¹⁵ 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, nheptyl, 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-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2- dimethylhexyl, 3,325 dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, and the like. You

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

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

As used herein, the term "heteroaryl" or similar terms means a monocyclic or polycyclic heteroaromatic ring comprising ring members of carbon atoms and one or more ring members of heteroatoms (such as, for example, oxygen, sulfur or nitrogen) . Typically, a heteroaryl group has about 1 to 5 ring members of heteroatoms and about 1 to 14 ring members of carbon atoms. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzo(b)thienyl. A heteroatom can be substituted with a protecting group known to those skilled in the art, for example, hydrogen in a nitrogen can be substituted with a tert-butoxycarbonyl group. Heteroaryl groups may 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 a

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

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

As used herein, 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 may 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 are from 3 to 7 members. Preferred 3- to 7-membered monocyclic heterocycloalkyl groups are those having 5 or 6 ring atoms. A heteroatom may be substituted with a protecting group known to those skilled in the art, for example, hydrogen in a nitrogen may be substituted with a tert-butoxycarbonyl group. In addition, heterocycloalkyl groups may be optionally substituted with one or more substituents. Furthermore, the point of attachment of a heterocyclic ring to another group may be at a carbon atom or at a heteroatom of a heterocyclic ring. Only stable isomers of such substituted heterocyclic groups are envisaged in this definition.

As used herein, the term "substituent" or "substituted" means that a hydrogen radical in a compound or group is exchanged for any desired group that is substantially stable at

12/26 reaction conditions in an unprotected form or when protecting itself using a protecting group. Examples of preferred substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as the halogens (chlorine, iodine, bromine, or fluorine);

alkyl, alkene; alkyne; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyan; starch; phosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone, aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl, which may be fused or unfused monocyclic or polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); or a heterocycloalkyl, which may be fused or unfused monocyclic or polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), fused or unfused monocyclic or polycyclic aryl, or heteroaryl (e.g., fenfl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzoyluranyl); amino (primary, secondary or tertiary); CO₂CH₃; CONH₂; OCH₂CONH₂; NH₂; ONLY₂NH₂; OCHF₂; CF₃; OCF₃; and such functions may also be optionally replaced by a ring or fused bridge structure, for example -OCH₂O-. These 20 substituents may optionally be substituted with a substituent selected from such groups. In certain embodiments, the term substituent or adjective "substituted" refers to a substituent selected from the group consisting of an alkyl, an alkene, an alkyne, a cycloalkyl, a cycloalkene, a heterocycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroarylalkyl, a haloalkyl, C(O)NR R , -NR¹³COLOR¹⁴, a halo, -OR¹³, cyano, nitro, a haloalkoxy, C(O)R¹³, -NR^noR¹², -SR¹³, -C(O)OR¹³, -THE COLOR¹³, -NR^,3C(O)NR^noR¹², OC(O)NR^noR¹², -NR^,3C(O)OR¹⁴, -S(O)rR¹³, -NR¹³S(O)rR¹⁴, -OS(O)rR¹⁴, S(O)rNR^noR¹², -O, -S, and -NR¹³, where r is equal to or 2;Re R¹², for each

13/26 occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an optionally substituted cycloalkyl, an optionally substituted cycloalkene, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl substituted, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl; ouR¹¹ and R¹² together with the nitrogen to which they are attached are an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl; and 10 R¹³ and R¹⁴ are, for each occurrence, independently, H, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an optionally substituted cycloalkyl, an optionally substituted cycloalkene, 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 which can be substantially ionized and which allows the compound to be soluble in a desired solvent, such as, for example, water or a water-containing solvent. Furthermore, the solubilizing group can be one that increases the lipophilicity of the compound or 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 substituted with cycloheteroalkyl or heteroaryl, or a phosphate, sulfate, or carboxylic acid.

14/26

For example, by "solubilizing group" here refers to one of the following:

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

an amino group which may be a saturated cyclic amino group which may be substituted with a group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl.

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

<img file="BRPI0807626B1_D0008.tif" />

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

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

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

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

H

<img file="BRPI0807626B1_D0009.tif" />

HN

CO

<img file="BRPI0807626B1_D0010.tif" />

in which:

R and R₂ are independently selected from 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 goes 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 having any combination, at 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 4pindyl group, which may additionally comprise any combination of one or

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

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

One aspect of the invention is a method for preparing 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 (Intl), acyl chloride (Int2) and ammonium thiocyanate (Int3) in a suitable solvent to form (IV), where:

Ra may be methyl, trifluoromethyl, isopropyl or an optionally substituted phenyl,

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

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

The substituent R₃ in (Int4) and 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, at any ring position, of one or

17/26 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 bear any combination of one or more 5 substituents such as halogens, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy;

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

18/26

Scheme II

<img file="BRPI0807626B1_D0011.tif" />

Int5

<img file="BRPI0807626B1_D0012.tif" />

<img file="BRPI0807626B1_D0013.tif" />

c) 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 (Int5) using a suitable coupling procedure in a suitable solvent.

Rb can be a hydroxyl, alkoxy or halogen group.

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

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

m goes 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="BRPI0807626B1_D0014.tif" />

(V) in which:

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

m goes from 0 to 5.

