Process for the synthesis of 2-aminothiazole compounds as kinase inhibitors

[0001] The present invention relates to an industrial process for the synthesis of pharmaceutical compounds of formula I:

<img file="PL2118099T3_D0001.tif" />

^R3 (I) useful as some type of tyrosine kinase inhibitors, more particularly c-kit and bcrabl inhibitors. Groups R1 and R2, identical or different, represent hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, solubilizing group; m is a number in the range 0 - 5, an - 0 - 4; the R3 group is an aryl or heteroaryl group as described in these claims.

BACKGROUND OF THE INVENTION [0002] Tyrosine kinases are receptor or non-receptor type proteins that send the ATP phosphate terminal group to protein tyrosine residues, activating or deactivating signal transduction pathways. According to the state of the art of these proteins, they are involved in many cellular mechanisms, the disruption of which leads to disorders such as abnormal cell multiplication and migration, as well as inflammation.

[0003] Currently, about 58 receptor tyrosine kinases are known. These include the well-known VEGF receptors (Kimetal., Nature 362, pp. 841 844,1993), PDGF receptors, c-kit, Flt-3 and the FLK family. These receptors can relay signals to other tyrosine kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes / Fps, Fak, Jak, Ack, etc.

[0004] Among the tyrosine kinase based receptors, type c-kit is of particular interest. The c-kit type is in fact a key receptor that activates mast cells for which direct or indirect involvement in many disease processes has been demonstrated, for which the applicant has submitted applications 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.

[0005] We have determined that mast cells found in patient tissues are involved or contribute to diseases such as diseases to the occurrence of autoimmune rheumatoid arthritis, inflammatory bowel disease (IBD), allergies, bone defects, cancers such as solid tumors, leukemia and GIST, tumor angiogenesis, inflammation, interstitial cystitis, mastocytosis, graft versus host disease, infections, poor metabolism, fibrosis, diabetes mellitus and central nervous system diseases. For these diseases, mast cells have been shown to participate in tissue destruction by releasing a mixture of various proteases and transporters such as histamine, neutral proteases, fat derived transporters (prostaglandins, thromboxanes and leukotrienes) (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-ά, GM-CSF, MIP-1a, MIP-1bMIP-2 and 1FN-a).

[0006] The c-kit receptor may also be constitutively activated by mutations, leading to excessive cell proliferation and the development of diseases such as mastocytosis (D816V mutation) and the development of various cancers such as GIST (c-kitA27, perimembrane removal).

[0007] In addition, 60% to 70% of AML patients have b-cells expressing c-kit, a receptor for stem cell factor (SCF) (Broudy, 1997). SCF promotes the growth of hematopoietic precursors and acts as a factor in the survival of AML blast cells. In some (1 to 2%) cases of AML, a mutation in preserved kinase domain residues (Kit816) has been described, resulting in constitutional activation of the c-kit receptor (Beghini et al., 2000; Longley et al., 2001). This function mutation (replacement of Asp by Val / Tyr) has been identified in leukemia mast cell lines and in samples derived from patients with mastocytosis (Longley et al.,

1996).

[0008] We have further examined approximately 300 patients affected by systemic mastocytosis, expressing the Kit816 mutation in approximately 60% of cases. Therefore, we have submitted the application WO 04/076693 regarding adapted treatment of various forms of mastocytosis depending on the occurrence or absence of the Kit816 mutation.

[0009] Therefore, we have recently proposed to define as the target the c-kit receptor clears mast cells responsible for these diseases. Further to this, we discovered new, potent and selective inhibitors of the c-kit receptor, which are 2- (3-aminoaryl) amino-4-aryl-thiazoles described in our PCT application WO 2004/014903.

