WO1992021666A1 - Angiotensin ii receptor antagonist thiazole devivatives - Google Patents

Abstract

Derivatives of formula (I), addition salts thereof, and therapeutical uses thereof, particularly for treating cardiovascular diseases, and especially for treating hypertension, heart failure and arterial wall diseases.

Description

 THIAZOLE DERIVATIVES ANTAQMDSTES FROM ANGEIENSIN II RECEPTORS

The present invention relates, as new products, to the thiazole derivatives of general formula (I) below as well as their addition salts, in particular the pharmaceutically acceptable addition salts.

The compounds in question have a very interesting pharmacological profile insofar as they are endowed with antagonistic properties of the Angiotensin II receptors. They are therefore particularly indicated for the treatment of cardiovascular diseases, in particular for the treatment of hypertension, for the treatment of heart failure and for the treatment of diseases of the arterial wall.

The present invention also relates to the process for the preparation of said products and their applications in therapy. These thiazole derivatives are characterized in that they correspond to the general formula (I):

25 in which: λ represents a lower alkyl radical of 1 to 7 carbon atoms or a C3-C7 cyctoalkyl radical,

R2 represents the hydrogen atom, a halogen atom, a lower alkyl radical

From 1 to 7 carbon atoms, a lower haloalkyl radical from 1 to 7 carbon atoms, a C ₃ -C ₇ cyctoalkyl radical; an aromatic nucleus; R ₂ can also represent a group X- (CH ₂ ) _n -CN, X- (CH2) _n -COOR ₄ , X- (CH ₂ ) _n -OR ₄ , X- (CH2) - SR ₄ , X- (CH2) _n -NR'R ", X-fCH ^ n-CO-NR'R '' or X- (CH ₂ ) _n -NHCOR ₅ ; in these groups, X

"λ represents a bond, a sulfur atom or an NH group, n is an integer

35 from 0 to 5, R4 represents a hydrogen atom, a lower alkyl radical from 1 to 7 atoms of carbon, a halo lower alkyl radical of 1 to 7 carbon atoms, a C ₃ -C ₇ cycloalkyl radical, R5 has the same meaning as R ₄ but can also be an aromatic ring or an OR ₄ group in which R ₄ has the same meaning as indicated above, R 'and R "independently represent a hydrogen atom, a lower afcyl radical of 1 to 7 carbon atoms or a C ₃ -C ₇ cycloalkyl radical or can form together with the atom d nitrogen to which they are attached a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, the latter being able to be substituted on the second nitrogen atom by a lower alkyl of 1 to 7 carbon atoms or a nucleus aromatic.

R ₃ represents one of the following groups

in which R7 represents a hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms or even a benzyl radical, Y and Z independently represent a hydrogen atom, a halogen atom, a lower alkyl radical of 1 with 7 carbon atoms, an O-lower alkyl radical or a trifluoromethyl.

These derivatives can be in the form of addition salts, in particular pharmaceutically acceptable addition salts.

In the description and the claims, the term lower alkyl means a hydrocarbon chain having from 1 to 7 carbon atoms, linear or branched. Lower alkyl is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl radical. By C ₃ -C ₇ cycloalkyl radical. we mean a saturated cyclic radical, this is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

Halogen means a chlorine, bromine, iodine or fluorine atom.

The term “halo lower alkyl radical of 1 to 7 carbon atoms” means an alkyl radical in which 1 to 7 hydrogen atoms have been substituted by 1 to 7 halogen atoms. A halogeno lower alkyl radical is for example a trifluoromethyl radical, a 2,2,2-trifluoro ethyl radical, a pentafluoro ethyl radical, a 2,2-difluoro 3,3,3-trifluoropropyl radical, a heptafluoro propyl radical.

The term “aromatic ring” is intended to mean a phenyl ring which is unsubstituted or mono or di substituted by a lower alkyl group, a halogen, a halo lower alkyl group, an O-lower alkyl radical or an S-lower alkyl radical.

The invention relates in particular to the derivatives of general formula (I) in which: R 1 represents a lower alkyl radical of 1 to 7 carbon atoms, R ₂ represents the hydrogen atom, a lower alkyl radical of 1 to 7 atoms carbon, an aromatic nucleus; R ₂ can also represent a group X- (CH ₂ ) _n -COOR ₄ , X- (CH ₂ ) _n -OR ₄ , X- (CH ₂ ) _n -SR ₄ , X-fCH ^ n NR'R ", X- (CH ₂ ) _n -NH COR ₅ ; in these groups X represents a bond, a sulfur atom or an NH group, n is an integer from 0 to 5, R ', R ", R ₄ and R ₅ represent a hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms, or R ₅ represents OR ₄ , R3 represents an acid group, 2-sulfoxy benzoyl amino, 2-carboxy benzoyl amino, 2-carboxy 3,6 -dichlorobenzoyl amino, 2- (1-H-tetrazol-5-yl) phenyl.

According to an alternative embodiment, R- _\ is an n-propyl group;

According to an alternative embodiment, R is a methyl group;

According to another alternative embodiment, R ₂ is a methoxy methylene group; According to an alternative embodiment, R ₃ is a 2-sulfoxy benzoyl amino group;

According to another alternative embodiment, R ₃ is a (tetrazol-5-yl) -2 phenyl group.

The particularly preferred compounds of the invention are those which are chosen from the products of formula:

According to the invention, the compounds of formula (I) can be synthesized by the following reactions:

First, we will synthesize vinyl ketones of formula (II): R, - CO — CH = CH ₂

Formula (II)

in which R-, is defined as above.

These vinyl ketones are commercial like vinyl methyl ketone, or can be prepared according to known methods and described in the literature: R.B. WOODWARD, F. SONDHEIMER, D. TAUB, K. HEUSLER and W.M. Me LAMORE: J. Am. Chem. Soc. 1952, TA, 4223

A. ARCHER, WB DICKINSON and MJ UNSER: J. Org. Chem. 1957, __≥, 92 i.e., by Friedel and Craft reaction with an acid chloride of formula Ri COCI, in which Ri is defined as above, in the presence of aluminum chloride, on the ethylene, we will get the chloroketones of formula RrCO-CH ₂ -CH ₂ -CI where Ri is defined as above, which will be dechlorohydrated by distillation in the presence of sodium benzoate to lead to vinyl ketones of formula (II).

By addition of a diazo derivative of formula (III) in the presence of cupric chloride

Formula (III)

according to the conditions described in patent DT 1,128, 429 (1962), on the vinyl ketones of formula (II), the chloroketones of formula (IV) will be obtained

Formula (IV)

in which R- is defined as above.

The diazo derivatives of formula (III) are obtained according to the conventional methods of diazotization of anilines of formula (V) by NaN0 ₂ in the presence of hydrochloric acid

Formula (V)

In formulas (III), (IV) and (V), V can represent:

- a nrtro group, in this case we will use the paranitro aniline which is commercial

a COOR7 group in which R ₇ is defined as above, in this case we will use p-amino benzoic acid which is commercial or preferably one of its esters

- in which R ₇ is defined as above,

in this case, the anilines necessary for this preparation will be synthesized by hydrogenation in the presence of Raney nickel at atmospheric pressure of 4'-n ^" rtro-2-biphenylcarboxylic acid or one of its esters, synthesized according to the method described by DANNLEY RL and STERNFELD MJ Am. Chem. Soc. 1954, 22, 4543

prepared according to the previous reference, will be treated with thionyl chloride and the acid thus obtained will react with ammonia to lead to 2- (4-nitro phenyl) benzamide. The latter will be dehydrated according to conventional methods known to those skilled in the art, for example treatment with oxyphosphorus chloride in dimethyl formamide or with thionyl chloride. The hydrogenation in the presence of Raney nickel at atmospheric pressure of the 2- (4-nitrophenyl) benzonitrile thus obtained

will lead to the anilines of formula (V) where V represents

Another variant of preparation of the halo ketone derivatives of formula (IV) will consist in preparing the keto esters of formula (II ′) for example according to the method known to those skilled in the art using Meldrum acid which can be found in the literature with reference:

- OIKAWA Y.; SUGANO K.; YONEMITSU O .; J. Org. Chem. 1978, 42 (10), 2087-88 according to the following reaction scheme:

Formula (II ')

it being understood that in formula (II ′) Ri has the same meaning as above.

By benzylation of the compounds of formula (II ') with compounds of formula (II ")

W

Formula (II ") in the presence of a base such as a sodium, cesium or potassium carbonate in acetone or dichloromethane, a sodium or potassium alcoholate in an alcohol, a sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethyl formamide for example, at a temperature between 50 and 100 ° C or alternatively, in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropylethylamine at reflux of tetrahydrofuran according to the reference: SUNG-EUN YOO; KYU YANG Yl; Bull, Korean. Chem. Soc. 1989, 10 (1), 112; We will get your compounds of formula (IIP)

Formula (III ') which will be halogenated, for example chlorinated with sulfuryl chloride then hydrolyzed and decarboxylated by heating in toluene in the presence of paratoluene sulfonic acid to lead to the halo ketones of formula (IV) according to the diagram:

Formula (III ') Formula (IV)

in the formulas (II "), (III '), (III"), V has the same meaning as above, in the formula (II ") W is a halogen, preferably bromine or chlorine, in the formulas (III ') and (III ") Ri has the same meaning as above; when V is:

- a nitro group, in this case we will use p-nitro benzyl chloride or p-nitrobenzyl bromide which are commercial, - a COOR7 group in which R7 is defined as above, in this case the derivative of formula (it " ) will then be prepared by chlorination or bromination using N-chloro succiπimide or N-bromo succinimide in a solvent such as carbon tetrachloride or te dibromo ethane of an ester of p-methyl benzoic acid which is commercially available, according to the reference: - JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 1962 (2), 2247.

in which R ₇ is defined as above,

the compounds of formula (II ") are then prepared by reaction of a magnesian of p-bromo toluene with a compound of formula

to get a compound of formula

which is hydrolyzed to yield the compound of formula

The operating modes for the three stages described above are found in the reference: - MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc. 1975, 27, 7383.

The acid is then esterified with an alcohol of formula R ₇ OH, R being defined as above.

These derivatives are then brominated or chlorinated, for example with N-bromo succinimide or N-chloro succinimide in a solvent such as carbon tetrachloride or dibromoethane to yield the compounds of formula (II ") where V is the group:

- the, in this case you composed

previously prepared will be transformed into primary amide by the action of acid chloride, obtained with thionyl chloride or phosphorus oxychloride, on ammonia and this amide will be transformed into nitrile by action of phosphorus roxychloride in dimethylformamide or chloride thionyle. This nitrile, of formula

can also be synthesized by directly transforming the oxazoline compound

previously obtained as a nitrile derivative by treatment in pyridine in the presence of phosphorus oxychloride.

The nitrile is then brominated or chlorinated under the same conditions as the previous ester to yield the compounds of formula (II ") where V is the group:

The reaction of derivatives of formula (VI):

R ₂ - C— NH ₂ II S

Formula (VI)

in which R ₂ is defined as above, on the chloroketones of formula (IV) by heating to a temperature between 20 and

90 ° C without solvent or in an alcohol will lead to the derivatives of formula (VII):

Formula (VII) in which Ri, R ₂ and V are defined as above.

