SK286911B6 - 2-(iminomethyl)amino-phenyl derivatives, method of their preparation, pharmaceutical preparation containing them and their application - Google Patents

Abstract

2-(iminomethyl)amino-phenyl derivatives of the general formula (I), whose substituents are defined in patent claims, method of their preparation, pharmaceutical preparation containing them and their application as medicines for inhibition of NO synthase as well as for inhibition of peroxidation of lipids. The invention further relates to intermediates of the general formulas (II), (III), (V), (VI) for production of compounds of the general formula (I).

Description

SK 286911Β6

Technical field

The present invention relates to 2- (iminomethyl) aminophenyl derivatives having inhibitory activity for NO-synthase enzymes producing NO nitric oxide and / or reactive oxygen species (ROS) trapping activity. The invention relates to derivatives which correspond to the defined general formula (I), processes for their preparation, pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and as selective or non-selective scavengers of reactive oxygen species.

BACKGROUND OF THE INVENTION

In view of the potential role of NO and ROS substances in physiopathology, the novel derivatives described which correspond to the general formula (I) described may have beneficial or beneficial effects in the treatment of pathologies in which these chemicals are involved. specifically:

Cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, arterial high pressure, septic shock, ischemic or haemorrhagic heart or brain infarction, ischemia and thrombosis;

Disorders of the central or peripheral nervous system, such as neurodegenerative diseases, in which cerebral infarctions, subarachnoid haemorrhages, aging, senile dementias including Alzheimer's disease, Huntington's disease, Parkinson's disease, Kreutzfeld-Jakob's disease and prion disease but amyotrophic disease may be mentioned pain, cerebral and bone marrow injuries, opioid addiction, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathy, encephalopathy of viral or toxic origin;

Skeletal muscle and neuromuscular connective tissue disorders (myopathy, myosis) as well as cutaneous diseases;

• proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, respiratory insufficiency, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibrosis, amyloidosis, inflammations of the gastrointestinal system (colitis, Crohn's disease) and pulmonary respiratory tract , sinusitis, rhinitis);

• organ transplants;

Autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis;

• cancer;

• neurological diseases associated with intoxications (cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatment (radiotherapy) or disorders of genetic origin (Wilson's disease);

• all pathological conditions characterized by excessive or dysfunctional NO and / or ROS substances.

In all these pathological conditions, there is experimental evidence demonstrating the inclusion of NO or ROS substances (J. Med. Chem. (1995) 38,4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).

Furthermore, the present inventors have already described NO synthase inhibitors and their use in previous patents (US Patent 5,081,148; US Patent 5,360,925 and later described the association of these inhibitors with products having antioxidant or antiradical properties (unpublished patent application).

SUMMARY OF THE INVENTION

The present invention provides 2- (iminomethyl) aminophenyl derivatives, a process for their preparation and their therapeutic use.

The compounds according to the invention correspond to the general formula (I)

B in which

A is a hydrogen atom or, preferably, an aroma which corresponds to the structure:

SK 286911 Β6

in which

R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms,

R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having from 1 to 6 carbon atoms, or

B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from a linear or branched alkyl radical having from 1 to 6 carbon atoms; an alkoxy radical having from 1 to 6 carbon atoms or halogen;

X is -CO-N (R ³ ) -X'-, -NH-CO-X ¹ -, -CH =, -CO- or a bond,

X 'is (CH ₂ ) _n wherein n is an integer from 0 to 6;

Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, Y'-CO, -N (R ³ ) -Y'-, -Y' -N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O-, -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6;

Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole , pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, thiazolidine, thiazolidine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazol-3-one tetrazole, tetrahydropyridine, except for the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;

it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical.

Compounds of formula (I) containing one or more asymmetric centers have isomeric forms. Racemates and enantiomers of these compounds are also part of this invention. Similarly, the compounds of the invention may also exist in the form of bases or acid addition salts.

More particularly, the invention relates to a compound of formula (I) wherein:

A is a hydrogen atom or, preferably, an aroma which corresponds to the structure:

l in which

R ¹ and R ² represent, independently, a linear or branched alkyl radical having 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms,

SK 286911Β6

R ³ represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;

B is a 5 membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 up to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or halogen;

X is -NH-CO-X'-, -CH =, -CO- or a bond,

X 'is (CH ₂ ) _n -, wherein n is an integer from 0 to 6;

Y is -Y'-, -Υ'-ΝΗ-CO-, -Y'-CO-, -Υ'-O-, -Y'-O-Y'-, -Y'-N (R ³ ) - Y'- or a bond, Y * represents - (CH ₂ ) _n , wherein n is an integer from 0 to 6;

Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as:

oxethane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-thio, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isooxazoline, oxazolidine, oxazolidinone, thiazole, thiazole, thiazole, thiazole, thiazolidinone, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4- triazol-3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;

it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical.

More particularly, the invention relates to a compound of formula (I) wherein:

A is a hydrogen atom or aromatic which corresponds to the structure:

in which

R ¹ and R ² are independently linear or branched alkyl radical having from 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents hydrogen or a linear or branched alkyl radical having from 1 to 6 carbon atoms; B represents a thiophene ring, the carbons of which are optionally substituted by one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen;

X is -NH-CO-X'-, -CH =, -CO- or a bond,

X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6;

Y is -Y'-, -Υ'-ΝΗ-CO-, -Υ'-CO-, -Y'-O-, -Υ'-OV-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6;

Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole , pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, thiazolidone, thiazolidine, thiazolidine 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazol-3-one tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-amino-piperidine;

it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical.

The invention preferably relates to the following substances:

N- [4- (1H-imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide; N- [4- (3-tiazolidinylmetyl) phenyl] -2-thiophenecarboximidamide;

- N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate; -N- [4- (1H-imidazol-1-ylmethyl) phenyl] -2-thiophenecarboximidamide hydrochloride;

N- [4- {2- (3-thiazolidinyl) ethyl} phenyl] -2-thiophenecarboximidamide; N- {4- [2- (1H-imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide;

N- {4- [2- (1,2,3,6-tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate; N- [4- (3-tiazolidinylkarbonylmetyl) phenyl] -2-thiophenecarboximidamide;

-N- (4 - {[2-thiazolidinyl] carbonylaminomethyl} phenyl) -2-thiophenecarboximidamide fumarate;

N- (3,5-di-tert-butyl-4-hydroxyphenyl) -5- [4- {imino (2-thienyl) methylamino} phenyl] -2-furan carboxamide hydroiodide;

3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride;

SK 286911 Β6

2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride;

5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- (imino (2-thienyl) methylamino} phenyl) -2,4-imidazolidinedione fumarate;

2- (S) -4- (S) -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl)] methyl) amino] phenoxy} -propenamide hydrochloride;

- 5,6-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1- (2H) -pyridinecarboxamide hydrochloride;

- N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2- (R, S) - {4 - [(imino (2-thienyl) methyl) amino] phenyl} - 4- (R) -thiazolidinecarboxamide fumarate;

- N- [4- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide hydrobromide;

- N- [4-hydroxy-3,5-bis- (1,1-dimethyl) ethylphenyl] -2- {4 - [(immo (2-thienyl) methyl) -amino] -phenyl} -4-thiazolecarboxamide hydrochloride ;

or salts or enantiomers thereof.