[0010] The synthesis of substituted 2-aminothiazoles is known from the literature. In the following publications, the general synthesis of these compounds is usually carried out according to a two-step scheme, which includes bromination of the starting ketones (A) (G. Crank and R. Kahn, Austria J. Chem,

38 (3), 447-458 (1985)), followed by cyclocondensation of transient ά-bromoketones (C) with thiourea, (B) by heating to reflux in ethanol and methanol (M. Maziere et al,

Bull. Soc. Chim. France, 1000-1003 (1963); JD Spivack, US Patent US 3299087)

<img file="PL2118099T3_D0002.tif" />

[0011] However, if R is an electron withdrawing group such as nitro functional groups, the cycloaddition efficiency does not exceed 65% (SP Singh et al, Indian j. Chem. Sect. B, 29 (6), 533-538, (1990) ). This disadvantage is probably due to the instability of the nitroarylthiourea, leading to the formation of both impurities and a highly reactive by-product during the reaction in the presence of a base.

[0012] The above demonstrates that this methodology used for nitroarylthiourea is associated with synthesis disadvantages regarding one or more of the following characteristics: efficiency, scalability for synthesis in multigram quantities, and purification. Our goal was to develop a process that can be used on an industrial scale in which can be achieved by using simple industrial operations.

[0013] We have found that the reaction of acetylated nitroarylmeter with α-bromoketoaryl is carried out in methanol at room temperature in the presence of a base such as potassium carbonate, giving after 3-6 hours the desired thiazole in excellent yield (90-97%).

[0014] In addition, pure thiazoles were obtained by simple filtration after adding water to the reaction mixture. [0015] Therefore, the present invention includes a new industrial process for the synthesis of 2amino (nitroaryl) thiazole, in good yield, due to the reaction of stable acetylated nitroarylthiourea with α-bromoketoaryl under mild conditions.

Description [0016] The object of the invention is a process for the production of a compound of formula:

(R2)

<img file="PL2118099T3_D0003.tif" />

^R3 either its salt or solvate, where

R1 and R2 are independently selected from the following: hydrogen, halogen, linear or branched alkyl, cycloalkyl containing from 1 to 10 carbon atoms, trifluoromethyl, acloxy, cyano, dialkylamino or solubilizing group, m is 0-5 an 0-4,

R3 is one of the following:

an aryl group, such as a phenyl group or a substituted variant thereof, more substituents with any combination of one or such as halogen, ring group, such substituents, containing an alkyl group containing from 1 to 10 carbon atoms, a trufluoromethyl, cyano and alkoxy group, in any position ring.

(ii) a heteroaryl group such as group 2, 3, or

4-pyridyl, which may contain in any position any combination of one or more like halogen, an alkyl group up to 10 carbon atoms, an aromatic group 2-thienyl, 3-thienyl, 2 and 1 trufluoromethyl and alkoxy;

(iii) a five-membered heterocyclic, such as e.g.

thiazolyl, 4-thiazolyl, 5-thiazolyl, which may further have any combination of one or more substituents such as halogen, alkyl group containing 1 to 10 carbon atoms, trifluoromethyl group and alkoxy group; comprising stages consisting of:

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

(RJnT

<img file="PL2118099T3_D0004.tif" />

N ^ N ^ R

SO

NO2 (IV)

With Int4 intermediate product of formula

Br Int4 where Ra may be a methyl, trifluoromethyl, isopropyl or phenyl group, with the possibility of substitution, and

R2, R3 and n correspond to the above description to form compound (III):

(R2) y-n

<img file="PL2118099T3_D0005.tif" />

WELL

III

Where R2, R3 and n correspond to the above description; b) reducing the nitro group of said compound (III) to form a compound of formula II:

<img file="PL2118099T3_D0006.tif" />

Where R2, R3 and n are as described above;

c) compressing in the aprotic solvent of compound (II):

with the compound of formula Int5:

<img file="PL2118099T3_D0007.tif" />

[0017] alkoxy

Where Rb is or halogen, the hydroxyl group or a R1 and m are as described above to form compound (I).

[0018] In a preferred mode of implementation, in step

c) compound (II) is treated with 3.0 equivalents of acid

Lewis and is added to the solution 1.0 equivalent of ester

1.0 (Int5). The Lewis acid is trimethylaluminum.

[0019] In another preferred embodiment, in step c) a solution of 1.0 equivalent of acid chloride (Int5) is added to the solution of 0.8 equivalent of the compound of formula II. The reaction is carried out in an alkaline medium and the base may be, for example, triethylamine.