Compound (VIII) can be prepared by adding nitroaniline (intld) 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 (Int4d) under basic condition, preferably with potassium carbonate in a polar protic solvent such as methanol.

Compound (VII) is reduced to form 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 one

In one embodiment, 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="BRPI0807626B1_D0015.tif" />

nh₄scn,

<img file="BRPI0807626B1_D0016.tif" />

Acetone

<img file="BRPI0807626B1_D0017.tif" />

YOU

VIII

<img file="BRPI0807626B1_D0018.tif" />

at the₂ O

<img file="BRPI0807626B1_D0019.tif" />

int4a

K₂CO₃, MeOH

Ni Raney, H₂

THF, MeOH

<img file="BRPI0807626B1_D0020.tif" />

<img file="BRPI0807626B1_D0021.tif" />

Compound (V) is obtained using different conditions:

i) Rb being an alkoxy group, the ester (Int5a) being coupled with (VI) using trimethylaluminum as the activating agent in an aprotic solvent such as dichloromethane or toluene.

ii) Rb being a halogen such as a chloride, acid chloride (Int5a) being coupled with (VI) in basic condition using preferably triethylamine in an aprotic solvent such as dichloromethane.

iii) Rb being 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 l) and 2-methyl5-nitroaniline (Intl) (42 kg, 276. 04 moles). The temperature was maintained at 25 ± 10°C for approximately 4 hours. Water (413 L) 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% 1 H NMR (DMSO-14 ): 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=8.4Hz); 2.33 (3H, s); 2.18 (3H, s).

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

Mp = 205°C.

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

In a reactor, methanol (1,120 l), potassium carbonate (287 kg, 2,076.70 mol) and 1-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 off, washed with water and diisopropylether. The product was then dried in a dish dryer at 45 - 50°C.

Yield = 95% '^H NMR (DMSO-7₆): δ = 9.83 (1H, s); 9.60 (1H, d, 7=2.5Hz); 9.18 (1H, d, 7=1.9Hz); 8.53 (1H, dd, 7=4.6, 1.5Hz); 8.27 (1H, dt, 7=8.0, 1.9Hz); 7.80 (1H, dd, 7=8.2, 2.5Hz); 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)-(4-pyridin-3-yl-thiazol-2-yl)-amine (40 kg, 128.06 mol), Raney Nickel (2.7 kg, 46.00 mol) and methanol (600 l), 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 under 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, 1.7Hz); 8.20 (1H, dt, 7=8.0, 2.1Hz); 7.42 (1H, ddd, 7=7.8, 4.8, 0.8Hz); 7.38 (1H, s); 7.09 (1H, d, 7=2.3Hz); 6.85 (1H, d, 7=8.0Hz); 6.29 (1H, dd, 7=8.0, 2.3Hz); 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-ylamino)-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 (2 1). To this suspension cooled to 5°C, a 2M/n-hexane solution of trimethylaluminum 5 (588 ml) was added dropwise. The reaction mixture was brought progressively to 15°C, and kept under stirring for 2 hours. 4-(4-Methylpiperazin-1-ylmethyl)-benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 ml) was added over 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 dropwise 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 under vacuum. The brown solid obtained 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 (0 - 5°C) suspension of 4-Methyl-N3-(4-pyridin-3-ylthiazol-2-yl)-benzene-1,3-diamine (0.8 eq) and thietylamine (2, 2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintained at a temperature below 5°C. The reaction mixture was heated until

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- 30°C and stirred at the same temperature for 10 hours. Methanol (2 vol) and water (5 vol) were added to the reactive mixture and stirred. After separating the layers, methanol (2 vol), dichloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, until the pH reached 9.5 - 10.0) were added to the aqueous layer and stirred. for 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 pan 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 successively added triethylamine (5 eq ), 2-chloro-1-methylpyridinium iodide (2 eq) and 4-(415-methyl-piperazin-1-ylmethyl)-benzoic acid (2 eq). The reaction mixture was stirred for 7 hours at room temperature. Then, the mixture was diluted in diethyl ether and washed with water and NaHCO₃ saturated aqueous, dried over Na₂ONLY₄and concentrated. The crude product was purified by column chromatography using 100% EtOAc elution to give a yellow solid.

Yield = 51% 'H NMR (CDC1₃): 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=8.3Hz); 7.45 (2H, m); 7.21-7.38 (4H, m); 6.89 (1H, s); 3.56 (2H, s); 2.50 (8H, brs); 2.31 (6H, br s).

MS (Cl) m/z = 499 (M+H)⁺.

²⁵ A further aspect of the present invention relates to a particular polymorph of the methanesulfonic acid salt of N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide of formula (IX) :

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<img file="BRPI0807626B1_D0022.tif" />

(SAW)

Ε 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 stays dry at a relative humidity of 80% and is thermodynamically stable at temperatures below 200°C.

The polymorph of this form 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 0, 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)phenyl]-benzamide with 1.0 to 1.2 equivalents 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 thereof.

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 above-mentioned polymorphic form of 4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide methanesulfonate¹⁰ 4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylthiazol-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 held for 6 hours. The product was filtered and dried in a vacuum pan dryer at 55 - 60°C. Yield = 85 - 90%. Initial melting point (Pfi) = 236°C.