In particular, the invention relates to the following substances:

N- [4- (1H-imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide;

N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidaniide fumarate; N- {4- [2- (1H-imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide;

N- {4- [2- (1,2,3,6-tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate; N- (4 - {[3-thiazolidinyl] carbonylmethyl} phenyl) -2-thiophenecarboximidamide;

3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride;

-2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride;

5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {immo (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione fumarate;

- 2- (S) -4- (S) -N- [4-Hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl)) methyl) amino] phenoxy} -prolinamide hydrochloride;

- 5,6-dihydro-N- {4 - [(immo (2-thienyl) methyl) amino) phenyl} -1- (2H) -pyridinecarboxamide hydrochloride;

N- [4-hydroxy-3,5-bis- (1,1-dimethyl) ethylphenyl] -2- {4 - [(immo (2-thienyl) methyl) amino) phenyl} -4-thiazolecarboxamide hydrochloride;

or salts or enantiomers thereof.

Finally, the invention more particularly relates to N- [4- (1,2,3,6-tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate or salts thereof.

The present invention provides compounds of formula (I) as described above, or pharmaceutically acceptable salts thereof, as well as medicaments. The invention also relates to pharmaceutical formulations comprising these substances or pharmaceutically acceptable salts thereof, as well as the use of these substances or pharmaceutically acceptable salts thereof for the manufacture of medicaments for inhibiting NO synthase, inhibiting lipid peroxidation or providing a dual function of NO synthase inhibition and peroxidation inhibition. lipids.

Pharmaceutically acceptable salts include certain inorganic acid addition salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, hydroiodide and nitrate, or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p- toluenesulfonate, 1,1'-methylene-bis (2-hydroxy-3-naphthoate), oxalate and stearate. Salts formed with bases such as sodium or potassium hydroxide are also within the scope of this invention when they can be used. Further examples of pharmaceutically acceptable salts can be found in "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).

The pharmaceutical composition may be in the form of a solid, for example, powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing a compound of the invention may also exist in the form of a liquid, for example, as solutions, emulsions, suspensions, or syrups. Appropriate liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as mixtures thereof in various ratios in water.

The medicaments of the invention may be administered by topical, oral or parenteral routes, by intramuscular injection, etc.

The contemplated administered dose of the drug of the invention is comprised between 0.1 mg and 10 g, depending on the type of active agent used.

The invention also provides as novel industrial products, intermediates in the synthesis of products of formula (I), namely, products of formula (II), (III), (V), (VI) and (VID).

SK 286911Β6

In which

A is a hydrogen atom or aromatic which corresponds to the structure:

in which

R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms,

R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms, or a -COR ⁴ radical, R ⁴ represents an alkyl radical having from 1 to 6 carbon atoms, or

B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: 15 thiophene, furan, pyrrole or thiazole, wherein the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen;

X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond,

X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6;

SK 286911 Β6

Y is -Y ¹ -, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) n -, wherein n is an integer from 0 to 6;

Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'SR ³ and such as: oxetane, pyrrole , pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, thiazolidone, thiazolidine, thiazolidine 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazol-3-one tetrazole, tetrahydropyridine, except for the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;

G _p - represents a protective group of an amine function, preferably cleavable in an anhydrous acidic medium, such as the tert-butyl, trichloroethyl or trimethylsilylethyl carbamates, or also trityl.

Finally, the invention provides a process for the preparation of the compounds of formula (I) and comprising, for example, a reaction in a lower alcohol such as methanol, ethanol, isopropyl alcohol or tert-butanol, preferably isopropyl alcohol, at a temperature between 20 and 90 ° C. , for example at 50 ° C, and for one to 48 hours, preferably for 15 to 24 hours, optionally in the presence of DMF, a compound of formula (III), with a compound of formula (IV)

(H1) (iv), this compound of formula (IV) is optionally converted into a salt by means of mineral acid G, B is as defined above and L is a leaving group and especially alkoxy, thioalkyl, sulfonic acid, halide, aryl alcohol or tosyl radical leaving groups well known to those skilled in the art that can optionally be used in the present invention are described in the following work: Advanced Organic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315). Preferably G is HCl, HBr or H1.

Other methods of preparation may be contemplated and are available in the literature (for example: The Chemistry of Amidines and Imidates, Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991).

For the above process, the compounds of formula (I), (III), (IV), (VI) and (VII) are those in which:

A is a hydrogen atom or aromatic which corresponds to the structure

in which

R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms,

R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, or

B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen;

X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond,

X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6;

Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6;

Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazole, thiazole, thiazole, thiazole, thiazole, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole-3- one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine;

G _p - represents a protective group of an amine function, preferably cleavable in an anhydrous acidic medium, such as the tert-butyl, trichloroethyl or trimethylsilylethyl carbamates, or also trityl. According to the invention, the compounds of formula (I) may be prepared by the above process.

Preparation of compounds of formula (I)

Compounds of formula (I) may be prepared starting from intermediates of formula (II), (ΠΙ) or (V) according to Scheme 1.

removal of protecting groups

(I)

Reduction of the nitro group of intermediates of formula (II) is generally accomplished by catalytic hydrogenation in ethanol in the presence of Pd / C, except when the molecules contain an unsaturated bond

Or sulfur atom, which is a catalyst poison for Pd / C. In this case, the nitro group is selectively reduced, for example, by heating the product in solution in ethyl acetate with a small amount of ethanol in the presence of SnCl ₂ (J. Heterocyclic. Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, 8). , 839-842) or using Raney nickel with the addition of hydrazine hydrate (Monatshefte fiir Chemie, (1995), 126,725-732).

The thus obtained aniline derivatives of formula (III) may be condensed to derivatives of formula (IV), for example derivatives of the O-alkylthioimidate or S-alkylthioimidate type, to produce the final compound of formula (I) (see Scheme 1). For example, for B = thiophene, derivatives of formula (III) may be condensed to S-methylthiophenethiocarboxamide hydroiodide, prepared according to literature method (Ann. Chim. (1962), 7, 303-337). The condensation may be carried out by heating 10 in an alcohol (e.g. methanol or isopropanol), optionally in the presence of DMF at a temperature between 50 and 100 ° C for a period generally ranging from several hours to night time.

The final molecules of formula (I) are also available by another synthesis process that passes the intermediates of formula (V) that carry a Gp-protected heterocyclic amine function, for example 2- (trimethylsilyl) ethoxymethyl (SEM) or 15. by another protecting group listed in: Protective groups in organic synthesis, 2nd edition, (John Wiley & Sons Inc., 1991). The reduction and condensation steps leading to intermediates (VI) and (VII) are carried out under the same conditions as described above. The last step of the synthesis consists in the regeneration of the protected heterocyclic amine function, for example in an acidic medium or in the presence of a fluoride ion.

Alternatively, the intermediates of formula (V) may be converted directly to an intermediate of formula (II) by liberating the heterocyclic amine by treatment, for example, with an acidic medium or in the presence of a fluoride ion.

Preparation of compounds of formula (II), (III) and (V)

Intermediates of formula (II), (III) and (V) can be prepared by various illustrated synthetic procedures.