[0020] In another preferred embodiment in step c), 1.0 equivalent of the compound of formula II is coupled with 1.1 equivalent of benzoic acid (Int5). This reaction is carried out using an activating agent such as Mukaiyama reagent (2-chloro-1-methylpyridine iodide).

[0021] In step a), the reaction mixture is dissolved in water and the precipitated product is isolated by filtration.

[0022] In step b) of the method described above, the compound (II) is obtained by reducing the corresponding nitro compound by hydrogenation. The hydrogenation can be carried out in the presence of a catalyst such as Raney nickel and the reaction is carried out in a polar protic solvent such as methanol or ethanol.

[0023] In step b), the reaction mixture is dissolved in water and the precipitated product is isolated by filtration.

[0024] In a further preferred embodiment in step a), the cyclization is carried out in an alkaline medium at a temperature between 20 and 30 ° C. The base may be potassium carbonate and the reaction is carried out in a polar solvent such as methanol or ethanol.

[0025] The method described above may comprise the next step, the preparation of compound (IV), comprising the reaction of the Intl intermediate of formula:

NH2 (R2) n-iT ^WELL2 int1

With an Int2 compound with the formula:

Ck.Ra

T

ABOUT

And with compound Int3 of the formula NH4SCN, where Ra, R2 and n are as described above:

Ideally, the reaction should be carried out in an aprotic solvent such as acetone. In addition, the reaction mixture is successfully dissolved in water, and the precipitated product is isolated by filtration.

[0026] Unless otherwise specified, the following terms used herein are defined as follows:

[0027] As used herein, the term "aryl" means a monocyclic or polycyclic aromatic radical containing carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracens, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzofused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group may be unsubstituted or substituted with one or more substituents.

[0028] In one embodiment, the aryl group is a monocyclic ring in which the ring consists of 6 carbon atoms, referred to herein as "aryl (C6)".

[0029] As used herein, the term "alkyl" means a saturated unbranched or branched non-cyclic hydrocarbon with 1 to 10 carbon atoms. Representative saturated unbranched alkyls are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, noctyl, n-nonyl and n-decyl; branched saturated alkyl is isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, methylpentyl, methylhexyl, dimethylbutyl,

2-methylpentyl,

2-methylhexyl,

5-methylhexyl,

332.33-methylbutyl,

4- methylpentyl,

4-methylhexyl,

2,3-dimethylpentyl, 2,4-dimethylpentyl,

2.3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,

3.3- 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. The alkyl groups included in the compounds with which the present invention is concerned may be optionally substituted with one or more substituents.

[0030] As used herein, the term "alkoxy" refers to an alkyl group attached to another part of the molecule through an oxygen atom. Examples of alkoxy groups are methoxy, isopropoxy, ethoxy, tert-butoxy etc. Alkoxy groups may be optionally substituted with one or more substituents.

[0031] As used herein, the term "heteroaryl" and the like means a heteroaromatic monocyclic or polycyclic ring containing as ring elements carbon atoms and one or more heteroatoms (such as, for example, oxygen, sulfur or nitrogen). The heteroaryl group usually contains 1 to 5 heteroatoms and 1 to 14 carbon atoms as ring elements. Representative heteroaryl groups are pyridyl, 1-oxopyridyl, furanyl; benzo [1,3] dioxolyl, benzo [1,4] dioxinyl, thienyl, pyril, ocazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadinolol, indocholazol, indocholazol benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolidyl pyrazolo [3,4] pyrimidinyl, imidazo [1,2-a] pyridyl, and benzo (b) thienyl. The heteroatom may be substituted with a protecting group; as is known to persons having ordinary skill in the subject, nitrogen-bonded hydrogen may be substituted, for example, with a tert-butoxycarbonyl group. Heteroaryl groups may be optionally substituted with one or more substituents. In addition, the nitrogen or sulfur heteroatom, which is part of the ring, may be oxidized. In one embodiment, the heteroatom ring is selected from 5-8 membered monocyclic aryl rings. The point of attachment of the heteroaromatic or heteroaryl ring to another group may be a carbon atom or a heteroatom of a heteroaromatic or heteroaryl ring.

[0032] As used herein, the term "heterocyclic" refers jointly to heterocycloalkyl and heteroaryl groups.