The derivatives of formula (VI) can be commercial when it is a thiourea, an ester or a salt of amino carbodithioic acid, thioacetamide, cyanothioacetamide for example, or can be prepared according to conventional methods known to those skilled in the art by the action of H ₂ S in the presence of a base such as pyridine or triethylamine on the corresponding nitrile derivatives or by the action of P2S5 or of the Lawesson reagent (2,4-bis (4-methoxy phenyl) -1, 3-dithia-2,4-diphosphetane-2,4 disulfide), on the corresponding amide derivatives. These reactions can be found at the following references:

S. EGGERS; V.V. KANE; G. LOWE; J. Chem. Soc. 1965, 1262. W. WOLFGANG; K.D. BODE; Justus Liebigs Am. Chem. 1966, 222, 131. M. ERNE; H. ERLENMEYER; Helv. Chim. Acta. 1948, 652. A. BONZOM; J. METZGER; Bull. Soc. Chim. Fr. 1963, __1. 2582. O. WALLACH; Ber. 1899, 2Z, 1874.

N. SCHENK; FV GRAEWENITZ; Z. Physiol. Chem. 1924, MI, 138. A. WEDDIGE; J. Pr. Chem. 1874,, 133. WR BOON; J. Chem. Soc. 1945, 601. JF OLIN; TB JOHNSON Rec. Trav. Chim. 1931, ≤Û, 72.

The derivatives of formula (VII) in which: - V is a nitro group may undergo catalytic hydrogenation, for example in the presence of Raney nickel in an alcohol at atmospheric pressure and at room temperature, to yield the compounds of formula (I) where R ₃ is an amino group.

By acting on these derivatives of a suitably substituted phthalic anhydride, the compounds of general formula (I) where R3 represents the group will be obtained

in which Y and Z are defined as above, the acid obtained can then be esterified to obtain the group

in which Y, Z and R ₇ are defined as above.

Similarly, by the action of a cyclic anhydride of ortho sulfobenzoic acid suitably substituted on these amino compounds, the compounds of general formula (I) will be obtained in which R ₃ represents the group.

where Y and Z are defined as above.

- V is a group COOR7 could be hydrolyzed in an acidic or basic medium or else hydrogenated in the case where R ₇ is a benzyl in order to respect the other ester functions which may be present, to lead to the compounds of formula (I) where R ₃ is a COOH group.

- V is a in the same way will be hydrolyzed

or hydrogenated in the presence of a catalyst such as palladium on carbon in the case where R ₇ is a benzyl, to yield the compounds of formula (I) where R ₃ is a

V is a will be able to react with an equivalent of azide

sodium in a solvent such as dimethyl formamide in the presence of an ammonium salt such as ammonium chloride or also with a trialkyl tin azide at the reflux of toluene then with gaseous hydrochloric acid in tetrahydrofuran to lead to compounds of general formula (I) where R ₃ represents a group:

Addition salts of certain compounds of formula (I) can be obtained, in particular pharmaceutically acceptable addition salts. Mention may be made in particular when R ₂ or R ₃ has an acid or tetrazole function the sodium, potassium, calcium, amine salts such as dicyclohexylamine or amino acid salts such as lysine. When R ₂ or R ₃ has an amino function, a mineral or organic acid salt such as hydrochloride, methane sulfonate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate for example.

The new compounds according to the invention have remarkable properties as angiotensin II receptor antagonists and can be used therapeutically for the treatment of cardiovascular diseases, in particular for treating hypertension, heart failure and diseases of the arterial wall.

Thus, the invention extends to pharmaceutical compositions containing as active principle, the drugs consisting of a pharmaceutically effective amount of at least one compound of formula (I), as defined above, or optionally one of its addition salts pharmaceutically acceptable.

These compositions can be administered by the oral, rectal, parenteral, transdermal or ocular route.

These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, transdermal systems and eye drops: they are prepared according to the usual methods. The active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined above or one of its pharmaceutically acceptable addition salts can be incorporated therein into excipients usually employed in these pharmaceutical compositions, such that talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous vehicles or not, fatty substances d animal or vegetable origin, giycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colors.

The invention also covers a pharmaceutical composition with angiotensin II receptor antagonist activity which makes it possible in particular to favorably treat cardiovascular diseases, in particular hypertension and heart failure, characterized in that it comprises a pharmaceutically effective amount of at least one aforementioned compound of formula (I) or a pharmaceutically acceptable addition salt thereof which can be incorporated into a pharmaceutically acceptable excipient, vehicle or carrier.

The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

For example, in adults of average weight 60 to 70 kg, it can vary between 1 and 400 mg of active principle in one or more daily doses, orally or from 0.01 to 50 mg in one or more daily doses. parenterally.

The invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutical amount is incorporated effective of at least one compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, in a pharmaceutically acceptable excipient, vehicle or support. According to a particular characteristic, this pharmaceutical composition is formulated in the form of capsules, tablets dosed from 1 to 400 mg or in the form of injectable preparations dosed from 0.01 to 50 mg.

The invention also covers a method of therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above or one of its addition salts is administered to this mammal pharmaceutically acceptable. In animal therapy, the usable daily dose should usually be between 1 and 100 mg per kg.

Other characteristics and advantages of the invention will be better understood on reading which will follow from a few examples of preparation which are in no way limitative, but given by way of illustration.

Example 1 3-chloro 4- (4-nitrop enyl) butan 2-one

Formula IV: R-i-CHa V≈NO-,

27.6 g of 4-nitroaniline are dissolved in 180 ml of 20% hydrochloric acid. The solution is cooled to 0-5 ° C. and then a solution of 12.7 g of sodium nitrite in 30 ml of water is added slowly while cooling. The pH is then raised using a 25% sodium hydroxide solution to pH 3 while maintaining the temperature at 5-10 ° C. A solution of 4.7g of CuC.2 in 25ml of water is added and then 17.3ml of 3-buten 2-one in solution in 180m! acetone. The temperature is allowed to return to ambient. After one night, the reaction mixture is decanted, the organic phase concentrated. The residue is taken up in water and extracted with chloroform. After drying, the filtrate is concentrated to give a red oil which is purified by chromatography on a silica column (eluent: chloroform-petroleum ether 50/50) to give 15.4 g of 3-chloro 4- (4-nitrophenyl) butan 2-one in the form of an orange solid with a melting point F = 86 ° C.

Example 2 2,4-dimethyl 5- (4-nitrobenzyl) thiazole

Formula VII: R ^ O- ^ R ^ CHs V = N0 ₂

4.7g of 3-chioro 4- (4-nitrophenyl) butan 2-one and 2.4g of thioacetamide are dissolved in 60m! ethanol and brought to reflux for 12 hours. The reaction medium is concentrated, the residue taken up in water, the solution basified with sodium carbonate and extracted with chloroform. After concentrating the organic phase, the solid obtained is taken up in hot pentane to give 3.5 g of 2,4-dimethyl 5- (4-n ^' ιtrobenzyl) thiazole in the form of yellow crystals with a melting point F = 66 ° C.

Example 3 2,4-dimethyl 5- (4-amlno benzyl) thiazole

Formula I: Rι = CH ₃ R ₂ = CH ₃ R ₃ = NH2

3.5 g of 2,4-dimethyl 5- (4-nitro benzyl) thiazole in 50 ml of methanol are hydrogenated at pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the reaction medium, 3 g of 2,4-dimethyl 5- (4-amino benzyl) thiazole are obtained in the form of a brown solid with a melting point of F = 120 ° C. Example 4 2- [4 - ((2,4-dimethyl thiazol-5-yl _. Methyl) phenyl aminocarbonyl] benzoic acid

Formula I: Rι = CH ₃ R ^ C ^

3 g of 2,4-dimethyl 5- (4-amino benzyl) thiazole are dissolved in 75 ml of acetonitrile and 2 g of phtaiic anhydride are added in portions. The medium is stirred for 6 hours at room temperature then the precipitate is filtered, washed with ethyl acetate to give 3.3 g of 2- [4 - ((2,4-dimethyl thiazol-5-yl) methyl acid ) phenyl aminocarbonyl] benzoic in the form of crystals with a melting point F = 182 ° C.

Example 5 (4-methyl 5- (4-nitrobenzyl) thiazol-2-yl) amino ethyl acetate

Formula VII: R- = CH ₃ R ₂ = -NHCH ₂ COOEt V = N0 ₂

7.6 g of 3-chloro 4- (4-nitrophenyl) butan 2-one and 4.5 g of N-carboxymethyl thiourea (NH ₂ CS NH CH ₂ COOH) are dissolved in 100 ml of ethanol and brought to reflux for 12 hours . The reaction medium is concentrated and the residue recrystallized from isopropanol to give 9.5 g of (4-methyl 5- (4-nitrobenzyl) thiazol-2-yl) amino ethyl acetate.

Example 6 (4-methyl 5- (4-aminobenzyl) thiazol-2-yl) amino ethyl acetate

Formula I: R ^ CHs R2 = -NHCH ₂ COOEt R ₃ = NH ₂

9.2 g of (4-methyl 5- (4-nitrobenzyl) thiazol-2-yl) amino ethyl acetate in 500 ml of an ethanol-methoxyethanol mixture are hydrogenated at pressure and ambient temperature in the presence of Raney nickel. / After filtration of the catalyst and concentration of the reaction medium, a brown oil is obtained which is taken up in acid water, the aqueous phase extracted with chloroform and then basified, and the precipitate obtained filtered to give 6.1 g of (4-methyl 5- (4-aminobenzyl) thiazol-2-yl) amino ethyl acetate in the form of a brown solid with a melting point of M = 116 ° C.

Example 7 (4-methyl 5- (4- (2-carboxy benzoylamino) benzyl) thiazol-2-yl) amino ethyl acetate

Formula I: Rj-CHs R2 = -NHCH ₂ COOEt

6 g of (4-methyl 5- (4-aminobenzyl) thiazol-2-yl) amino ethyl acetate are dissolved in 150 ml of tetrahydrofuran and 2.9 g of phthalic anhydride are added in portions. The medium is stirred for 4 hours at room temperature then the insoluble material is removed, the filtrate concentrated. The residue is taken up in water basified with sodium bicarbonate, the solution washed with chloroform and then acidified to give 2.2 g of (4-methyl 5- (4- (2-carboxy benzoylamino) benzyl) thiazoI-2-yl) amino ethyl acetate in the form of crystals with melting point F = 206-8 ° C.

Example 8 2-chloro 1- (4-nitrophenyl) hexan 3-one

Formula IV: R, - CH ₂ CH ₂ CH ₃ V = NC> 2

60g of 4-nitroaniIine are dissolved in 485ml of 20% hydrochloric acid. The solution is cooled to 0-5 ° C then a solution of 26.7g of sodium nitrite in 65m! water is added slowly as it cools. The pH is raised using a 25% sodium hydroxide solution to pH3 (300ml) while maintaining the temperature at 5-10 ° C. A solution of 11.6g of CuCl2 in 75ml of water is added and then 44.3g of 1-hexen 3-one in solution in 390ml of acetone. The temperature is allowed to return to ambient, then a release of nitrogen and a rise in temperature are observed. We leave overnight. The reaction mixture is decanted, the organic phase concentrated. The residue is taken up in water and extracted with chloroform. After drying, the filtrate is concentrated to give a red oil which is purified by chromatography on a silica column (eluent: cyclohexane) to give 57.9g of 2-chloro 1 - (4-nitrophenyl) hexan 3-one in the form of a orange oil. Example 9 2-methyl 4-n-propyl 5- (4-nltrobenzyl) thiazole

Formula VII: Rι = CH ₂ CH ₂ CH ₃ R ^ CH ₃ V = N0

A mixture of 5.9g of 2-chloro 1- (4-nitrophenyl) hexan 3-one and 1.7g of thioacetamide is heated at 90-100 ° C for 6 hours then it is cooled and taken up in acetate. ethyl. The precipitate formed is drained and washed with ethyl acetate and then with ether to give 5.6 g of 2-methyl 4-n-propyl 5- (4-nitro benzyl) thiazole in the form of crystals of melting point Mp 124 ° C.