When: Het = imidazole, tetrahydropyridine, thiazolidine, dihydroimidazol-2-όη and Y = -Y’30

The amines of formula (II), Scheme 2, in which A, X, Y and Het are as defined, can be obtained by nucleophilic substitution of commercial halogenated derivatives of formula (IX) with a heterocyclic amine of formula (VII). The reaction is carried out in acetonitrile, THF or DMF in the presence of a base such as K ₂ CO ₃ at a temperature ranging from 20 to 110 ° C. The synthesis of heterocyclic derivatives of formula (VIII) that is not commercially available is described.

Scheme 2 (VIII) (IX)

(II)

When: Het = imidazole, thiazolidine, tetrahydropyridine and Y = -Y'-.

Heterocyclic amines of formula (III), Scheme 3, wherein A, X, Y and Het are as defined, are prepared in two steps starting from amines of formula (VIII) (see below). A mixture of a brominated derivative of formula (X), the synthesis of which is explained in detail, with an amine of formula (VIII) in a solvent such as acetonitrile or DMF in the presence of a base leads to intermediates of formula (XI). Deprotection of the amine function in an organic acidic medium allows to obtain compounds of formula (III).

Scheme 3

A-X

W (III)

When: Het = thiazolidine and Y = -CO-Y'-.

The carboxamides of formula (III), Scheme 4, wherein A, X, Y and Het are as defined, are prepared by condensation of the amines of formula (VIII) described above with the carboxylic acids of formula (X.2). Carboxamide bonds are formed under standard peptide synthesis conditions (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Veriag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC). 1,1'-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The Chemical Synthesis of Peptides, 54 (Clarendon Press, Oxford, 1991). The synthesis of carboxylic acids of formula (X.2) is described. The intermediates of formula (XII) are then deprotected in an acidic medium using, for example, trifluoroacetic acid or an organic solution of HCl.

Scheme 4 (VIII)

(III) (X.1)

When: Het = thiazolidine and Y = -CO-NH-Y'-.

The carboxamides of formula (V), Scheme 5, in which A, X, Y and Het are as defined, are prepared by condensing the carboxylic acids of formula (ΧΙΠ) with commercial amines of formula (XTV) under standard conditions for peptide synthesis. The synthesis of carboxylic acids of formula (XIII) is described.

SK 286911 Β6

Scheme 5 (xiv) (XIII)

When: Het = thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine and X = -NH-CO-X'-.

The carboxamides of formula (II), Scheme 6, in which A, X, Y and Het are as defined, are prepared by condensation of anilines of formula (XV) with carboxylic acids of formula (XVI) under standard peptide coupling conditions. The anilines of formula (XV) are obtained by hydrogenation of the corresponding nitrobenzene derivatives in the presence of a catalytic amount of Pd / C, which are themselves synthesized according to a method described in the literature (J. Org. Chem. (1968), 33 (1), 223-226) . The acids of formula (XVI), Scheme 6, which are not commercially available, are prepared according to methods described in the literature.

The synthesis of pyrroles is described in Chem. Heterocycl. Compd., 1982, 13, 375. Substituted prolines are available starting from commercial hydroxyprolines and are prepared according to the methods described in J. Org. Chem., 1991, 56, 3009.

The synthesis of thiazole and tetrahydropyridine derivatives is described.

Scheme 6

A — NH ₂ + HO ₂ CX '—Het — Y (XV) (XVI)

When: Het = hydantoin and Y = -Y'-.

(II)

The hydantoins of formula (II), Scheme 7, wherein A, X, Y and Het are as defined, are prepared in 3 steps starting from the anilines of formula (XV) described above. The aniline substitution with ethyl bromoacetate is carried out in the presence of sodium acetate in ethanol at a temperature of about 60-70 ° C. The monosubstituted product of formula (XVII) is then condensed to an isocyanate of formula (XVIII) in an organic solvent such as dichloromethane at a temperature of about 20 ° C. Urea cyclization (XIX) is performed by heating to 50 ° C in ethanol according to the experimental procedure described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608). Isocyanates of formula (XVIII) are synthesized starting from the corresponding commercial primary amines, triphosgene and tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).

(XV) (XVII) (XIX)

SK 286911 Β6

IN

(II)

When:

Het = thiazolidinone and Y = -Y'thiazolidinones of formula (II), Scheme 8, wherein A, X, Y and Het are defined, are prepared starting from commercial amines of formula (XIV) and aldehydes of formula (XX) in the presence of mercaptoacetic acid according to the experimental procedure described in the literature (J. Med. Chem., (1992), 35, 2910-2 2912).

(XIV)

(H) (XX)

When: Het = hydantoin

X = -CH = and Y = -Y'-.

The hydantoins of formula (II), Scheme 9, wherein A, X, Y and Het are as defined, are prepared in 2 stages starting from the isocyanates of formula (XVIII) described above. The reaction of sarcosine ethyl ester with isocyanates of formula (XVIII) is carried out according to the experimental procedure described in the literature (J. Heterocyclic Chem., (1979), 16, 607-608) and leads to the formation of heterocycles of compounds of formula (XXI). The hydantoin substitution is carried out in the presence of a weak base, b-alanine and an aldehyde of formula (XX) according to the experimental conditions described in J. Med. Chem., (1994), 37, 322-328.

(XX)

(XXI

SK 286911 Β6

Scheme 9 - continued

(Π)

When: Het = pyrrolidine, thiazolidine

X = -NH-CO-X'- and Y = -O-Y'- or -YCarboxamides of Formula (V), Scheme 10, wherein A, X, Y and Het are defined, are prepared by condensation of anilines of Formula (XV) described above, with acids of formula (XXII) under standard conditions for peptide synthesis. Syntheses of carboxylic acids (XXII) that are not commercially available are described.

Scheme 10

(X) (XV) (XV)

When: Het = tetrahydropyridine and Y -CO-NH-Y'-.

The ureas of formula (II), Scheme 11, wherein A, X, Y and Het are as defined, are prepared by condensing the heterocyclic amines of formula (VIII) described above with isocyanates of formula (XVIII) (see above) in a solvent, such as dichloromethane at 20 ° C in the presence of a tertiary amine (e.g. diisopropylethylamine).

Scheme 11

A-X

When: Het = pyrrolidine, thiazole, thiadiazole and X = -CO-NH-X'-.

The carboxamides of formula (II), Scheme 12, wherein A, X, Y and Het are as defined, are prepared by condensation of commercial carboxylic acids of formula (XXIII) with amines of formula (XXIV) under standard conditions for peptide synthesis. Syntheses of amines of formula (XXIV) that are not commercially available are described.

(II)

Scheme 12

A - CO ₂ H + H ₂ N - X - Het - Y (XXIII) (xxiv)

When: Het = imidazole, oxazole and thiazole and Y = -CH (R ³ ) -N (R ³ ) -CO-Y'-.

The carboxamides of formula (V), Scheme 13, wherein A, X, Y and Het are as defined, are prepared by condensing amines of formula (XXV) with commercial carboxylic acids (or corresponding acid chlorides) of formula (XXVI) under standard conditions for peptide synthesis. The synthesis of imidazole derivatives of general formula (XXV) is described.