[0033] As used herein, the term "heterocycloalkyl" means a monocyclic or polycyclic group with at least one heteroatom from the group O, N and S, and 2-11 carbon atoms, which may be saturated or unsaturated but not aromatic. Examples of heteroalkyl groups include: piperidinyl, piperazinyl, 2oksopiperazynyl, 2-oksopiperydinyl, 2-oksopirolidinyl, 4piperydonyl, pyrrolidonyl, hidantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydro-pyranyl, tetrahydrothiopiranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, sulfone, tetrahydrothiopyranyl sulfoxide, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, thiomorpholinyl, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothienyl and tetrahydro1,1-dioxothienyl. Monocyclic heterocycloalkyl groups usually have 3 to 7 members. Of the monocyclic 3-7 membered heterocycloalkyl groups, 5 to 6 ring atoms are preferred. The heteroatom may be substituted with a protecting group; as is known to persons having ordinary skill in the subject, nitrogen-bonded hydrogen may be substituted, for example, with a tert-butoxycarbonyl group. In addition, heterocycloalkyl groups may be optionally substituted with one or more substituents. In addition, the point of attachment of the heterocyclic ring to another group may be a carbon atom or hetero atom of the heterocyclic ring. In this definition, pyrrolidinyl, orthiazinyl), only stable isomers of such substituted heterocyclic groups are contemplated.

[0034] As used herein, the term "substituent" or "substituted" means that the hydrogen radical in the compound or group is replaced by any desired group that is substantially stable under reaction conditions in a protected form or when protected by a protecting group. Examples of preferred substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogens (chlorine, bromine, iodine or fluorine); alkyl; alkenyl; alkynyl; hydroxyl, alkoxy, nitro groups; thiol ether, imino, cyano, amide, foaphonate, phosphine, carboxyl, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, oxygen (-0); haloalkyl (e.g. trifluoromethyl); cycloalkyl which may be monocyclic or fused or unfused polycyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocycloalkyl which may be monocyclic or fused or unfused polycyclic (e.g.

piperidinyl, piperazinyl, morpholinyl, monocyclic or fused or unfused polycyclic aryls or heteroaryls (e.g. phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, benzidimidinyl, benzidimidinyl amino (primary, secondary or tertiary); C02CH3; CONH 2; OCH2CONH2; NH2; S02NH2; OCHF 2; CF 3; OCF3 and such parts of the molecules that can be optionally substituted with a fused ring structure or bridge, e.g. -OCH20-. These substituents may be optionally further substituted with substituents selected from such groups. In some embodiments, the term "substituent" or the adjective form "substituted" refers to a substituent selected from the group consisting of alkali, alkenyl, or alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, aralkyl, cycloalkyl, haloalkyl, -C (0) R13, -NR11R12, -SR13, C (0) OR13, -OC (0) R13, -NR13C (0) NR11R12, -OC (0) NR11R12, NR13C (0) OR14, -S (0) rR13, -NR13S (0) rR14, -OS (0) rR14,

S (O) rNR11R12, -0, -S, and -N-R13, where r is 1 or 2; R11 and R12 are, for individual occurrences, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, substituted cycloalkyl, optionally cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted araloalkyl or optionally substituted heteroarylalkyl or R1 and R12, treated together with the nitrogen to which they are attached, are optionally substituted heterocycloalkyl or optionally substituted heteroaryls, and R13 and R14 for the individual occurrences are, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted optionally substituted cycloalkenyl, substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl , optionally substituted araloalkyl or optionally substituted heteroarylalkyl. In some embodiments, the term "substituent" or adjective form, optionally substituted cycloalkyl, optionally "substituted," refers to a solubilizing group.

[0035] The solubilizing group is selected from the following:

- an alkyl group substituted with one or more heteroatoms such as N, O, S, each optionally substituted with an alkyl group, independently substituted with an alkoxy, amino, alkylamino, dialkylamino, carboxy, cyano or substituted cycloheteroalkyl or heteroaryl or phosphate, sulfate or carboxylic acid .

- an alkyl, aryl or heteroaryl group containing at least one nitrogen or hydrogen atom or which group is substituted by at least one amino or 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, amine, monoalkylamine, dialkylamine, carbamoyl, monoalkylcarbamoyl or dicarbamoyl.