Example 10 2-methyl 4-n-propyl 5- (4-amino benzyl) thiazole

Formula I: R- = CH ₂ CH ₂ CH ₃ R2 = CH ₃ R ₃ = NH ₂

5.5 g of 2-methyl 4-n-propyl 5- (4-nitro benzyl) thiazole in 60 ml of methanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the residue is taken up in isopropyl ether, filtered, then taken up in ethanol and passed to animal black to give, after concentration, 3.4 g of 2-methyl 4-n-propyl 5- (4-amino benzyl) thiazole in the form of a greenish solid used as such for the following.

Example 11 2- [4- (2-methyl 4-n-propyl thiazol-5-yl methyl) phenylaminocarbonyl] benzo sulfonic acid

Formula I R- = CH ₂ CH ₂ CH ₃ R ^ CHs

3.4 g of 2-methyl 4-n-propyl 5- (4-amino benzyl) thiazole are dissolved in 40 ml of acetonitrile and treated with 2.54 g of o-sulfo benzoic anhydride in solution in 20 ml of acetonitrile. The mixture is stirred for 2 hours at 50 ° C. and then methanol is added until a solid divided in suspension is obtained. After cooling the precipitate is drained. 2.9 g of 2- [4- (2-methyl 4-n-propyl thiazol-5-yl methyl) acid are thus obtained. phenylaminocarbonyl] benzo sulfonic in the form of a white powder with a melting point F = 293-4 ° C.

Example 12 4- (amino thiocarbonyl mercapto) ethyl butyrate

Formula VI: R ₂ = -S (CH ₂ ) ₃ COOEt

A mixture of 10g of ammonium dithiocarbamate (i.e. 34g of a 30% aqueous solution) and 17.7g of ethyl 4-bromo butyrate in 70ml of ethanol is kept stirring for 2 days at room temperature. The reaction medium is extracted with dichioromethane, the organic phase dried and then concentrated to give 19 g of 4- (amino thiocarbonyl mercapto) ethyl butyrate in the form of a semi-crystallized yellow oil.

The ammonium dithiocarbamate solution is obtained as follows: 30 g of carbon disulfide are dissolved in 200 ml of isopropyl acetate. A stream of ammonia is bubbled in, keeping the temperature between 20 and 30 ° C for 3.5 hours. There is a significant precipitate. This is dissolved by the addition of approximately 100g of water, weighed exactly. The reaction medium is stirred and then decanted. The aqueous phase is recovered and weighed, the difference with the weight of water added corresponds to ammonium dithiocarbamate (ie 42 g). This solution is kept cold, protected from light.

Example 13 4-f [4-n-propyl 5- (4-nitrobenzyl) thiazol-2-yl] mercapto] ethyl butyrate

Formula VII: V = N0 ₂ R. = CH ₂ CH ₂ CH ₃ R ₂ = -S (CH2) ₃ COOEt

A mixture of 4g of 2-chloro 1- (4-nitrophenyl) hexan 3-one and 3.7g of 4- (aminothiocarbonyl mercapto) ethyl butyrate is heated for 12 hours at 90-100 ° C. It is then taken up in chloroform, the insoluble material removed, the filtrate concentrated to give a brown oil. After purification on a silica column (eluent: ethyl acetate-cyclohexane 6/4), 3 g of 4 - [[4-n-propyI 5- (4-nitrobenzyl) thiazol-2-yl] mercapto] butyrate are obtained. ethyle in the form of an oil used as it is for the following operations. Example 14 4 - [[4-n-propyl 5- (4-amino benzyl) thiazol-2-yl] mercapto] ethyl butyrate

Formula I: Rι = CH ₂ CH ₂ CH ₃ Rj-≈ -S (CH ₂ ) ₃ COOEt R ₃ = NH ₂

3g of 4 - [[4-n-propyl 5- (4-nitro benzyl) thiazol-2-yl] mercapto] ethyl butyrate in 50ml of ethanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel .

After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up in acidic water. The aqueous phase is extracted with chloroform, basified with dilute sodium hydroxide and extracted with ether. The ethereal solution is dried and concentrated to give a yellow oil which is purified on a silica column (eluent: cyclohexane-ethyl acetate 7/3). 0.6 g of 4 - [[4-n-propyl 5- (4-amino benzyl) thiazol-2-yl] mercapto] ethyl butyrate is thus obtained in the form of pink oil.

Example 15 4 - [[4-n-propyl 5- (4- (2-sulfo benzoylamino) benzyl) thiazol-2-yl] mercapto] ethyl butyrate

Formula IR _1β CH ₂ CH ₂ CH ₃ R ₂ = -S (CH ₂ ) ₃ COOEt

0.6g of 4 - [[4-n-propyl 5- (4-amino benzyl) thiazol-2-yl] mercapto] ethyl butyrate are dissolved in 20ml of acetonitrile and treated with 0.3g of anhydride o - benzoic sulfo. The mixture is stirred for 6 hours at room temperature then the precipitate formed is drained. 0.8 g of 4 - [[4-n-propyl 5- (4- (2-sulfo benzoylamino) benzyl) thiazol-2-yl] mercapto] ethyl butyrate is thus obtained in the form of a white point powder melting point F = 97-8 ° C

Example 16 methoxy thioacetamide

Formula VI: Rj-≈ -C ^ OCHa A mixture of 25 g of methoxy acetonitrile, 35 ml of pyridine and 25 ml of triethylamine is treated with a stream of H ₂ S for 4 hours. The reaction is exothermic, it is necessary to cool to maintain the temperature at room temperature. .After the end of the reaction, the reaction mixture is poured into a saturated solution of sodium chloride and then extracted with ether. The ethereal phase is washed with acidic water and then with water. .After drying and concentration of the solvent, the orange oil obtained is taken up cold in petroleum ether, the precipitate formed drained. 28.8 g of methoxy thioacetamide are thus obtained in the form of crystals with a melting point F = 63-4 ° C.

Example 17 2-methoxymethyl 4-n-propyl 5- (4-nitro benzyl) thiazole

Formula VII: R ₁ = CH ₂ CH ₂ CH ₃ R ₂ = -CH ₂ OCH ₃ V = N0 ₂

A mixture of 1.2 g of methoxy thioacetamide and 3 g of 2-chloro 1 - (4-nitrophenyl) hexan 3-one is heated at 90-100 ° C for 4 hours then it is cooled and taken up in ethyl acetate . The solution obtained is passed over animal black and then evaporated. The brown oil obtained is purified on a silica column (eluent: cyclohexane-ethyl acetate 6/4). 0.9g of 2-methoxymethyl 4-n-propyl 5- (4-nitro benzyl) thiazole is thus obtained in the form of a brown oil used as it is for the following.

Example 18 2-methoxymethyl 4-n-propyl 5- (4-amino benzyl) thiazole

Formula I: R ₁ ≈ CH ₂ CH ₂ CH ₃ R2 = -CH ₂ OCH ₃ R ₃ = NH ₂

0.9 g of 2-methoxymethyl 4-n-propyl 5- (4-nitro benzyl) thiazole in 50 ml of methanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel.

After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up in acid water. The aqueous phase is extracted with ether, basified with dilute sodium hydroxide and extracted with ethyl acetate. The organic phase is dried and concentrated to give 0.5 g of 2-methoxymethyl 4-n-propyI 5- (4-amino benzyl) thiazole in the form of an orange oil used as such below.

Example 19 2- [4- (2-methoxymethyl 4-n-propyl thiazol-5-yl methyl) phenylaminocarbonyl] benzo sulfonic acid Formula I: R _{1 =} CH ₂ CH ₂ CH ₃ R2 = -CH ₂ OCH ₃

0.5 g of 2-methoxymethyl 4-n-propyl 5- (4-amino benzyl) thiazole are dissolved in

50ml of acetonitrile and treated with 0.3g of o-sulfo benzoic anhydride. The mixture is stirred

6 hours at room temperature then the precipitate formed is drained. 0.5 g of 2- [4- (2-methoxymethyl 4-n-propyl thiazol-5-yl methyl) phenylaminocarbonyl] benzo sulfonic acid is thus obtained in the form of a beige powder with melting point F = 242.5 ° C.

Example 20 (4-n-propyl 5- (4-nitrobenzyl) thiazol-2-yl) amino methyl acetate

Formula VII: R- = CH CH ₂ CH ₃ R2 = -NHCH ₂ COOMe V≈ N0 ₂

A mixture of 2.5 g of 3-chloro 4- (4-nitrophenyl) butan 2-one and 1.3 g of N-carboxymethyl thiourea is heated at 90-100 ° C for 4 hours then it is cooled and taken up in ethyl acetate. The precipitate formed is drained, and washed with ethyl acetate then with ether. it is then dissolved in 30ml of methanol and 1ml of thionyl chloride is added dropwise. The reaction medium is brought to reflux for 6 hours, the solvent is then evaporated, the residue taken up in acid water. The aqueous phase is basified with sodium bicarbonate, extracted with ether. After drying and concentration of the ether, the yellow solid is taken up in petroleum ether and filtered. 2.7 g of (4-n-propyl 5- (4-nitrobenzyl) thiazol-2-yl) amino methyl acetate are obtained in the form of a yellow powder with a melting point of F = 105 ° C.

Example 21 (4-n-propyl 5- (4-aminobenzyl) thiazol-2-yl) amino methyl acetate

Formula I: R1 = CH ₂ CH ₂ CH ₃ R ₂ ≈ -NHCH ₂ COOMe R ₃ = NH ₂

2.6g of (4-n-propyl 5- (4-nitrobenzyi) thiazol-2-yl) methyl amino acetate in 60ml of methanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel.

-After filtration of the catalyst and concentration of the filtrate, the residue is taken up in acid water. The aqueous phase is extracted with ether, basified with sodium carbonate, extracted with ethyl acetate. After drying and concentration, the residue is taken up in pentane. 1.8 g of (4-n-propyI 5- (4-aminobenzyl) thiazol-2-yl) amino methyl acetate are thus obtained in the form of a beige solid with a melting point of F = 106 ° C.

Example 22 (4-n-propyl 5- (4- (2-sulfo benzoylamino) benzyl) thiazol-2-yl) amino methyl acetate

Formula I: R _{1 =} CH ₂ CH ₂ CH ₃ R-_≈ -NHCH ₂ COOMe

1.8 g of (4-n-propyl 5- (4-aminobeπzyl) thiazol-2-yl) amino methyl acetate are dissolved in 40 ml of acetonitrile and treated with 1.08 g of o-sulfo benzoic anhydride in solution in 10ml of acetonitrile. The mixture is stirred for 24 hours at 25 ° C. then the solution is concentrated, the residue taken up in ethyl acetate and the precipitate is drained. This is chromatographed on a silica column in the presence of triethylamine. 1.9 g of triethylamine salt of (4-n-propyl 5- (4- (2-sulfo benzoylamino) benzyl) thiazol-2-yl) amino methyl acetate are thus obtained in the form of a white point-point powder. mp F = 95-6 ° C.