Scheme 13

(XXVI)

When: Het = imidazole and Y = -CH ₂ -N (R ³ ) -Y'-.

The amines of formula (V), Scheme 14, wherein A, X, Y and Het are as defined, are prepared by condensation of amines of formula (XXV) (see below) with commercial halogenated derivatives of formula (IX) under the conditions described.

Scheme 14 (XXV) (IX)

When: Het = dihydroimidazol-2-one and Y = -CO-Y '.

The amines of formula (II), Scheme 15, wherein A, X, Y and Het are as defined, are prepared using

Condensation of amines of formula (VIII) (see below) with commercial halogenated derivatives of formula (XXVII), for example in a mixture of acetonitrile and THF and in the presence of a base such as K ₂ CO ₃ .

Scheme 15 (VIII) +

(XXVII) No ₂

When: Het = oxazolidinone and Y = -Y’-O-.

The oxazolidinones of formula (II), Scheme 16, are prepared starting from diols of formula (XXVII), the synthesis of which is described in the literature (Daumas, M., Tetrahedron, 1992, 48 (12), 2373). Formation of carbonates of formula (XXVIII) is achieved, for example, in the presence of carbonyldiimidazole (Kutney, JP, Synth. Commun., J975, 5 (1), 47) or in the presence of low temperature triphosgene as described in Synth. Commun., 1994, 24 (3), 305. The formation of oxazolidinone takes place during heating of amines of formula (XV) with carbonates of formula (XXVIII) in the presence of an acid catalyst such as ZnCl ₂ at reflux of xylene to eliminate the water formed during the reaction (Laas, H., Synthesis, 1981, 958).

Scheme 16

(XXVII) (XXVIII) (XV) a-nh ₂ ---->

▼

When: Het = isoxazoline, isoxazole, oxazole, thiazole and Y = -Y'-CO-NH-Y '

The carboxamides of formula (II), Scheme 17, in which A, X, Y and Het are as defined, can be prepared starting from commercial amines of formula (XIV) and carboxylic acids of formula (XXVIII) by condensation in the presence of isobutyl chlorophthiate (Org. Prep. Proced Int (1975), 7, 215).

SK 286911Β6

The preparation of oxazoles of formula (XXVIII) is carried out according to the experimental procedure described in Tetrahedron Lett, 1994, 35 (13), 2039. Similarly, the synthesis of thiazoles of formula (XXVIII) is performed: J. Med. Chem., 1983, 26, 884. The preparation of isoxazoline is described.

Scheme 17

A - Het - Y'-CO ₂ H (XXVIII)

When: Het = pyrrolidine, piperidine X = -CO-NHaY = -O-Y'-.

(II)

The carboxamides of formula (II), Scheme 18, wherein A, X, Y and Het are as defined, can be prepared by condensation from commercial carboxylic acids of formula (XXIII) with amines of formula (XXIX) under standard conditions for peptide synthesis. Syntheses of amines of formula (XXIX) are described.

(XXIII)

When: Het = isoxazoline, oxazole, thiazole, imidazole and Y = -Y'-O-Y'- or -Y'-N (R ³ ) -Y'Eteroxides of formula (II), Scheme 19, wherein A, X, Y and Het are as defined may be prepared starting from esters of formula (XXVIII.4), Scheme 17.1, by reaction with hydrides, for example LiAlH 4, in a solvent such as anhydrous THF. The primary alcohols thus obtained are then condensed to halogenated derivatives of formula (IX) using a base such as KOH in an organic medium and in the presence of a phase transfer catalyst such as Aliquat 336.

Primary alcohols (XXXI) can also be activated in the form of sulfonate derivatives, with tosyl chloride in the presence of pyridine, to form intermediates of formula (XXXII). The condensation of alcohols of formula (XXII.2) is then carried out in the presence of a strong base such as NaH in an aprotic solvent (THF or DMF) at a temperature between 20 ° C and 80 ° C to give the ether oxide of formula (II).

Similarly, amines of formula (II), Scheme 19, are obtained by substituting the tosylate functionality of intermediates of formula (XXXII), obtained in a standard manner starting from alcohols of formula (XXXI) and tosyl chloride in the presence of pyridine, with commercial amines of formula (XXX). by reaction in a solvent such as acetonitrile or DMF in the presence of a base (K ₂ CO ₃ ) at a temperature between 20 and 85 ° C.

Scheme 19

A-Het-Y-CO ₂ R ³ (XXVIII) reduction

IN

_A-Y-Het-CH2 OH (XXXI)

Scheme 19 - continued

U

_{A-Y-Het-CH2-O-Ts} (XXXII)

(II)

When: Het = azetidine

X = -CO-NH and Y = -O-Y'Carboxamides of formula (III), Scheme 20, wherein A, X, Y and Het are as defined, can be prepared by condensation of commercial carboxylic acids of formula (XXIII) with amines of formula (XXXII) under standard conditions for peptide synthesis. The synthesis of amines of formula (XXXII) is described. The aniline deprotection is carried out with a strong acid, such as trifluoroacetic acid, optionally in the presence of triethylsilane.

Scheme 20 (XXIII) α-co ₂ h +

^Η -θ- ^Υ -Ο · _(ί ^ _ο , ΙΒυ (XXXII)

When: Het = azetidine

X = -NH-CO-X 'and Y = -O-Y'-.

_z tBu

H (XXXIII)

The ureas of formula (III), Scheme 21, wherein A, X, Y and Het are as defined, can be prepared by addition of amines of formula (XXXII) to isocyanates (XXXIV) obtained from the reaction of amines of formula (XV) with triphosgene in in the presence of a tertiary amine such as diisopropylethylamine in a neutral solvent such as dichloromethane (J. Org. Chem. (1994), 59 (7), 1937-1938). The ureas thus obtained (XXXV) are deprotected by treatment with a strong acid medium as described above. The synthesis of amines of formula (XXXII) is described.

Scheme 21 (XXXII) a-nh ₂

A-NCO (XV) XXXIV

When: Het = thiazole and Y = -CH ₂ -N (R ³ ) -Y'-.

(XXXV) ’(ΙΠ)

The amines of formula (II), Scheme 22, wherein A, X, Y and Het are as defined, are prepared by condensation of amines of formula (XXV) (see below) with commercial halogenated derivatives of formula (IX) under the conditions described.

Scheme 22 (XXV) +

NO ₂ σχ)

Ha) -Y

Preparation of various synthesis intermediates

Synthesis of intermediates (VIII)

The syntheses of intermediates of formula (VIII) are illustrated in Schemes 2.1 and 2.2.

Intermediates of general formula (VIII), Scheme 2.1, can be prepared, for example, in 3 steps starting from 4-imidazolecarboxylic acid. Nitrogen protection of heterocycles is carried out using (Boc) ₂ O in the presence of a base such as K ₂ CO ₃ in DMF. Coupling with amines of formula (XV) (see above) is carried out in a standard manner under the conditions for peptide synthesis to form intermediates of formula (VIII.3). The amine heterocycles are regenerated by treatment in an acidic medium, and in particular with trifluoroacetic acid, to form intermediates of formula (VIII).