- one of the structures a) to i) below, in which they correspond to the point of formula I.

I \ with^N \ a

corrugated line and sagittal line attached to the core structure

<img file="PL2118099T3_D0008.tif" />

bc

<img file="PL2118099T3_D0009.tif" />

[0036] The term "cycloalkyl" means a saturated cyclic alkyl radical having from 3 to 10 carbon atoms. Representative cycloalkyls are cyclopropyl, 1-methylcyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl and cyclodecyl. Cycloalkyl groups may be optionally substituted with one or more substituents.

[0037] The term "halogen" means -F, -Cl, -Br or

-AND.

[0038] In one embodiment, the invention provides a method for the synthesis of optionally substituted 2- (3aminoaryl) amino-4-aryl-thiazoles of formula I.

<img file="PL2118099T3_D0010.tif" />

^R3 (R1) m (I) [0039] Where:

R1 and R2 are groups independently selected from the group: hydrogen, halogen, linear or branched alkyl, cycloalkyl carbon atoms, amino, alkylamino group containing from 1 to 10 trifluoromethyl, alkoxy, dialkylamino or solubilizing, m is 0 - 5 an 0 - 4.

R3 can be:

(i) an aryl group, such as a phenyl group or a substituted variant thereof, having in one or more positions a combination of one or more as halogen, an alkyl group up to 10 carbon atoms, a trufluoromethyl, cyano and alkoxy group.

(ii) a heteroaryl group such as group 2, 3, or

4-pyridyl, which may contain in any position any combination of one or more like halogen, an alkyl group up to 10 carbon atoms, a ring group, any substituents such as having 1 ring, such substituents containing an aromatic group

One preparation from 1 trufluoromethyl and alkoxy;

(iii) a five-membered heterocyclic, such as e.g. 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may furthermore have any combination of one or more substituents such as halogen, an alkyl group having from 1 to 10 carbon atoms, trifluoromethyl group and alkoxy group;

of aspects of the invention is the 2- (3-aminoaryl) amino-4-aryl-thiazole (I) method or a pharmaceutically acceptable salt of Scheme II, comprising:

a) The reaction of nitroaniline (Intl), carboxylic acid chloride (Int2) and ammonium thiocyanate (Int3) in a suitable solvent to form compound (IV), where:

Ra may be a methyl, trifluoromethyl, isopropyl or phenyl group, optionally substituted.

R2 is independently selected from: hydrogen, halogen, linear or branched alkyl, cycloalkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing group.

N is 0 - 4.

b) Reaction of bromoketone (Int4) with protected thiourea (IV) in a suitable solvent, using appropriate bases.

The R3 substituent in (Int4) and in compounds (III), (II) and (I) shown in diagram II below is one of the following:

(i) an aryl group, such as a phenyl group or a substituted variant thereof, having in one or more positions a combination of one or more halogen, an alkyl group up to 10 carbon atoms, a trufluoromethyl, cyano and alkoxy group.

(ii) a heteroaryl group such as group 2, 3, or

4-pyridyl, which may contain in any position any combination of one or more as halogen, an alkyl group up to 10 carbon atoms, a ring group, any substituents such as having 1 ring, such substituents containing an aromatic group from 1 trufluoromethyl and alkoxy;

(iii) a five-membered heterocyclic, such as e.g. 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may furthermore have any combination of one or more substituents such as halogen, an alkyl group having from 1 to 10 carbon atoms, trifluoromethyl group and alkoxy group;

NH2 (R2) n-nNO2

int1

<img file="PL2118099T3_D0011.tif" />

II nh₄scn _ "

int3

<img file="PL2118099T3_D0012.tif" />

III

<img file="PL2118099T3_D0013.tif" />

Int5

<img file="PL2118099T3_D0014.tif" />

c) Reduction in a suitable solvent of the nitro group of compound (III) to the corresponding amine (II).

d) Reaction of aniline (II) with (Int5) in a suitable solvent using the appropriate coupling procedure. Rb may be hydroxy, alkoxy or halogen.