Example 23 methyl thioacetamido acetate

Formula VI: R ₂ = CH ₂ C0 ₂ CH ₃

A stream of H ₂ S is bubble in a mixture of methyl cyanoacetate (70 g, 710 mmol), pyridine (70 ml, 710 mmol), and triethylamine (49.6 ml, 350 mmol). The exothermic reaction, cooled with an ice bath, is followed by TLC. At the end of the reaction, the reaction mixture is washed with a dilute acid solution and extracted with ether. After drying over magnesium sulfate and concentration under vacuum, an orange oil is obtained which crystallizes. The yellow solid obtained is washed with ether, then drained. 83.3 g of methyl thioacetamido acetate are thus obtained, melting point F = 78-9 ° C. Example 24 2-methylacetate 5- (4-nltrobenzyl) 4-n-propyl thiazole

Formula VII: R-- ≈ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ C0 ₂ CH ₃ ; V ≈ N0 ₂

An equimolar mixture (13 mmol) of 2-chloro 1- (4-nitrophenyl) hexan 3-one and methyl thioacetamido acetate is heated at 60 ° C for 24 hours. The reaction mixture is taken up in dichloromethane, stirred for ten minutes and filtered. The filtrate is concentrated and the residue taken up in isopropyl ether to give 2.8 g of 2-methylacetate 5- (4-nitrobenzyl) 4-n-propyl thiazole, yellow powder with melting point 102 ° C.

Example 25 2-methylacetate 5- (4-aminobenzyl) 4-n-propyl thiazole

Formula I: RT = CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ C0 ₂ CH ₃ ; R ₃ = NH ₂

2.7 g of 2-methylacetate 5- (4-nitrobenzyl) 4-n-propyl thiazole (8.1 mmol) in 50 ml of methanol are hydrogenated at room temperature under 1 atmosphere, in the presence of 3 g of Raney nickel . The reaction mixture is filtered, then concentrated to give 2 g of amino derivative in the form of a brown oil.

Example 26 2- [4- (methylacetate 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid

Formula I: Ri = CH2CH ₂ CH ₃ ; R ₂ = CH ₂ C0 ₂ CH ₃ ;

2 g of 2-methylacetate 5- (4-aminobenzyl) 4-n-propyl thiazole (5.6 mmol) dissolved in 20 mL of acetonitrile are treated with 1.06 g of o-sulfobeπzoic anhydride in solution in 10 mL acetonitrile, at room temperature. The reaction is stirred for one day at this temperature, then concentrated in vacuo. The brown oil obtained is taken up in methanol to give 300 mg of 2- [4- (2-methylacetate 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid, beige powder with melting point 203 ° C. . Example 27 2-ethoxycarbonyl aminothioacetamide

Formula VI: R ₂ ≈ CH ₂ NHC0 ₂ CH ₂ CH ₃

61 ml of triethylamine (0.44 mol) are added to 20 g of aminoacetonitrile hydrochloride

(0.22 mol) dissolved in a mixture (1: 1 v / v) of tetrahydrofuran-chloroform. 21 ml of ethyl chloroformate (0.22 mol) are then added dropwise. The reaction medium is stirred for 8 hours at room temperature, 1 hour at 50 ° C, and filtered. The filtrate is concentrated, the residue washed with water and extracted with chloroform. After drying over magnesium sulfate, filtration and concentration, 27.5 g of ethoxycarbonyl aminoacetonitrile, brown liquid, are obtained.

A stream of H ₂ S is passed through a mixture of 27.5 g of ethoxycarbonyl aminoacetonitrile (210 mmol), pyridine (21 ml, 210 mmol), and triethylamine (14.5 ml, 105 mmol) according to the procedure of the example 23. After 4 hours of stirring at room temperature and washing with water, a beige precipitate is obtained which is drained. This gives 6.6 g of ethoxycarbonyl aminothioacetamide, a beige powder with a melting point of 116 ° C.

Example 28 2-ethoxycarbonyl aminomethyl 5- (4-nitrobenzyl) 4-n-propyl thiazole

Formula VII RT = CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ NHC0 ₂ CH ₂ CH ₃ ; V = N0 ₂

An equimolar mixture (19.6 mmol) of 2-chloro 1- (4-nitrophenyl) hexan 3-one and ethoxycarbonyl aminothioacetamide is heated at 90 ° C for 12 hours. The reaction mixture is taken up in ethyl acetate. The precipitate obtained is drained (4.8 g) which is none other than the 2-ethoxycarbonyl aminomethyl 5- (4-nitrobeπzyl) 4-n-propyl thiazole derivative, with a melting point of 118 ° C.

Example 29 2-ethoxycarbonyl aminomethyl 5- (4-aminobenzyl) 4-n-propyl thiazole

Formula I: R- = CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ NHC0 ₂ CH ₂ CH ₃ ; R ₃ = NH ₂

4.7 g of 2-ethoxycarbonyl aminomethyl 5- (4-nitrobenzyl) 4-n-propyl thiazole (13 mmol) in 100 ml of ethanol are hydrogenated at room temperature under 1 atmosphere, in the presence of 5 g of Raney nickel. The reaction mixture is filtered and then concentrated to give 2 g of 2-ethoxycarbonyl aminomethyl 5- (4-aminobenzyl) 4-propyl thiazole in the form of a beige powder, with a melting point of 126 ° C.

Example 30 2- [4- (2-ethoxycarbonyl aminomethyl 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid:

Formula I: Ri = CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ NHC0 ₂ CH ₂ CH ₃ ;

2.9 g of 2-ethoxycarbonyl aminomethyl 5- (4-aminobenzyl) 4-n-propyl thiazole (8.7 mmol) dissolved in 50 mL of tetrahydrofuran are treated with 1.6 g of o-sulfobenzoic anhydride added in small portions, at room temperature. The reaction is stirred for one day at this temperature, then concentrated in vacuo. The precipitate formed is drained, washed with ethyl acetate and then with ether. The solid obtained is purified by chromatography on silica gel (isopropanol / acetone / triethylamine 9: 1: 0.5) to give an orange oil which is taken up in acidic water. A white precipitate is then obtained which is drained and washed with acetone, which is none other than 2- [4- (2-ethoxycarbonyl aminomethyl 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] acid. benzosulfonic, melting point 189 ° C.

Example 31 2-amino 5- (4-nitrobenzyl) 4-n-propyl thiazole

Formula VII: R- = CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ; V = N0 ₂

An equimolar mixture (19.6 mmol) of 2-chloro 1- (4-nitrophenyl) hexan 3-one and thiourea is heated at 60 ° C for 6 hours. The reaction mixture is taken up in dichloromethane, and the pale yellow precipitate obtained drained. After recrystallization from CH ₃ CN, 4.7 g of 2-amino 5- (4-nitrobenzyl) 4-n-propyl thiazole derivative are obtained, in the form of beige crystals, with a melting point of 156 ° C. Example 32 2-amino 5- (4-aminobenzyl) 4-n-propyl thiazole:

Formula I: Ri = CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ; R ₃ = NH ₂

4.0 g of 2-amino 5- (4-nitrobenzyl) 4-n-propyl thiazole (13 mmol) in 100 ml of ethanol are hydrogenated according to example 25. 1.9 g of 2-amino 5- ( 4-aminobenzyl) 4-n-propyI thiazole, in the form of a brown oil.

Example 33 2- [4- (2-amino 4-n-propyl thiazol 5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid

Formula I: RT = CH ₂ CH ₂ CH ₃ ; R ₂ = NH2

2.0 g of 2-amino 5- (4-aminobenzyl) 4-n-propyl thiazole (8.08 mmol) dissolved in 50 ml of tetrahydrofuran are treated with 1.5 g of o-sulfobenzoic anhydride added in small portions , at room temperature. The reaction is stirred for one day at this temperature, then concentrated in vacuo. The reaction mixture is taken up in a methanol-ethyl acetate mixture. The insoluble material drained is none other than 2- [4- (2- amino 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid, with a melting point of 253 ° C.

Example 34 2-acetamido 5- (4-nitrobenzyl) 4-n-propyl thiazole

Formula VII: R1 = CH ₂ CH ₂ CH ₃ ; R ₂ = NHCOCH ₃ ; V = N0 ₂

2 g (7.2 mmol) of 2-amino 5- (4-π ^' ιtrobenzyl) 4-n-propyl thiazole in 2.5 ml of acetic anhydride, in the presence of 88 mg of 4-dimethylamino pyridine (0, 72 mmol), are heated at 80 ° C for 1 hour. While cooling the reaction mixture, the formation of a precipitate is observed which is filtered off and washed with ether. 1.6 g of 2-acetamido 5- (4-n ^" ιtrobenzyl) 4-n-propyl thiazole derivative, pale yellow solid, with a melting point of 170 ° C. are thus obtained. Example 35 2-acetamido 5- (4-aminobenzyl) 4-n-propyl thiazoie:

Formula I: R- = CH ₂ CH ₂ CH ₃ ; R ₂ = NHCOCH ₃ ; R ₃ = NH ₂

1.6 g of 2-acetamido 5- (4-nitrobenzyl) 4-n-propyl thiazole (5 mmol) are hydrogenated at room temperature according to example 25. The reaction mixture is filtered and then concentrated to give 1.3 g of 2-acetamido 5- (4-aminobenzyl) 4-n-propyl thiazole as a pale yellow solid, melting point 146 ° C.

Example 36 2- [4- (2-acetamido 4-n-propyl thiazol 5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid

Formula I: R, = CH ₂ CH ₂ CH ₃ ; R ₂ = NHCOCH ₃ ;

1, 3 g of 2-acetamido 5- (4-aminobenzyl) 4-n-propyl thiazole (4.5 mmol) dissolved in 50 ml of acetonitrile, are treated with 0.8 g of o-sulfobenzoic anhydride dissolved in 10 mL acetonitrile, at room temperature. The reaction is stirred for one day at this temperature, then concentrated in vacuo. The precipitate formed is drained, washed with ether, then purified by acid-base passage. 1.19 g of 2- [4- (2-acetamido 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid are then obtained in the form of a whitish powder with a melting point of 195 ° C.

Example 37 2-chloro 1- (4-nitrophenyl) octan 3-one

Formula IV: R, = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , V = N0 ₂

2-chloro 1- (4-nitrophenyl) octan 3-oπe is prepared according to the procedure of Example 1. The red oil obtained after concentration of the reaction mixture being purified by chromatography on a silica gel column (chloroform / cyclohexane 7: 3), crystallizes, melting point 118-120 ° C. Example 38 2-methyl 5- (4-nitrobenzyl) 4-n-pentyl thiazole

Formula VII: Rx = CH ₂ CH ₂ CH2CH2CH ₃ ; R ₂ = CH ₃ ; V = NC-2

An equimolar mixture (19.6 mmol) of 2-chtoro 1- (4-neutrophenyl) octan 3-one and thioacetamide is heated at 60 ° C for 24 hours. After cooling to room temperature, the reaction mixture is concentrated and taken up in isopropyl ether to give 1.7 g of 2-methyl 5- (4-nitrobenzyl) 4-n-pentyl thiazole, pale yellow solid with melting point 57 ° C.