Figure 2.1 (XV) A-NH ₂

(VIII.1) (VIII.2) (VIII.3)

SK 286911Β6

(VIII).

The dihydroimidazol-2-ones of formula (VIII), Scheme 2.2, can be prepared, for example, in 2 steps starting from the anilines of formula (XV) (see above) which are condensed to 2-chloroethyl isocyanate in DMF at 20 ° C to to form ureas of formula (VIII.4). The cyclization to form (VIII) is then carried out by treatment in a basic medium using, for example, tBuOK in DMF.

Scheme 2.2

OCN ^ / ^ - ^C] a-nh ₂ ------>

(VIII.3) (XV)

(VIII)

Synthesis of intermediates (X)

Intermediates of formula (X), Scheme 3.1, can be prepared starting from commercial carboxylic acids of formula (X.1). Protection of the amine function in the form of carbamate is followed by a selective reduction of carboxylic acid functionality with lithium hydride and aluminum 15 in a solvent such as THF at 20 ° C. The intermediate (X.3) is then brominated in the presence of carbon tetrabromide and triphenylphosphine in a solvent such as dichloromethane.

Scheme 3.1

SK 286911-6 (X.2) (X.3) (X) (Boc ^ O

H

Synthesis of intermediates (XIII)

Intermediates of general formula (XIII), Scheme 5.1, can be prepared starting from (R or S) thiazolidinecarboxylic acid derivatives in the presence of (Boc) ₂ O under standard conditions.

Scheme 5.1

(XIII)

Synthesis of intermediates (XVI)

Intermediates of formula (XVI), Scheme 6.1, can be prepared starting from commercial carboxamide derivatives of formula (XVI.1). These carboxamides were treated with Lawesson's reagent in a solvent such as 1,4-dioxane for 2-3 hours at a temperature varying from 25 ° C to the reflux temperature of the mixture. The thiocarboxamides of formula (XVI.2) are then treated with ethyl bromopyruvate at 20 ° C in DMF according to the experimental procedure described in J. Med. Chem., (1983), 26, 884-891, to form thiazoles of formula (XVI.3). Saponification of the ester is carried out for 15 hours with an aqueous solution of potassium carbonate in acetone.

Figure 6.1

SK 286911 Β6

KOH

IN

Tetrahydropyridines of formula (XVI), Scheme 6.2, can be prepared starting from commercial tetrahydro-4-pyridinecarboxylic acids. The esterification is carried out in a standard manner in the presence of paratoluenesulfonic acid in methanol to form intermediate (XVI.4), which is then condensed to a halogenated derivative of general formula (IX) under the conditions described above. The acid of formula (XVI) is obtained by saponification in the presence of, for example, LiOH or KOH.

Figure 6.2

(IX)

Figure 6.2 - continued

Synthesis of intermediates (XXII)

Syntheses of intermediates of formula (XXII) are described in Schemes 10.1 and 10.2.

The tosylate functionality (L or D) of proline derivatives of formula (XXII.1) (Tetrahedron Lett., (1983), 24 (33), 3517-3520), Scheme 10.1, is substituted with alcoholates of derivatives of formula (XXII.2). ) generated in situ using a base such as NaH. The substitution is carried out at 20 ° C in a solvent such as N-methylpyrrolidinone, thereby causing an appropriate inversion of the carbon configuration of the reaction center (Tetrahedron Lett., (1983), 24 (33), 3517-3520). The intermediates of formula (XXII.3) thus obtained are then saponified in a standard manner using an alcoholic potassium carbonate solution.

Scheme 10.1

Intermediates of formula (XXII) can also be prepared (Scheme 10.2) starting from the condensation of cysteine (L or D) to the aldehyde of formula (XXII.5) according to the experimental procedure described in the literature (J. Org. Chem., (1957), 22, 943-946). The amine of the heterocycle is then protected as a carbamate to form intermediates of general formula (ΧΧΠ). Aldehydes of formula (XXII.5) that are not commercially available can be prepared according to J. Chem. Soc., Perkin Trans. 1, 1973, 1, 35.

Scheme 10.2 (XXII.4)

(XXII.5)

(Boc) ₂ 0

(XXII)

Bu

Synthesis of intermediates (XXIV)

The synthesis of intermediates of formula (XXIV) is described in Scheme 12.1.

The coupling of amines (R or S) of formula (XXIV.1), Scheme 12.1, to halogenated derivatives of formula (IX) is carried out in the presence of a base such as potassium carbonate in a solvent such as DMF. The condensation product (XXIV.2) is then deprotected in an acidic medium to form intermediates of general formula (XXIV).

Scheme 12.1

-Ύό (XXIV.l)

(XXIV.2) IX

SK 286911 Β6

(XXIV)

Synthesis of Intermediates (XXV)

The syntheses of intermediates of formula (XXV) are described in Schemes 13.1, 13.2, 13.3 and 13.4.

The imidazoles of general formula (XXV), Scheme 13.1, can be prepared in 4 steps starting from the commercial substances (XXV.1) and (XXV.2). The condensation between the bromoacetophenones of formula (XXV.1) and the carboxylic acids of formula (XXV.2) is carried out in the presence of cesium carbonate in DMF. The obtained ketoester (XXV.3) is cyclized in the presence of 15 equivalents of ammonium acetate by heating in a mixture of xylenes and simultaneous elimination of the water formed during the reaction to form imidazoles of formula (XXV.4). The nitrogen of the heterocycles is then protected, for example, using 2- (trimethylsilyl) ethoxymethyl (SEM) or another protecting group listed in: Protective groups in organic synthesis, second edition, (John Wiley & Sons Inc., 1991) to form intermediates of the general formula of formula (XXV.5). Release of the amine from the chain can be accomplished by hydrogenolysis in the presence of Pd / C.

Alternatively, intermediates of formula (XXV.4) may be alkylated in the presence of a base such as K ₂ CO ₃ , and agents such as R ³ -X in a solvent such as DMF or acetonitrile to form imidazoles of formula (XX). XXV.6). Side chain deprotection, as described above, provides intermediates of formula (XXV).

Figure 13.1 ^A Y% _r o (XXV.1)

Cs ₂ CO ₃

OR ³ O (XXV.3)

NH ₄ OAc

SK 286911 Β6

(XXV.5)

removal of protecting groups

(XXV)

Intermediates of formula (XXV) containing oxazole, thiazole or imidazole are also available using other synthetic procedures than those described in Bioorg. and Med. Chem. Lett, 1993, 3, 915 or 5 Tetrahedron Lett., 1993, 34, 1901. The intermediates of formula (XXV.7) thus obtained can be modified, Scheme 13.2, by saponification followed by decarboxylation, for example thermal, to form disubstituted heterocycles of formula (XXV.9). Release of the amine from the side chain, as described above, will make available intermediates of formula (XXV).

(XXV.7)

(XXV.8)

SK 286911 Β6

Q = O, NaI. WITH

(XXV)

Alternatively, the carboxyl functional groups of the heterocycles of formula (XXV.7) can be reduced, for example with NaBH ₄ , to form the alcohol derivatives of formula (XXV.10),

13.3 which may be alkylated in the presence of R ³ -X and a base such as K ₂ CO ₃ in a solvent such as acetonitrile or DMF. Release of the amine from the side chain, as described above, will make available intermediates of formula (XXV).