[0040] R1 is a group independently selected from: hydrogen, halogen, linear or branched alkyl, cycloalkyl containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino or solubilizing, m is 0-5.

[0041] In yet another embodiment, the method outlined in Scheme II is used to synthesize a compound of formula V or a pharmaceutically acceptable salt thereof,

<img file="PL2118099T3_D0015.tif" />

(V)

Where:

R1 is independently selected hydrogen, halogen, linear or branched alkyl, cycloalkyl containing from 1 to 10 carbon atoms, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino or solubilizing, m is 0-5.

(VIII) can be obtained by adding Intel) to a solution of ammonium thiocyanate and carboxylic acid chloride in an aprotic solvent, preferably acetone.

[0042] Compound (VII) is obtained by cyclizing compound (VIII) with bromoketone (Int4a) in among

A nitroaniline compound in an alkaline environment, preferably with potassium carbonate in a polar protic solvent such as methanol.

AND.

[0043] Compound (VII) is reduced to form compound (VI). The preferred way to perform the reduction reaction is to conduct it in the presence of a catalyst, such as Raney reactivated nickel. The reduction can be carried out in an alcoholic or polar aprotic solvent such as THF. In one embodiment, the reaction is carried out in the presence of hydrogen. The reaction can also be performed under phase transfer hydrogenation.

<img file="PL2118099T3_D0016.tif" />

[0044] Compound (V) is obtained under different conditions:

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

ii) Where Rb is a halogen such as chloride, the acid chloride (Int5a) is coupled with the compound (VI) in an alkaline medium, preferably using Tri ethylamine, in an aprotic solvent such as dichloromethane.

iii) Where Rb is a hydroxyl group, the carboxylic acid (Int5a) is coupled to compound (VI) using an activating agent such as Mukaiyama's reagent or HOBt / EDCI in an aprotic solvent, preferably DMF.

[0045] The invention is explained in detail in the following examples, which are for illustration only and should not be considered as exhaustive.

EXAMPLE 1

1-acetyl-3- (2-: methyl-5-nitrophenyl) -thiourea [0046] Ammonium thiocyanate (25 kg, 328.43: ola), acetyl chloride (24 kg, 337.53: ol) were introduced into the reactor, acetone (225 L) and 2-: ethyl-5-nitroaniline (Int1) (42 kg, 276.04: ola). These: the temperature was maintained at 25 ± 10 ° C for about 4 hours. Water (413 L) was added and: stirred: reaction mixture for about 1 hour. The precipitate was filtered and then washed with water and diisopropyl ether :. The product was then dried in a plate dryer at 45-50 ° C.

Yield = 84%.

1 H NMR (DMSO-d 6):? = 12.37 (1H, s); 11.68 (IH, s);

8.68 (1H, d, J = 2.5 Hz); 8.06 (1H, dd, J = 8.4, 2.5 Hz);

7.58 (1H, d, J = 8.4 Hz); 2.33 (3H, s); 2.18 (3H, s).

MS (ES +): 1z = 254.1 (M + H) +; (ES "): lz = 252.3 (MH) -.

Mp = 205 ° C.

EXAMPLE 2 (2-Methyl-5-nitrophenyl) - (4-pyridin-3-yl-thiazol-2-yl) amine [0047] Methanol (1120 L), potassium carbonate (287 kg, 2076.70 mol) were introduced into the reactor. ) and 1-acetyl-3- (2-methyl-5-nitrophenyl) -thiourea (67 kg, 264.53 mol). Then 2-bromo-1-pyridine-3-yl-ethanone (Int4) (52 kg, 259.96 mol) was added, and the temperature was kept at 25-30 ° C for 4 hours. Water (692 L) was added to the mixture, then the precipitate was filtered off and washed with water and diisopropyl ether. The product was then dried in a plate dryer at 45-50 ° C.

Yield = 95%.