Example 39 2-methyl 5- (4-aminobenzyl) 4-n-pentyl thiazole

Formula I: R- = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₃ ; R ₃ = NH ₂

1.7 g of 2-methyl 5- (4-nitrobenzyl) 4-n-pentyl thiazole (5.6 mmol) in 100 ml of ethanol are hydrogenated according to Example 25, and 1.4 g of 2 are obtained. -methyl 5- (4-aminobenzyl) 4-n-pentyl thiazole, in the form of a colorless oil.

Example 40 2- [4- (2-methyl 4-n-pentyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid

Formula I: Rt "CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₃ ;

1.4 g of 2-methyl 5- (4-aminobenzyl) 4-n-pentyI thiazole (5.1 mmol) and 0.9 g of o-sulfobenzoic anhydride are reacted according to the procedure of Example 26 The reaction is stirred for one day at room temperature. After concentrating the reaction mixture, a beige solid is obtained which is triturated in ether. The solid is taken up in water basified with Na ₂ Cθ ₃ . After washing with ether, réacid ^'IFIE the aqueous phase by passing a stream of S0 _2. The product is then extracted with chloroform. After drying and concentration, 1.7 g of 2- [4- (2-methyl 4-pentyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid, of melting point 157-158 ° C, are obtained. a whitish powder. Example 41 2- [4- (2-amino 4-n-propyl thiazol 5-yl methyl) phenyl aminocarbonyl] 3,6-dichloro benzoic acid

Formula I: RT = CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ;

1.9 g of 2-amino 5- (4-aminobenzyl) 4-n-propyl thiazole (7.65 mmol) and 1.7 g of 3,6-dichlorophthalic anhydride are reacted according to the conditions of the Example 26. The reaction is stirred for one day at room temperature. After concentrating the reaction mixture, a beige solid is obtained which is triturated in ether. 2.2 g of 2- [4- (2-amino 4-n-propyl thiazol 5-yl methyl) phenylaminocarbonyl] 3,6- dichloro benzoic acid, of melting point 153 ° C., are obtained in the form of a beige powder.

Example 42 2-amino 5- (4-nitrobenzyl) 4-n-pentyl thiazole

Formula VII: R <ι ≈ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ; V = N0 ₂

An equimolar mixture (18 mmol) of 2-chloro 1 - (4-nitrophenyl) octan 3-one and thiourea is heated at 60 ° C for 6 hours. The reaction mixture is taken up in dichloromethane and filtered. After concentration, the filtrate is washed with basic water and extracted with chloroform. 3 g of 2-amino 5- (4-nitrobenzyl) 4-n-pentyl thiazole are thus obtained, in the form of a brown oil, used as it is subsequently.

Example 43 2-amino 5- (4-aminobenzyl) 4-n-pentyl thiazole

Formula I: Ri = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ; R ₃ = NH ₂

3.0 g of 2-amino 5- (4-nitrobenzyl) 4-n-pentyl thiazole (9.8 mmol) in 100 ml of ethanol are hydrogenated according to example 25, and 3 g of 2-amino are obtained 5- (4- aminobenzyl) 4-n-pentyl thiazole, in the form of a brown oil. Example 44 2- [4- (2-amino 4-n-pentyl thiazol 5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid

Formula I: R. = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = NH ₂ ;

3 g of 2-amino 5- (4-aminobenzyl) 4-n-pentyl thiazole (10 mmol) and 2 g of o-sulfobenzoic anhydride are reacted according to the conditions of Example 26. The reaction is stirred one day at room temperature. After concentrating the reaction mixture, a pinkish solid is obtained which is triturated in ether. 2.1 g of 2- [4- (2-amino 4-n-pentyl thiazol 5-yl methyl) phenylaminocarbonyl] benzosulfonic acid, with a melting point of 266 ° C., are thus obtained in the form of a crystallized powder.

Example 45 2-methoxy methyl 5- (4-nitrobenzyl) 4-n-pentyl thiazole

Formula VU: R- = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ OCH ₃ : V = N0 ₂

A mixture of 5 g of 2-chloro 1- (4-nitrophenyl) octan 3-one (18 mmol) and 2.8 g of methoxy thioacetamide (27 mmol) is heated at 60 ° C for 12 hours. The reaction medium is taken up in dichloromethane and filtered. After concentration, the filtrate is washed with a 2N NaOH solution and extracted with chloroform. After drying over magnesium sulfate and concentration, 4 g of 2-methoxy methyl 5- (4-nitrobenzyl) 4-pentyl thiazole are obtained, in the form of an orange oil.

Example 46 2-methoxy methyl 5- (4-amlnobenzyl) 4-n-pentyl thiazole

Formula I: R- = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ OCH ₃ ; R ₃ = NH ₂

4 g of 2-methoxy methyl 5- (4-nitrobeπzyl) 4-n-pentyl thiazole (0.012 mol) are hydrogenated according to the procedure of Example 25 to give 3.4 g of 2-methoxy methyl 5- (4- aminobenzyl) 4-n-pentyl thiazole as a brown oil. Example 47 2- [4- (2-methoxy methyl 4-n-pentyl thiazol 5-yl) phenyl amino carbonyl] benzosulfonic acid

Formula I: R- = CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ OCH ₃ ;

3.4 g of 2-methoxy methyl 5- (4-aminobenzyl) 4-n-pentyl thiazole (0.01 mol) and 1.9 g of o-sulfo benzoic anhydride are treated according to the conditions of Example 26 After concentration of the reaction medium and trituration in ether, 4.7 g of a brown powder are obtained which is purified by acid-base passage and extraction with ethyl acetate, to obtain 4 g of 2- [4- (2-methoxy methyl 4-n-pentyl thiazole 5-yl) phenyl amino carbonyl] benzosulfonic acid in the form of a light beige powder, with a melting point of 216-217 ° C.

Example 48 methylthio thioacetamide

Formula VI: R ₂ = CH ₂ SCH ₃

H ₂ S is bubble for 6 hours in a mixture of 25 g (0.29 mol) of methylthio acetonitrile, 30 ml (0.37 mol) of pyridine and 20.2 ml (0.145 mol) of triethylamine at 0 ° C. The reaction medium is then poured onto a dilute acid solution, cooled, and extracted with ether. After drying over magnesium sulfate and concentration, a green oil is obtained which crystallizes. The solid is taken up in isopropyl ether. Finally, 22 g of gray green crystals with a melting point of 65 ° C. are obtained.

Example 49 2-methylthiomethyl 5- (4-nitrobenzyl) 4-n-propyl thiazole

Formula VII: R ₂ = CH ₂ SCH ₃ ; R = CH ₂ CH ₂ CH ₃ ; V = N0 ₂

A mixture of 5 g of 2-chloro 1- (4-nitrophenyl) hexan 3-one (0.02 mol) and 2.6 g of methylthio thioacetamide (0.022 mol) is heated at 60 ° C for 24 h. The reaction is followed by TLC (cyclohexane / ethyl acetate 7: 3). The reaction medium is then treated according to the method of Example 45 to give 5.6 g of 2-methylthiomethyl 5- (4-nitrobenzyl) 4-n-propyl thiazole, in the form of an orange oil.

Example 50 2-methylthiomethyl 5- (4-aminobenzyl) 4-n-propyl thiazole

Formula I: RT = CH ₂ CH ₂ CH ₃ ; R ₂ ≈ CH ₂ SCH ₃ ; R ₃ = NH ₂

5.6 g of 2- (methylthiomethyl) 5- (4-nitrobenzyl) 4-n-propyl thiazole (0.017 mol) are hydrogenated according to the procedure of Example 25. A 1: 1 mixture of 2-methyl 5 is obtained - (4-aminobenzyl) 4-n-pr opyl thiazole / 2-methylthiomethyl 5- (4-aminobeπzyl) 4-n-propyl thiazole which is separated by chromatography on silica, (eluent: dichloromethane-ethyl acetate 95 / 5). 1.3 g of 2-methylthiomethyl 5- (4-aminobenzyl) 4-n-propyl thiazole are finally obtained in the form of a brown oil, used as such for the following.

Example 51 2- [4- (2-methylthiomethyl 4-n-propyl thiazol 5-yl methyl) phenyl amino carbonyl] benzosulfonic acid

Formula I: R- ≈ CH ₂ CH ₂ CH ₃ ; R ₂ = CH ₂ SCH ₃ :

1.3 g (3.7 mmol) of 2-methyl thiomethyl 5- (4-amiπo benzyl) 4-n-propyl thiazole and 700 mg of o-sulfobenzoic anhydride are treated according to the procedure of Example 26. The reaction is stirred at room temperature for 6 hours. The reaction medium is then filtered, and the pale yellow solid obtained is rinsed with ether. 1.7 g of 2- [4- (2-methylthiomethyl 4-n-propyl thiazol 5-yl methyl) phenyl amino carbonyl] benzosulfonic acid are thus obtained, with a melting point of 254-256 ° C.

Example 52 2- (2-chloro phenyl) 5- (4-nitrobenzyl) 4-n-propyl thiazole

Formula VII: Rt = CH ₂ CH ₂ CH ₃ ; R ₂ = 2-chtoro phenyl; V = O2

An equimolecular mixture (11.7 mmol) of 2-chloro 1- (4-nitrophenyl) hexan 3-one, prepared in Example 8, and of 2-chloro thiobeπzamide prepared from 2-chloro Benzonitrile by bubbling H ₂ S in the presence of amino triethanol, is heated at 60 ° C for 8 hours, the reaction being followed by TLC. (eluent chloroform). The reaction mixture is then taken up in chloroform and filtered. The filtrate is washed with a saturated aqueous solution of sodium chloride. After drying and concentrating the organic phase, a brown oil is obtained which crystallizes in an ether - petroleum ether mixture. After draining, 2.9 g of 2- (2-chlorophenyl) 5- (4-nitrobenzyl) 4-n-propyl thiazole are obtained, in the form of a yellow powder with a melting point of 77-80 ° C.

Example 53 2- (2-chlorophenyl) 5- (4-amlnobenzyl) 4-n-propyl thiazole

Formula I: RT = CH ₂ CH ₂ CH ₃ ; R ₂ : 2-chlorophenyl; R ₃ = NH ₂

2 g (5.4 mmol) of 2- (2-chlorophenyl) 5- (4-nitrobenzyl) 4-n-propyi thiazole are hydrogenated according to the method of Example 25. 1.8 g of 2- ( 2-chlorophenyl) 5- (4-aminobenzyl) 4-n-propyl thiazole in the form of a brown oil which crystallizes in an ether - petroleum ether mixture in the form of a yellow powder with melting point 75-77 ° C

Example 54 2- [4- [2- (2-chloro phenyl) 4-n-propyl thiazol 5-yl methyl] phenyl amino carbonyl] benzo sulfonic acid

Formula I: t = CH ₂ CH ₂ CH ₃ ; R ₂ = 2-chtorophenyl;

300 mg of 2- (2-chlorophenyl) 5- (4-aminobenzyl) 4-n-propyl thiazole and 200 mg of o-sulfo benzoic anhydride are treated according to the method of Example 26, in an acetonitrile-tetrahydrofuran mixture . The reaction is stirred at room temperature for 6 hours. The reaction mixture is then evaporated to dryness under vacuum. The cream solid obtained is washed with acetonitrile then with ether and dried. 400 mg of 2- [4- [2- (2-chlorophenyl) 4-n-propyl thiazol 5-yl methyl] phenyl amino carbonyl] benzo sulfonic acid are obtained in the form of a beige powder with melting point 143- 145 ° C Example 554-n-propvl 5 - [(4-amino phenyl) methyl] thiazole

Formula IR, = (CH ^ CH. R_≈HR ₃ = NH ₂

5 g of chloroketone synthesized in Example 8 and 33.5 g (12.5 eq.) Of ethyl thiooxamate are heated for 48 hours at 60 ° C., then taken up in dichloromethane. After filtration, the solution is washed with water, with a 10% solution of sodium carbonate, then with brine, dried over magnesium sulfate and concentrated. 6.7 g is obtained of [4-n-propyl 5 - [(4-n ^'ιtro phenyl) methyl] thiazol-2-yl carboxylate as a red oil which are hydrogenated as such in ethanol 150ml at pressure and ambient temperature in the presence of raney nickel. After filtration of the catalyst, the ethanolic solution is heated for 4 hours at reflux and then evaporated. The residue is chromatographed on silica gel (eluent dichloromethane-ethyl acetate 9/1). 0.22 g of 4-n-propyl 5 - [(4-amino phenyl) methyl] thiazole is thus obtained.