Scheme 13.3

(XXV.7)

Q = O, Nal.

(XXV.10)

Thiazoles of formula (XXV), Scheme 13.4, can also be prepared in 4 steps starting from commercial sarcosamide hydrochloride. The amine is first protected in the standard manner as tBu carbamate and the carboxamide function is converted to a thiocarboxamide in the presence of Lawesson's reagent. The formation of the thiazole ring is carried out by reaction of thiocarboxamide with an intermediate of formula (XXV.1) according to the experimental procedure described in the literature (J. Org. Chem., (1995),

SK 286911 Β6

60, 5638-5642) The amino function is regenerated by treatment with an intermediate of formula (XXV.12) in a strong acid medium such as trifluoroacetic acid.

Scheme 13.4 (XXV.1) ^A Y ^with Br O

^A = ^CH =

O (ytBu (XXV. 12) ^b H (XXV)

Synthesis of intermediates (XXVIII)

The isoxazolines and isoxazoles of formula (XXVIII), Scheme 17.1, are prepared by reacting commercial aldehydes of formula (XX) with hydroxylamine hydrochloride. The oxime (XXVIII.1) thus obtained is activated as oxime chloride (XXVIII.2) by reaction with N-chlorosuccinimide in DMF prior to reaction with esters of formula (XXVIII.3) to form isoxazoline derivatives or with esters of formula (XXVIII.4) to form isoxazole derivatives according to the experimental procedure described in the literature (Tetrahedron Lett, 1996, 37 (26), 4455; J. Med. Chem., 1997, 40, 50-60 and 2064-2084). The saponification of the isoxazoles or isoxazoles of formula (XXVIH.5) is then carried out in a standard manner under the conditions described above.

Unsaturated esters of formula (XXVIII.3) and (XXVIII.4), which are not commercially available, can be prepared according to a method described in the literature (J. Med. Chem., 1987, 30, 193; J. Org. Chem. 1980, 45, 5017).

Scheme 17.1

A-CHO

NH ₂ OH _h

-................*· If

N-OH ci ^A_ 4

NCH (XX) (XXVin.1) (XXVDI.2) y-co ₂ r ³ (ΧΧΥΙΠ.3)

(Xxvm.5)

HT-CO / I ³ (XXVIII.3)

(XXVID)

Synthesis of Intermediates (XXIX)

The syntheses of intermediates of formula (XXIX) are described in Schemes 18.1, 18.2, 18.3 and 18.4.

Intermediates of formula (XXIX) can be prepared, Scheme 18.1, starting from intermediates of formula (XXII.3), as described above, by treatment in a strong acid environment to regenerate the heterocyclic amine functionality. Selective reduction of the carboxyl function in the presence of, for example, sodium borohydride in a solvent such as anhydrous THF will allow the intermediate of formula (XXIX) bearing the primary alcohol function to be obtained without touching the nitro group (Rao, AVR, J. Chem. Soc. Chem. Commun 1992, 11, 859).

SK 286911 Β6

Scheme 18.1

H ⁺ y

reduction

Intermediates of formula (XXIX) may also be prepared, Scheme 18.2, starting from intermediates of formula (XXIX.1) (R or S) whose preparation is similar to the preparation of compounds of formula (XXII.1). The condensation of alcohol derivatives of formula (XXII.2) to intermediates of formula (XXIX.1) is also described. The release of the heterocyclic amine is carried out in the presence of an organic solution of a strong acid, for example trifluoroacetic acid.

Scheme 18.2

SK 286911Β6

I tBu

(XXIX.l)

(XXIX)

The amines of formula (XXIX), Scheme 18.3, are also available starting from the substitution of tosylated derivatives of formula (XXIX.1) with commercial amines of formula (XXX). The tearing off of the carbamate functionality from the intermediates of formula (XXIX.3) is carried out as described above.

Scheme 18.3

(XXIX)

Intermediates of formula (XXIX) may also be prepared, Scheme 18.4, by reacting halogenated derivatives of formula (IX) with an alcohol of formula (XXIX.4) in the presence of a base such as tBuO'K ⁺ in an anhydrous solvent such as e.g. THF. The thus obtained intermediate of formula (XXIX.5) is then deprotected in a strong acid medium (HCl or TFA).

Scheme 18.4

(XXIX)

(XXĽX.4)

Synthesis of intermediates (XXXII)

Intermediates of formula (XXXII) can be prepared, Scheme 20.1, by reacting halogenated derivatives of formula (IX) with commercial 1- (diphenylmethyl) -3-hydroxyazetidine (XXXII.1) in the presence of a base such as NaH in an anhydrous solvent, such as THF. In this case, the nitro group of the intermediate of formula (XXXII.2) is reduced in the presence of SnCl ₂ as described above to form the intermediate of formula (XXXII.3), the amine of which is then protected as tert-butyl carbamate. The deprotection of the diphenylmethyl protecting group is then carried out in a standard manner by hydrogenolysis in the presence of Pd (OH) ₂ to form the intermediate of formula (XXXII).

Scheme 20.1

(ΧΧΧΠ.2)

(ΧΧΧΠ.3)

(XXXII)

SK 286911 Β6

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Similarly, all publications, patent applications, patents, and other references cited herein are incorporated by reference.

The following examples are provided to illustrate the above procedures and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N- [4- (1H-Imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide (1)

1.1 1- (4-Nitrophenyl) -1H-imidazole g (64.5 mmol) potassium carbonate and 5 g (3.75 ml; 35.2 mmol) 1-fluoro-4-nitrobenzene were added to a solution of 2 g imidazole ( 29.4 mmol) in 14 mL DMF. The reaction mixture was shaken for 1.5 hours at 110 ° C. Ethyl acetate (50 mL) was added to the medium, which was washed 3 times with 50 mL of water. The organic phases were dried over magnesium sulfate and concentrated in vacuo. Thus, 4.4 g of product (yield = 80%) were obtained in the form of a clear oil and were used in the next steps without further purification.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 6.92 (t, 1H, aromatic H imidazole), 7.16 (s, 1H, aromatic H imidazole), 7.24-7.32-

8.18-8.27 (4s, 4H, aromatic H), 7.59 (s, 1H, aromatic H imidazole).

1.2 1- (4-Aminophenyl) -1H-imidazole 1- (4-Nitrophenyl) -1H-imidazole (4.4 g; 23.5 mmol) was dissolved in anhydrous methanol (140 mL) and the palladium on carbon (0.44 g) was added. The reaction medium was placed under hydrogen for 4 hours. The catalyst was filtered off and the solvent was evaporated to dryness. The expected product was obtained in a seemingly pure state in a yield of 89% (3.3 g).

NMR 1 H (CDCl 3, 100 MHz, δ): 6.61 - 6.69 - 6.95 - 7.05 (4s, 4H, aromatic H), 6.88 (t, 1H, aromatic H imidazole) 7.07 (s, 1H, aromatic, H imidazole), 7.52 (s, 1H, aromatic, H imidazole).