1 H NMR (DMSO-d 6): δ = 9.83 (1H, s); 9.60 (1H, d, J = 2.5 Hz); 9.18 (IH, d, J = 1.9 Hz); 8.53 (1H, dd, J = 4.6,

1.5 Hz); 8.27 (IH, dt, J = 8.0, 1.9 Hz); 7.80 (1H, dd, J = 8.2, 2.5 Hz); 7.66 (IH, 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-pyridine-3-yl-thiazol-2-yl) -benzene-1,3-diamine [0048] In the reactor, a mixture of (2-methyl-5-nitrophenyl) - (4-pyridine-3-yl- thiazol-2-yl) -amine (40 kg, 128.06 mol), Raney nickel (2.7 kg, 46.00 mol) and methanol (600 L) were heated to 40-45 ° C and hydrogenated under pressure hydrogen (5 kg / cm2) for 2 hours. The reaction mixture was filtered and concentrated. Water was added to the residue and stirred. The product was then filtered and dried in a plate dryer at 45-50 ° C.

Yield = 85%.

1 H NMR (DMSO-cfg):? = 9.20 (1H, s); 9.09 (1H, dd,

J = 2.3, 0.76 Hz); 9.48 (IH, dd, J = 4.8, 1.7 Hz); 8.20 (1H, dt, J = 8.0, 2.1 Hz); 7.42 (1H, ddd, J = 7.8, 4.8, 0.8 Hz);

7.38 (IH, s); 7.09 (1H, d, J = 2.3 Hz); 6.85 (1H, d, J = 8.0

Hz); 6.29 (1H, dd, J = 8.0, 2.3 Hz); 4.95 (IH, s); 2.10 (3H, s).

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

Mp = 136 ° C.

EXAMPLE 4

Pochodne_N- [4: Methyl-3- (4-pyridin-3-yl-thiazol-2-ylamino) -phenyl] -benzamide

Method A [0049] To the reactor under low nitrogen pressure was added 4-methyl-N3- (4-pyridin-3-ylthiazol-2-yl) -benzene-1,3-diamine (95 g, 336.45 mmol) and dichloromethane (2 L). To this suspension, cooled to 5 ° C, a 2 M (588 mL) solution of trimethylaluminum in hexane was added dropwise. The reaction mixture was gradually brought to 15 ° C and kept there for 2 h with stirring. 4- (4-Methyl-piperazine-1-methyl) -benzoic acid methyl ester (100 g, 402.71 mmol) in dichloromethane (200 mL) was added over 10 minutes. After 1 h stirring at room temperature, the reaction mixture was heated to reflux for 20 h and cooled to room temperature. This solution was transferred dropwise through a cannula into a reactor containing 2 N NaOH (2.1 L) cooled to 5 ° C. After stirring for 3 h 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, dried over MgSO 4, and then concentrated under reduced pressure. The resulting brown solid was recrystallized from i-Pr2O, yielding 130.7 g (78%) of a beige powder.

Method B

Preparation of acid chloride [0050] To a mixture of 4- (4-methyl-piperazine-1-yl-methyl) -benzoic acid dichloride (1.0 equivalent), dichloromethane (7 volumes) and triethylamine (2.15 equivalent) was added at 18- 28 ° C thionyl chloride. The reaction mixture was stirred at 2832 ° C for 1 hour.

Acid chloride coupling with amino thiazole.

[0051] To cooled (0-5 ° C) suspension of 4-methylN3- (4-pyridine-3-yl-thiazol-2-yl) -benzene-1,3-diamine (0.8 equivalent) and triethylamine ( 2.2 equivalents) in dichloromethane (3 volumes) was added a solution of acid chloride (prepared below) maintaining the temperature below 5 ° C. The reaction mixture was heated to 25-30 ° C and stirred in it for 10 h. Methanol (2 volumes) and water (5 volumes) were added to the reaction mixture, followed by mixing. After separation of the layers, methanol (2 volumes), dichloromethane (5 volumes) and sodium hydroxide solution (aqueous, 10%, to reach pH 9.5-10.0) were added to the aqueous layer, followed by stirring for 10 minutes. Layers have been separated. The organic layer was washed with water and saturated sodium chloride solution. The organic layer was concentrated, then ethanol (2 volumes) was added and mixed. The mixture was concentrated. Ethanol was added to the residue and mixed. The product was filtered and dried at 50-55 ° C in a vacuum disc dryer.

Yield = 65 - 75%.