Preparation of ethyl thiooxamate:

20 g of ethyl oxamate are dissolved in 150 ml of toluene and heated for 2 hours under reflux in the presence of 11.1 g (0.3 eq.) Of P ₂ Ss. After evaporation of the solvent and filtration on celite, 11 are obtained, 5g of ethyl thiooxamate in the form of a red oil which crystallizes.

Example 56 2- [4- (4-n-propyl thiazoI-5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid

IR formula, =

213 mg of 4-n-propyl 5 - [(4-amino phenyl) methyl] thiazole obtained in the previous example are dissolved in 10 ml of acetonitrile and treated with 200 mg (1, 2 eq.) Of orthosulfo benzoic anhydride. The medium is stirred for 6 h at room temperature, then the precipitate formed is drained and washed with ether. 330 mg of 2- [4- (4-n-propyl thiazol - 5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid are thus obtained in the form of a beige solid with a melting point of F = 262-263 ° C.

Example 572-dimethylamino 4-n-propyl 5 - [(4-amino phenyl) methyl] thiazole Formula IR, = (CH - .. CH _. R ₂ = N (CH _{3. 2} R ₃ = NH ₂

3 g of chloroketone synthesized in Example 8 and 1.2 g (1 eq.) Of N, N-dimethyl thiourea are heated 3 to 60 ° C., then taken up in dichloromethane. After filtration, the solution is washed with water, with a 10% solution of sodium carbonate, then with brine, dried over magnesium sulfate and concentrated. 3.5 g of 2-dimethylamino 4-n-propyl 5- [(4-nitro phenyl) methyl] thiazole are obtained in the form of an orange oil which is hydrogenated in 50 ml of ethanol at pressure and ambient temperature in the presence of nickel of raney. After filtration of the catalyst, the ethanolic solution is evaporated. 3.3 g of 2-dimethyl amino 4-n-propyl 5 - [(4-amino phenyl) methyl] thiazole are thus obtained in the form of an oil used as such for the following.

Example 58 2- [4 - [(2-dimethylamino 4-n-propyl thiazol-5-yl) methyl] phenyl aminocarbonyl] benzosulfonic acid

Formula IR, = (CH ₂ ) ₂ CH ₃

1g of 2-dimethylamino 4-n-propyl 5 - [(4-amino phenyl) methyl] thiazole are dissolved in 30ml of acetonitrile and treated with 0.735g (1.1 eq.) Of orthosulfo benzoic anhydride. The medium is stirred for 6 h at room temperature, then the precipitate formed is drained and washed with ether. 0.5 g of 2- [4- (2-dimethylamino 4-n-propyl thiazol-5-yl methyl) phenyl aminocarbonyl] benzosulfonic acid is thus obtained in the form of a pink solid with a melting point F = 176-177 ° C

Example 59 Ethyl 4- (2-chloro 3-oxo hexyl) benzoate

Formula IV R, = (CH ₂ ) ₂ CH ₃ V = COOC ₂ H ₅

According to the procedure of Example 8, 24 g of ethyl 4-amino benzoate gave 38.3 g of ethyl 4- (2-chloro 3-oxo hexyl) benzoate in the form of an oil used as it is. the next step. Example 604- | Y2-methvl 4-n-propyl thiazol-5-yl) methyl] ethyl benzoate

Formula I R.≈ .CHJ-CH. R ₂ = CH ₃ R ₃ ≈ COOC ₂ H _s

According to the procedure of Example 9, starting from 5 g of 4- (2-chloro 3-oxo hexyl) benzoate obtained in the previous example, 5.4 g of 4 - [(2-methyl 4 -n- propyl thiazol-5-yI) methyl] ethyl benzoate which is crystallized from a mixture of ethyl ether-tetrahydrofuran

Example 61 4 - [(2-methyl 4-n-propyl thiazol-5-yl) methyl] benzoic acid

Formula IR, = (CH-) ₂ CH ₃ R ₂ = CH ₃ R ₃ = COOH

2 g of 4 - [(2-methyl 4-n-propyl thiazol-5-yl) methyl] ethyl benzoate synthesized in the previous example are dissolved in 20 ml of ethanol. After adding 6.6 ml of a 2N sodium hydroxide solution, the medium is heated to reflux for 10 h then concentrated and diluted with 10 ml of water. The aqueous solution is extracted with ether then acidified to pH 3 with a concentrated hydrochloric acid solution and extracted again with ether. After drying and concentrating the organic acid phase, 1.2 g of 4 - [(2-methyl 4-n-propyl thiazoI-5-yl) methyl] benzoic acid are obtained in the form of a yellow melting point solid F = 102 ° C

Example 62 4 '- (2-chloro 3-oxo hexyl) biphenyl-2-yl carboxylic acid HOOC

Formula IV R, = (CH ^ CH, V = -

According to the procedure of Example 8, 7g of 4'-amino biphenyl-2-yI carboxylic acid gave, after purification on a silica column (eluent, ethyl ether), 2.6g of 4'- (2-chloro acid 3-oxo hexyl) biphenyl-2-yl carboxylic acid in the form of a yellow oil.

Preparation of 4'-amino biphenyl-2-yl carboxylic acid

9.7 g of 4-nitro biphenyl-2-yl carboxylic acid synthesized according to the reference DANNLEY and STERNFELD, J. Am. Chem. Soc. 1954.22, 4543, are dissolved in 500ml of a mixture methanol-tetrahydrofuran 50-50 and hydrogenated at pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration 7 g of 4'-amino biphenyl-2-yl carboxylic acid are obtained in the form of a beige solid with a melting point of F = 206 ° C.

Example 63 4 '- [(2-methyl 4-n-propyl thiazol-5-yl) methyl] biphenyl -2-yl carboxylic acid

HOOC IR formula, = (CH ₂ ) ₂ CH ₃ R ₃ = - C> R ₂ = CH ₃

According to the procedure of Example 9, from 2.1 g of 4 '- (2-chloro 3-oxo hexyl) biphenyl-2-yl carboxylic acid obtained in the previous example, 0.4 g of 4 '- [(2- methyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid in the form of a beige solid with melting point F point 171-172 ° C

Example 64 4 '- [(2-methoxymethyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid

HOOC IR formula, = (CH ₂ ) ₂ CH ₃ R ₂ = CH ₂ OCH ₃ R ₃ = - y

According to the procedure of Example 17, starting with 5 g of 4 '- (2-chloro 3-oxo hexyl) biphenyl-2-yl carboxylic acid synthesized in Example 62 and after purification on a silica column (eluent ether-petroleum ether-acetic acid 80/20/2) 2.2 g of 4 '- [(2-methoxymethyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid are obtained under form of a beige solid with melting point F = 123.5-124.5 ° C

Example 65 4 'acid - [(2-methoxymethyl 4-n-propyl thiazol-5-yl) methyl] blphenyl-2-yl carboxylic potassium salt HOOC IR formula, = (CH-) ₂ CH ₃ R ₂ = CH ₂ OCH ₃ R ₃ = - ^~ y

537 mg of 4 'acid - [(2-methoxymethyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic synthesized in the previous example are dissolved in 200 ml of methanol and treated with a solution of 94 mg 85% potash (1 eq.) in 100ml of methanol. The precipitate is filtered and washed with methanol to give 0.5 g of potassium salt of 4'- [(2-methoxymethyl 4-n-propyl thiazoI-5-yl) methyl] biphenyl-4-yl carboxylic acid. melting point F = 269-270 ° C

Example 66 4 '- [(2-methylthiomethyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid

Formula IR, = (CH-) ₂ CH ₃

According to the procedure of Example 49, from 5 g of chloroketone synthesized in Example 62, 0.35 g of 4 '- [(2-methylthiomethyl 4-n-propyl thiazol-5-yl) methyl acid is obtained. ] biphenyl-2-yl carboxylic acid in the form of a beige solid with melting point F = 125-126 ° C

Example 67 4 '- (2-chloro 3-oxo octyl) biphenyl-2-yl carboxylic acid

Formula IV

According to the procedure of Example 37, 5.3 g of 4'-amino biphenyl-2-yl carboxylic acid synthesized according to Example 62 gave 5.5 g of 4 '- (2-chloro 3-oxo acid octyl) biphenyl-2-yI carboxylic in the form of an oil used as it is for the following.

EXAMPLE 68 4 '- [(2-methylthiometr yl 4-n-pentyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid HOOC IR formula, = (CH ₂ ) ₄ CH ₃ R ₂ = CH ₂ SCH ₃ R ₃ = - ζ%

According to the procedure of Example 49, starting from 5.5 g of 4 '- (2-chloro 3-oxo octyl) biphenyl-2-yl carboxylic acid synthesized in the previous example, 0.5 g of 4 '- [(2-methylthiomethyl 4-n-pentyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic acid in the form of a beige solid with melting point F = 82 ° C.

Example 69 t-butyl 3-oxo heptanoate

Formula II 'R, = (CH ₂ ) ₃ CH ₃

108.6 g of 2,2-dimethyl 1,3-dioxane 4,6-dione (0.75 mole) are dissolved in 300 ml of dichloromethane and 121 ml (2 eq.) Of pyridine and the solution is cooled to 0 ° vs. 100 g of valeryl chloride (0.83 mole, 1.1 eq.) Are then added dropwise at 0 ° C

The suspension obtained is stirred, allowing the temperature to rise to ambient and then left to stand overnight.

The reaction mixture is treated with a solution of 30 ml of concentrated hydrochloric acid in 500 ml of ice water, decanted, washed with the same solution, then with ice water. The solution obtained is dried and then concentrated at 30 ° C

The residue is taken up in 350 ml of toluene, 212 ml (3 eq.) Of terbutanol are added and the brown solution obtained is brought to reflux. A release of C0 _{2 is} then observed. The reflux is maintained until the end of gas evolution. After concentration, the residue is distilled under vacuum, 107.7 g of t-butyl 3-oxo heptanoate are thus obtained in the form of a colorless boiling point oil.

Eb ₀ .5 bar = 74-76 ^β C.