1.3 N- [4- (1H-Imidazol-1-yl) phenyl] -2-thiophenecarboximidamide hydroiodide (1) 1- (4-Aminophenyl) -1H-imidazole (0.3 g; 1.7 mmol) and S- methyl 2-thiophenethio carboximide hydroiodide (0.5 g;

1.75 mmol) was dissolved in 1 ml of isopropanol and 1 ml of DMF and the reaction mixture was shaken for 18 hours at 25 ° C. The precipitate formed was filtered off and washed with 15 ml of dichloromethane and 15 ml of ethanol. Thus the expected product (0.48 g; 73%) was obtained as a salt (hydroiodide). Mp .: 252-253 ° C (dec.).

NMR 1 H (DMSO, 400 MHz, δ): 7.24 (s, 1H, aromatic H), 7.38 (t, 1H, aromatic H), 7.55-7.57-7.85- 7.87 (4s, 4H, aromatic H), 7.89 (s, 1H, aromatic H), 8.10 (m, 2H, aromatic H), 8.50 (s, 1H, aromatic H) ).

IR: Von (amidine): 1585 cm ^-1 .

Example 2

N- [4- (3-Thiazolidinylmethyl) phenyl] -2-thiophenecarboximidamide (2)

2.1 1-Bromomethyl-4-nitrobenzene

4-Nitrobenzyl alcohol (6 g, 39 mmol) was dissolved in dichloromethane (100 mL) and carbon tetrabromide (14.9 g, 45 mmol) was added. Triphenylphosphine (11.8 g, 45 mmol) was added portionwise at 0 ° C. The mixture was then shaken for 2 hours at ambient temperature. The solvent was evaporated and the obtained product was purified on silica gel in ethyl acetate / heptane (1/2). Obtained as white needle-shaped crystals (7.2 g; 85%). Melting point: 97-98 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 4.53 (s, 2H, CH ₂ ). 7.53 - 7.61 - 8.18 - 8.27 (4 s, 4H, aromatic H).

2.2. 3- (4-Nitrobenzyl) -thiazolidine

A mixture of thiazolidine (0.9 g, 10 mmol) and potassium carbonate (2.5 g, 18 mmol) in acetonitrile (10 mL) was heated to 70 ° C. 1-Bromomethyl-4-nitrobenzene (2 g, 9.2 mmol) in acetonitrile solution (25 mL) was added dropwise and the reaction mixture was refluxed for 2 hours.

The precipitate formed was filtered off, the mother liquor was evaporated and the residue was dissolved in 50 ml of dichloromethane and washed 3 times with 50 ml of water. The organic phases were dried, evaporated and purified on silica gel with ethyl acetate / heptane (1/2). The expected product was obtained as a colorless oil (1.5 g, 72%).

NMR 1 H (CDCl 3, 100 MHz, δ): 3.05 (m, 4H, 2CH ₂ ), 3.68 (s, 2H, CH ₂ -S), 4.04 (s, 2H, CH ₂ ), 7.53 - 7.62 -

8.17-8.26 (4s, 4H, aromatic H).

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2.3 3- (4-Aminobenzyl) -thiazolidine

3- (4-Nitrobenzyl) -thiazolidine (1.1 g, 5 mmol) was dissolved in 10 mL of concentrated hydrochloric acid at 0 ° C. Tin (II) chloride dihydrate (7.7 g, 34 mmol) was added portionwise, the mixture was heated at reflux for 2 hours and the acid was evaporated under reduced pressure. The residue was then dissolved in 20 mL of water and neutralized with a 2 mol / L soda solution (approximately 100 mL). 100 ml of dichloromethane was added to the medium and the whole mixture was filtered through Celite to separate the salts from the suspension. The organic phase was extracted, washed 3 times with 50 ml of water, dried, filtered and evaporated to dryness under reduced pressure. The expected product was purified on silica gel in dichloromethane / methanol (98/2) and was obtained as a beige powder (0.6 g, 63%). Mp 73-74 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 3.02 (m, 4H, 2CH ₂ ). 3.44 (s, 2H, _CH2), 3.66 (br s, 2H, _NH2), 4.07 (s, 2H, _CH2), 6.62 to 6.71 - 7.10 to 7 27 (4 s, 4H, aromatic H).

2.4 [4- (3-Thiazolidinylmethyl) phenyl] -2-thiophenecarboximidamide (2)

3- (4-Aminobenzyl) -thiazolidine (0.6 g, 3 mmol) and S-methyl-2-thiophenothiocarboximide hydroiodide (1.14 g, 4 mmol) were dissolved in 7 mL of isopropanol / -DMF (2). / 5). The reaction medium was shaken for 18 hours at ambient temperature. Then 10 ml of ethyl acetate was added to the medium and the reaction product was extracted 3 times with 10 ml of water. The aqueous phase was separated and basified with saturated sodium bicarbonate solution, then the product was extracted 3 times with 10 ml of ethyl acetate. Purified on silica gel in dichloromethane / methanol (95/5) and obtained as a white powder (0.6 g, 65%). Melting point: 161.5-163.5 ° C. NMR 1 H (CDCl 3, 400 MHz, δ): 2.98 (t, 2H, CH ₂ ). 3.14 (t, 2H, _CH2), 3.54 (s, 2H, _CH2), 4.10 (s, 2H, _CH2),

4.85 (br s, 2H, _NH2), 6.98 (s, 1 H, arom. H), 7.00 (s, 1 H, arom. H), 7.10 (t, 1H, thiophene), 7.34 (s, 1H, aromatic H), 7.36 (s, 1H, aromatic H), 7.42 (t, 1H, thiophene), 7.45 (m, 1H, thiophene).

IR: _C-N (amidine): 1593 cm ^"1

Example 3

N- [4- (1,2,3,6-Tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate (3)

3.11- (4-Nitrophenyl) -1,2,3,6-tetrahydropyridine

The same experimental procedure as described for Intermediate 1.1 was used. 1,2,3,6-Tetrahydropyridine replaced imidazole. Colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 2.33 (m, 2H, CH ₂ ), 3.59 (t, 2H, CH ₂ ), 3.90 (m, 2H, CH ₂ ), δ, 90 (m, 2H, CH.dbd.CH), 6.75-6.82-8.07-8.18 (m, 4H, aromatic H).

3.2. 1- (4-Aminophenyl) -1,2,3,6-tetrahydropyridine

The same experimental procedure was used as described for Intermediate 2.3, 1- (4-nitrophenyl) -

1,2,3,6-tetrahydropyridine replaced 3- (4-nitrobenzyl) thiazolidine. Colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 2.31 (m, 2H, CH ₂ ), 3.21 (t, 2H, CH ₂ ), 3.43 (m, 2H, NH ₂ ), 3, 56 (m, 2H, CH ₂ ),

5.84 (m, 2H, CH.dbd.CH), 6.75 (m, 4H, aromatic H).

3.3. N- [4- (1,2,3,6-Tetrahydropyridin-1-yl) phenyl] -2-thiophenecarboximidamide fumarate (3)

The same experimental procedure as described for Intermediate 1.3, 1- (4-aminophenyl) -1,2,3,6-tetrahydropyridine was substituted for 1- (4-aminophenyl) -1H-imidazole. Beige powder. Melting point: 193-194 ° C.