Method C [0052] To a solution of 4-: ethyl-N3- (4-pyridine-3-ylthiazol-2-yl) -benzene-1,3-dia: iny (1.0 equivalent) in DMF (20 volumes) was added gradually triethyl: Ina (5 equivalents), 2-chloro-1-: ethylpyridine iodide (2 equivalents) and 4- (4-: ethyl-piperazine-1-yl: ethyl benzoic acid (2 equivalents). The reaction mixture was stirred for 7h in room temperature. Then: the mixture was diluted in diethyl ether: and then washed with water and saturated: aqueous: NaHCO3, dried over Na2SO4 and then concentrated. The crude product was purified by chro- matography: new chromatography, eluting with 100% EtOAc to give a yellow solid.

Yield = 51%.

1 H NMR (CDCl 3): [delta]? = 9.09 (1H, s, NH); 8.52 (IH, brs); 8.27 (IH, s); 8.13 (IH, s); 8.03 (IH, s); 7.85 (2H, d, J = 8.3 Hz); 7.45 (2H, :); 7.21-7.38 (4H, :); 6.89 (IH, s); 3.56 (2H, s); 2.50 (8H, brs); 2.31 (6H, brs).

MS (Cl): / z = 499 (M + H) +.

[0053] An additional: aspect: of the current process is the fact that it leads to the formation of a special: polyethylene salt: ethanesulfonic acid benzo: idu 4 (4-: ethyl-piperazine-1-yl-: ethyl-N- [ 4-: ethyl-3- (4-pyridine-3-yl-thiazol-2-yl-a: ino) -phenyl] of formula (IX)

<img file="PL2118099T3_D0017.tif" />

γ \ γ

O (IX) [0054] This document describes a polymorph (IX) that has the most advantageous processing, storage and preparation properties. For example, this form remains dry at a relative humidity of 80% and thermodynamically stable at temperatures below 200 C. The polymorph of this form has been characterized by the X-ray diffraction pattern shown in FIG. 1, with characteristic peaks at approximately 7.269, 9.120, 11.038, 13.704, 14.481, 15.43, 15.870, 16.718, 17.087, 17.43, 18.224, 19.248, 19.441.11.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.68 , 25,754, 26,777, 28,975, 29,609, 30,073 degrees c, and was further characterized by differential scanning calorimetry (DSC), with the result shown in FIG. II, on which a single maximum value is visible at a temperature of about 237.49 ± 0.3 ° C.

An X-ray diffraction pattern was obtained on a Bruker AXS (D8 advance). Differential scanning calorimetry (DSC) tests were carried out using a Perking Elmer Precisely (Diamond DSC) apparatus.

This polymorph can be obtained by treating 4- (4-methyl-piperazine-1 -yl-ethyl) -N- [4-methyl-3- (4-pyridine-3-yl-benzamide benzamide at the right temperature above) as a thiazolo -2-yl-a: ino) -phenyl] 1.0 to 1.2 equivalents of ethanesulfonic acid, preferably between 20 and 80 ° C.

The reaction is conducted in an appropriate:

solvent, especially polar solvent:

such as: ethanol or ethanol or ketones, such as acetone or in ether, such as diethyl ether or dioxane or in their mixture.

The present invention is explained by the following example: which: a is illustrative only and should not be exhaustive.

Preparation of the mentioned poly: phosphorous ethyl sulfonate benza: idu 4- (4-: ethyl piperazine-1-yl-: ethyl-N- [4-: ethyl-3- (4-pyridine-3-ylthiazole-2-yl- a: ino) -phenyl] of formula.

[0055] Benzo: id 4- (4-: ethyl-piperazine-1-yl-: ethyl) N- [4-: ethyl-3- (4-pyridine-3-yl-thiazol-2-yl-a: ino) phenyl] (1.0 equivalent) was dissolved in ethanol (4.5 volumes) at 65-70 ° C. Ethanesulfonic acid (1.0 equivalent) was slowly added at these temperatures. The mixture was cooled to kept at this temperature for 6 hours. Filtered and dried in a vacuum disc dryer at 55-60 ° C. Yield = 85-90%. Initial te: melting point S: p = 236 ° C.

these are: 25-30 ° C and Product

AB Science, France, Full: ocnik

Z-8745/11

EP 2 118 099