Example 70 t-butyl 3-oxo octanoate

Formula II "R, = (CH ₂ ) ₄ CH ₃

According to the preceding procedure, t-butyl 3-oxo octanoate is synthesized in the form of a colorless oil with boiling point Ebo, o ₃ mbar = 68 ° C. Example 71 t-butyl 3-oxo nonanoate

Formula II 'R, = (CH_) _S CH ₃

According to the procedure of Example 69, t-butyl 3-oxo nonanoate is synthesized in the form of a colorless oil with boiling point Ebo, i8mbar = 82-88 ° C

Example 72 t-butyl 3-oxo decanoate

Formula II 'R, = (CH ₂ ) ₆ CH ₃

According to the procedure of Example 69, t-butyl 3-oxo decanoate is synthesized in the form of a colorless oil with a boiling point Ebo.osm _b ar≈ 110 ° C

Example 733-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl heptanoate

Formula III 'R, = (CH ₂ ) ₃ CH ₃ V =

To 3.0 g (1.25 eq.) Of t-butyl 3-oxo heptanoate dissolved in 30 ml of tetrahydrofuran are added 4.15 ml (2 eq.) Of diisopropylethylamine. The solution is cooled to a temperature below 10 ° C. and 1.04 g (1 eq.) Of lithium bromide are added. An exothermic effect and the formation of a white precipitate are observed. The medium is stirred 0.75 h at the same temperature, then after rapid addition of 3.2 g (1 eq.) Of 4'-bromomethyl biphenyl-2-yl carbonitrile, the temperature is allowed to rise to room temperature and then brought to 24 hour reflux. The medium is concentrated, taken up in water, extracted with dichloromethane. After drying and evaporation the residue is purified by chromatography on a Si0 ₂ column (eluent petroleum ether-ethyl ether 9/1) to give 3.7 g of 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl heptanoate in the form of a pale yellow oil. Preparation of 4-bromomethyl-2-cyano-biphenyl:

A) 4-methyl-2-cyano-biphenyl:

18.5 g of (methyl-4 'biphenyl-yl-2) carboxylic acid prepared according to MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc, 1975, 22, 7383, are heated to reflux in 60 ml of thionyl chloride for two hours. The thionyl chloride is concentrated under vacuum and the residue is poured onto a 28% solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are drained and washed with ether then dried to give 14 , 5 g of (methyl-4 'biphenyl-yl-2) carboxamide in the form of crystals with a melting point of 128 ° C. These crystals are taken up in 50 ml of thionyl chloride and the mixture is heated for 3 hours at reflux then concentrated in vacuo to give 9 g of methyl-4 '2-cyano-biphenyl in the form of crystals of melting point 45-46 ° C.

B) 4-bromomethyl-2-cyano-biphenyl:

7.9 g of 4 'methyl-2-cyano-biphenyl prepared in A) are dissolved in 100 ml of carbon tetrachloride in the presence of 7.3 g of N-bromo succinimide and 0.3 g of benzoyl peroxide. The mixture is heated at reflux for 6 hours and the crystals are filtered, the remaining solution is concentrated in vacuo and the residue is crystallized from ether to give 6.6 g of 4-bromomethyl-2-cyano-biphenyl in the form of crystals of melting point 115-118 ° C.

Example 74 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl octanoate

NC Formula III 'R, = (CH ₂ ) ₄ CH ₃ v = - c'%

According to the preceding procedure, 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl octanoate is synthesized in the form of a weakly colored oil.

Example 75 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl nonanoate

NC

Formula III 'R, = (CH ₂ ) ₅ CH ₃ v = - c' S Seton the procedure of Example 73, synthesize 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl nonanoate in the form of a weakly colored oil

Example 76 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl decanoate

NC Formula 111 'R, = (CH ₂ ) ₆ CH ₃ v = - fi y

According to the procedure of Example 73, 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl decanoate is synthesized in the form of a weakly colored oil.

Example 774 '- (2-chloro 3-oxo heptyi) biphenyl-2-yl carbonitrile

Formula IV R, = (CH ₂ ) ₃ CH ₃ V =

3.7 g of 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl heptanoate obtained in the previous step are dissolved in 40 ml of dichloromethane. 0.85 ml (1.1 eq.) Of sulfuryl chloride are then poured dropwise at room temperature. An acid release is observed. The medium is stirred for 2 h then the solvent is evaporated and replaced with 50 ml of toluene. After adding a spatula tip of p-toluene sulfonic acid, the solution is brought to reflux for 2 hours, then cooled, washed with water, dried over magnesium sulfate and concentrated. 2.9 g of 4 '- (2-chloro 3-oxo heptyi) biphenyl-2-yl carbonitrile are thus obtained in the form of a pale yellow oil.

Example 784 '- (2-chloro 3-oxo octyl) biphenyl-2-yl carbonitrile

NC

Formula IV R, = (CH ₂ ) ₄ CH ₃ v = - fi \ \ ___ y

According to the preceding procedure, starting from 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl octanoate, the 4 '- (2-chloro 3-oxo octyl) biphenyl-2 is synthesized -yl carbonitrile in the form of a weakly colored oil Example 79 4 '2-chloro 3-oxo nonyl) biphenyl-2-yl carbonitrile

Formula IV

According to the procedure of Example 77, starting from 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl nonanoate, the 4 '- (2-chloro 3-oxo nonyl is synthesized ) biphenyl-2-yl carbonitrile in the form of a weakly colored oil.

Example 80 4 '- (2-chloro 3-oxo decyl) biphenyl-2-yl carbonitrile

NC

Formula IV R, = (CH ₂ ) ₆ CH ₃ v = - fi

According to the procedure of Example 77, starting from 3-oxo 2 - [(2'-cyano biphenyl-4-yl) methyl] t-butyl decanoate, the 4 '- (2-chloro 3-oxo decyl) is synthesized ) biphenyl-2-yl carbonitrile in the form of a weakly colored oil.

Example ^p 81 4'-ff2-methyl 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile

Formula I

According to the procedure of Example 9, starting from 4 '- (2-chloro 3-oxo heptyi) biphenyl-2-yl carbonitrile, the 4' - [(2-methyl 4-n-butyl thiazol-5-) is synthesized yl) methyl] biphenyl-2-yl carbonitrile in the form of a weakly colored oil.

Example 824'-r (2-methvl 4-n-pentyl thiazol-5-yl) methyl] blphenyl-2-yl carbonitrile

NC

Formula IR, = (CH ₂ ) ₄ CH ₃ R ₂ = CH ₃ R ₃ = - P y

According to the procedure of Example 9, starting from 4 '- (2-chloro 3-oxo octyl) biphenyl-2-yl carbonitrile, the 4' - [(2-methyl 4-n-pentyl thiazol-5-) is synthesized yl) methyl] biphenyl-2-yl carbonitrile in the form of a weakly colored oil. Example 834'- | ï2-rτtéthvl 4-n-hexyI thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile

NC IR formula, = (CH ^ CH, R ₂ = CH ₃ R ₃ = - fi

Set the procedure of Example 9 from 4 '- (2-chloro 3-oxo nonyl) biphenyl-2-yI carbonitrile the 4' - [(2-methyl 4-n-hexyl thiazol-5-) is synthesized yl) methyl] biphenyl-2-yl carbonitrile in the form of a weakly colored oil.

Example 844'-f .2-methyl 4-n-heptyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile

Formula I

According to the procedure of Example 9, starting from 4 '- (2-chloro 3-oxo decyl) biphenyl-2-yl carbonitrile, the 4' - [(2-methyl 4-n-heptyl thiazol-5-) is synthesized yl) methyl] biphenyl-2-yl carbonitrile in the form of a weakly colored oil.

Example 85 2-methyl 4-n-butyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

Formula I

4.4 g of 4 '- [(2-methyl 4-n-butyl thiazoI-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized in Example 81 are placed in solution in 50 ml of toluene with 2, 6 g (1.1 eq.) Of trimethyl tin azide and brought to reflux for 40 h. The solvent is evaporated and the residue chromatographed on Si0 ₂ (eluent dichloromethane-acetone 95/5 then ethyl acetate). After evaporation of the solvent the product is taken up in ether, filtered and washed. 0.7 g of 2-methyl 4-n-butyl 5 - [(2 '- (1-H-tetrazol-5-yI) biphenyl-4-yl) methyl] thiazole is thus obtained in the form of a white solid melting point F = 145 ° C Example 86 2-Methyl 4-n-pentyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

Formula I

According to the procedure of the previous example, 4.5 g 4 '- [(2-methyl 4-n-pentyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized in Example 82 are obtained. , 1.0g of 2-methyl 4-n-pentyl 5 - [(2 '- (1 -H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole as a white point solid melting F = 128 ° C

Example 87 2-methvl 4-n-hexyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

Formula I

According to the procedure of Example 85, 3.5 g of 4 ′ - [(2-methyl 4-n-hexyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized in example are obtained. 83, 0.8g of 2-methyl 4-n-hexyl 5 - [(2 '- (1-H-tetrazoi-5-yl) biphenyl-4-yl) methyl] thiazole as a white point solid melting point F = 148 ° C

Example ^p 88 2-methyl 4-n-heptyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

Formula IR, = (CH ₂ ) ₆ CH ₃

According to the procedure of Example 85, 3.4 g of 4 '- [(2-methyl 4-n-heptyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized in Example 84 are obtained. , 0.5g of 2- methyl 4-n-heptyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole in the form of a white point solid melting F = 117 ° C Example 89 3-oxo 2 - [(4-nitro phenyl) methyl] t-butyl heptanoate

Formula III 'R, - (CH ₂ ) ₃ CH ₃ V = N0 ₂

A mixture of 18.9 g of t-butyl 3-oxo heptanoate synthesized in Example 69 and 13.6 g of 4-nitro benzyl bromide dissolved in 60 ml of dichloromethane are treated with 8.7 g of potassium carbonate and 0, 9g of cesium carbonate then the medium is brought to reflux for 30 hours. The insoluble material is removed, the solvent evaporated and the residue purified on a silica column (eluent pentane-ether 8/2). 16.3 g of 3-oxo 2 - [(4-nitro phenyl) methyl] t-butyl heptanoate are obtained in the form of a yellow oil.

Example 90 2-chloro i- (4-nitro phenyl) heptan-3-one

Formula IV R, = (CH-) ₃ CH ₃ V≈ N0 ₂

6.7 g of 3-oxo 2 - [(4-nitro phenyl) methyl] t-butyl heptanoate obtained in the previous step are dissolved in 60 ml of dichloromethane. 1.62 ml (1.1 eq.) Of sulfuryl chloride are then poured dropwise at room temperature. An acid release is observed. The medium is stirred for 2 h then the solvent is evaporated and replaced with 65 ml of toluene. “After adding a spatula tip of p-toluene sulfonic acid, the solution is brought to reflux for 2 hours, then cooled, washed with water, dried over magnesium sulfate and concentrated. 5.5 g of 2-chloro 1 - (4-nitro phenyl) heptan-3-one are thus obtained in the form of a pale yellow oil.

Example 91 4-n-butyl 2-methyl 5 - [(4-nitro phenyl) methyl] thiazole

Formula VII R, = (CH-) ₃ CH ₃ R ₂ = CH ₃ V = N0 ₂

According to the procedure of Example 2, starting from 5.5 g of 2-chloro 1- (4-nitro phenyl) heptaπ-3-one, 2.4 g of 4-n-butyl 5 - [(4 -nitro phenyl) methyl] thiazole in the form of an oil used as it is in the next step.

Example 924-n-butyl 2-methyl 5 - [(4-amino phenyl) methyl] thiazole

Formula IR, = (CH ₂ ) ₃ CH ₃ R ₂ = CH ₃ R.≈ NH- According to the procedure of Example 3, starting from 2.4 g of 4-n-butyl 5- [4-nitro phenyl) methyl] thiazole, 0.9 g of 4-n-butyl 5 - [(4 -amino phenyl) methyl] thiazole in the form of a yellow oil used as it is in the next step.

Example 93 2- [4 - [(4-n-butyl 2-methyl thiazol-5-yl) methyl] phenyl aminocarbonyl] benzosulfonic acid

Formula IR, = (CH ₂ ) ₃ CH ₃

According to the procedure of Example 11, from 0.9 g of 4-n-butyl 5 - [(4-amino phenyl) methyl] thiazole, 0.95 g of 2- [4 - [( 4-n-butyl 2-methyl thiazol-5-yl) methyl] phenyl aminocarbonyl] benzosulfonic acid in the form of a white solid with a melting point of F = 262 ° C.

Example 94 4 '- [(2-methyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile,. „„. ” .. ^>

6.5 g of 4 ′ acid - [(2-methyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carboxylic synthesized according to Example 63, are treated with 13 ml of thionyl chloride, then the mixture is heated for 2 hours at reflux. The excess thionyl chloride is evaporated and the residue, taken up in 20 ml of toluene, poured at room temperature onto 20 ml of a concentrated aqueous ammonia solution. The medium is stirred for 2 h and then extracted with ether. The organic phase is dried and then concentrated. 7 ml of thionyl chloride are then poured dropwise onto the residue at 0 ° C., then the solution obtained is heated to reflux for 2 hours. The excess of thionyl chloride is evaporated, the medium taken up in water and extracted with chloroform. After washing to neutrality and drying, the solvent is evaporated to give, after purification on a silica column (eluent chloroform), 1.5 g of 4 '- [(2-methyl 4-n-propyi thiazol-5-yl) methyl] biphenyl- 2-yl carbonitrile as an oil. Example 952-methyl 4-n-propyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

N '' NH

Formula IR, = (CH-) ₂ CH ₃ R ₂ = CH ₃

According to the procedure of Example 85, one obtains from 1.5 g of 4 ′ - [(2-methyl 4-n-propyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized with previous example 60mg of 2-methyl 4-n-propyl 5 - [(2 '- (1 -H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole as a white solid with a melting point F≈ 83-85 ° C

Example 964 - 12-methvlthiométhvl 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile NC

Formula IR, - (CH ₂ ) ₃ CH ₃ R ₂ = CH ₂ SCH ₃ R ₃ = - fi

According to the procedure of Example 49, starting from 4 '- (2-chloro 3-oxo heptyi) biphenyl-2-yl carbonitrile, the 4' - [(2-methyl 4-n-butyl thiazol-5-) is synthesized yl) methyl] biphenyl-2-yl carbonitrile in the form of a brown oil used as such for the following.

Example 97 2-methylthiomethvl 4-n-butyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

Formula IR, = (CH ₂ ) ₃ CH ₃

According to the procedure of Example 85, 2.5 g of 4 '- [(2-methylthio methyl 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized with Example 96, 0.5 g of 2-methylthiomethyl 4-n-butyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole in the form of a white solid of melting point F = 75 ° C Example 984'-r (2-amino 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile

Formula IR, = (CH ₂ ) ₃ CH ₃

An equimolecular mixture of 5 g of 4 '- (2-chloro 3-oxo heptyi) biphenyl-2-yl carbonitrile and 1.12 g of thiourea is heated for 2 hours at reflux in 20 ml of ethanol. After returning to ambient temperature, the solid obtained is drained and recrystallized from ethanol to give 2.75 g of 4 '- [(2-amino 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile as a solid with melting point F = 207 ° C

Example 99 2-amino 4-n-butyl 5 - [(2 '- (1-H-tetrazol-5-yl) blphenyl-4-yl) methyl] thiazole

Formula IR, = (CH ₂ ) ₃ CH ₃

According to the procedure of Example 85, 2.5 g 4 '- [(2-amino 4-n-butyl thiazol-5-yl) methyl] biphenyl-2-yl carbonitrile synthesized in Example 98 are obtained. , 0.2g of 2-amino 4- n-butyl 5 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole in the form of a white solid with melting point F = 147.5 ° C.

PHARMACOLOGY

I. Principle

The affinity of the products of the examples for the angiotensin 11 receptors is evaluated by technique of displacement of a radioligand specifically fixed on the adrenal receptors of angiotensin II, in the rat.

H. Procedure

An aliquot of a homogenate of adrenal rats incubated in the presence of a single concentration of [ ¹²⁵ l] - SIAII (Sar, Tyr ⁴ , Ile ⁸ - angiotensin II), angiotensin II receptor antagonist, and two concentrations of competing agents (10- ⁵ M, 10- ⁷ M) for 60 min at 25 ° C.

The reaction is completed by adding buffer, then rapid filtration through sandpaper filters. Nonspecific binding is determined in the presence of angiotensin II.

III. Expression of results

The results are expressed, for the concentrations tested, as a percentage of displacement of the radioligand specifically fixed on the adrenal angiotensin II receptors. IV. Results

TOXICOLOGY

The products of the examples described exhibit, after oral administration, excellent tolerance.

Their lethal dose 50 in rats has been estimated to be greater than 300 mg / kg.

CONCLUSION

The products of the examples described have a good affinity for the angiotensin IA receptors. As such, they can be used with benefit in the various pathologies where angiotensin II is involved, in particular in the treatment of hypertension, heart failure, diseases of the arterial wall, at dosages of 1 to 400 mg orally and 0.01 to 50 mg intravenously, in one or more doses per day.

Claims

1. Thiazole derivatives characterized in that they correspond to the general formula

in which :

R 1 represents a lower alkyl radical of 1 to 7 carbon atoms or a C ₃ -C ₇ cycloalkyl radical,

R2 represents the hydrogen atom, a halogen atom, a lower alkyl radical of 1 to 7 carbon atoms, a lower haloalkyl radical of 1 to 7 carbon atoms, a C ₃ -C ₇ cyctoalkyl radical, a nucleus aromatic; R ₂ can also represent a group X- (CH ₂ ) _n -CN, X-fCH ^ n-COOR,}, X- (CH ₂ ) _n -OR ₄ , X- (CH ₂ ) n-SR ₄ , X - (CH2) _n -NR'R ". X- (CH ₂ ) _n -CONR'R" or X- (CH ₂ ) _n -NH-COR ₅ ; in these groups, X represents a bond, a sulfur atom or an NH group, n is an integer from 0 to 5, R ₄ represents a hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms, a halo lower alkyl radical of 1 to 7 carbon atoms, a C ₃ -C7 cycloalkyl radical, R5 has the same meaning as R ₄ but can also be an aromatic ring, or an OR4 group in which R ₄ has the same meaning as 'indicated above, R' and R "independently represent a hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms or a C ₃ -C7 cyctoalkyl radical can form together with the nitrogen atom to which they are attached a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, the latter being able to be substituted on the second nitrogen atom by a lower alkyl of 1 to 7 carbon atoms or an aromatic ring.

R3 represents a nitro, amino group or one of the following groups:

in which R ₇ represents a hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms or also a benzyl radical, Y and Z independently represent a hydrogen atom, a halogen atom, a lower alkyl radical of 1 to 7 carbon atoms, an O-lower alkyl radical or a trifluoromethyl; as well as their addition salts, in particular the pharmaceutically acceptable addition salts.

2. Derivatives of formula (I) according to claim 1, characterized in that: Rt represents a lower alkyl radical of 1 to 7 carbon atoms,

R2 represents the hydrogen atom, a lower alkyl radical of 1 to 7 carbon atoms, an aromatic ring; R2 can also represent a group X- (CH ₂ ) _n -COOR ₄ , X- (CH2) _n -OR ₄ , X- (CH ₂ ) _n -SR ₄ , X- (CH2) _n NR'R ", X - (CH ₂ ) _n -NHCOR ₅ : in these groups X represents a bond, a sulfur atom or an NH group, n is an integer from 0 to 5, R ', R ", R ₄ and R5 represent an atom of hydrogen, a lower alkyl radical of 1 to 7 carbon atoms, R5 can also represent an OR ₄ group.

R ₃ represents a nitro, amino, acid, 2-sulfoxy benzoyl amino, 2-carboxy benzoyl amino, 2-carboxy 3,6-dichlorobenzoyl amino, 2- (1-H-tetrazol-5-yl) phenyl group.

3. Derivatives according to claim 1 or 2, characterized in that Ri is an n-propyl group.

4. Derivatives according to any one of claims 1, 2 or 3 characterized in that R2 is a methyl group or a methoxy methylene group.

5. Derivatives according to any one of claims 1 to 4 characterized in that R ₃ is a 2-sulfoxy benzoyl amino group or a 2- (tetrazoI-yl-5) phenyl group.

6. Derivatives according to any one of claims 1 to 5, characterized in that they are chosen from derivatives: - 2- [4- (2-methyl 4-n-propyl thiazol-5-yl-methyl) phenyl amino carbonyl] benzo sulfonic acid

- 2- [4- (2-methoxy methyl 4-n-propyl thiazol-5-yl-methyl) phenyl amino carbonyl] benzo sulfonic acid

- 2-methyl 4-n-propyl 5 - [(2 '- (1-H-tetrazol-5-yl) biphenyl-4-yl) methyl] thiazole

7. Process for the preparation of derivatives of formula (I) according to any one of claims 1 to 6, characterized in that it comprises the action of a derivative of formula R _j - C - NH ₂ , in which R ₂ is defined as above on a derivative of formula

in which Ri is defined as above, A is an optimally chlorine or bromine halogen atom and V represents a nitro group, COOR7, a group

R ₇ being defined as above,

by heating to a temperature between 20 and 90 ° C without solvent or in an alcohol.

8. Synthetic intermediates for the preparation of derivatives of formula (I) according to any one of claims 1 to 6, characterized in that they correspond to formula (VII)

where Ri, R2 and V are defined as above.

9. Synthetic intermediates useful for the preparation of derivatives of formula (I) and corresponding to the formula of halo ketones:

in which Ri is defined as above and prepared by chlorination or bromination using chlorine, bromine or sulfuryl chloride of keto ester of formula

to give the derivatives of formula

which are then hydrolyzed and decarboxyied by heating in a solvent such as for example toluene in the presence of an acid such as for example para toluene sulfonic acid.

10. Pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 6, or one of its pharmaceutically acceptable addition salts, in combination with an excipient, vehicle or pharmaceutical carrier acceptable.

11. Pharmaceutical composition with angiotensin II receptor antagonist activity, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 6, or the one of its pharmaceutically acceptable addition salts, in combination with a pharmaceutically acceptable excipient, vehicle or support.

12. A method of preparing a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 6 is incorporated, or a salt thereof. pharmaceutically acceptable addition, in a pharmaceutically acceptable excipient, vehicle or carrier.

13. Method according to claim 12, characterized in that the pharmaceutical composition is formulated in the form of capsules, tablets dosed from 1 to 400 mg or in the form of injectable preparations dosed from 0.01 to 50 mg.