1 H NMR (DMSO, 400 MHz, δ): 2.23 (m, 2H, CH ₂ ), 3.29 (m, 2H, CH ₂ ), 3.61 (m, 2H, CH ₂ ), 84 (m, 2H, CH-CH), 6.56 (s, 1H, fumaric acid), 6.89 (m, 4H, aromatic H), 7.13 (m, 1H, aromatic H), 7 67 (m, 1H, aromatic H), 7.77 (m, 1H, aromatic H).

IR: _C-N (amidine): 1560 cm ^"first

Example 4

N- [4- (1H-Imidazol-1-ylmethyl) phenyl] -2-thiophenecarboximidamide hydrochloride (4)

4.1. 1- (4-Nitrobenzyl) -1H-imidazole

The same experimental procedure as described for Intermediate 1.1, 1-bromomethyl-4-nitrobenzene, was replaced by 1-fluoro-4-nitrobenzene. Colorless oil.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 5.26 (s, 2H, CH ₂ ), 6.92 (m, 1H, H imidazole), 7.16 (m, 1H, H imidazole), 7 59 (m, 1H, H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, aromatic H).

4.2 1- (4-Aminobenzyl) -1H-imidazole

The same experimental procedure as described for Intermediate 1.2, 1- (4-nitrobenzyl) -1H-imidazole was used, replacing 1- (4-aminophenyl) -1H-imidazole. Pale yellow powder. Melting point: 121-122 ° C.

SK 286911 Β6

NMR ¹ H (CDCl 3, 100 MHz, δ): 2.87 (broad s, 2H, NH ₂ ), 4.98 (s, 2H, CH ₂ ), 6.88 (m, 1H, H imidazole), 7 06 (m, 1H, H imidazole), 7.52 (m, 1H, H imidazole), 6.60-6.69-6.95-7.05 (4s, 4H, aromatic H).

4.3. N- [4- (1H-Imidazol-1-ylmethyl) phenyl] -2-thiophenecarboximidamide hydrochloride (4)

The same experimental procedure as described for Intermediate 2.4, 1- (4-aminobenzyl) -1H-imidazole, was substituted for 3- (4-aminobenzyl) thiazolidine. Beige salt formation with HCl mol / L anhydrous diethyl ether gives a beige powder. Melting point: 261-263 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 5.12 (s, 2H, CH ₂ ), 6.46 (broad s, 2H, NH ₂ ), 6.83 - 6.85 - 7.22 - 7 24 (4s, 4H, aromatic H), 6.90 (s, 1H, aromatic H), 7.09 (t, 1H, aromatic H), 7.20 (s, 1H, aromatic H) 7.60 (d, 1H, aromatic H), 7.74 (s, 2H, aromatic H).

IR: [nu] _C-N (amidine): 1599 cm <-1> ^.

Example 5

N- [4- {2- (3-Thiazolidinyl) ethyl} phenyl] -2-thiophenecarboximidamide (5)

5.1. 4- (tert-Butoxycarbonylamino) benzeneacetic acid

Para-aminophenylacetic acid (3 g, 20 mmol) was dissolved in 60 mL of THF / H ₂ O (2/1). Then 11 ml of a 10% sodium carbonate solution was added, followed by 6 g of di-tert-butyl dicarbonate (28 mmol) in a solution of 50 ml of THF / H ₂ O (2/1). Shaking was carried out for 18 hours at ambient temperature. Then, THF was evaporated under reduced pressure. The reaction medium was then acidified (pH = 2) with a 10% potassium hydrogen sulphate solution (approximately 45 mL) and the reaction product was extracted with 3 washes of ethyl acetate (3 x 50 mL). The organic phases were dried and evaporated to give 4.32 g (87%) of pure 4- (tert-butoxycarbonylamino) -benzeneacetic acid as a beige powder. M.p .: 149-150 ° C. NMR 1 H (CDCl 3, 100 MHz, δ) 1.52 (s, 9H, tBu), 3.60 (s, 2H, CH ₂ ), 4.12 (broad s, 1H, COOH), 6.55 (s) s, 1H, NH), 7.21 (m, 4H, aromatic H).

5.2 (tert-Butoxycarbonylamino) benzenethanol

4- (tert-butoxycarbonylamino) benzeneacetic acid (2.9 g, 11.4 mmol) was dissolved in 10 mL of anhydrous THF at 0 ° C and added to a suspension of L 1 AlH 4 (0.52 g, 13.6 mmol) in 30 ml THF. The reaction mixture was shaken at ambient temperature for 1.5 hours. 50 ml of ethyl acetate was added to the reaction medium, followed by 20 ml of 2 mol / L sodium carbonate. The expected product was extracted from the organic phase, which was then washed

3 times with 15 ml of water. The organic phase was dried and the solvent was evaporated under reduced pressure. Then the reaction product was purified on silica gel in dichloromethane / methanol (95/5). There was thus obtained 1.1 g (40%) as a colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.53 (s, 9H, tBu), 2.82 (t, 2H, CH ₂ ), 3.83 (q, 2H, CH ₂ -OH), δ 47 (s, 1H, NH);

7.23 (m, 4H, aromatic H).

5.3 (2-Bromomethyl-4-tert-butoxycarbonylamino) benzene

4- (tert-Butoxycarbonylamino) benzenethanol (0.75 g, 3.1 mmol) and carbon tetrachloride (1.2 g, 3.6 mmol) were dissolved in 20 mL of dichloromethane at 0 ° C. Triphenylphosphine (0.94 g, 3.6 mmol) was added portionwise and the whole was shaken for 1 hour at ambient temperature. The solvent was evaporated under reduced pressure and the obtained product was purified on silica gel in ethyl acetate / heptane (1/2) to give 1- (2-bromomethyl-4-tert-butoxycarbonylamino) benzene as a white powder (0.8 g, 84%). Melting point: 129-130 ° C.

NMR δ (CDCl 3, 100 MHz, δ): 1.52 (s, 9H, tBu), 3.11 (t, 2H, CH ₂ ), 3.54 (t, 2H, CH ₂ Br), 6.45 (s, 1H, NH).

7.22 (m, 4H, aromatic H).

5.4. 3- (2- (4- (tert-butoxycarbonylamino) phenyl) ethyl) thiazolidine

The same experimental procedure as described for Intermediate 2.2, (2-bromomethyl-4-tert-butoxycarbonylamino) benzene, was substituted for 1-bromomethyl-4-nitrobenzene. Colorless oil.

NMR δ (CDCl 3, 100 MHz, δ): 1.52 (s, 9H, tBu), 2.90 (m, 8H, 4CH ₂ ), 4.10 (s, 2H, N-CH ₂ -S), 6.46 (s, 1H, NH); 7.25 (m, 4H, aromatic H).

5.53- {2- [4-aminophenyl] ethyl} thiazolidine

2.3 g (20 mmol) of trifluoroacetic acid were added to a 100 ml flask containing a solution of 616 mg (2 mmol) of intermediate 5.4 in 10 ml of dichloromethane. After shaking for one hour at 20 ° C. The reaction mixture was concentrated to dryness in vacuo. The residue was diluted with a mixture of 20 mL of dichloromethane and 20 mL of 4 mol / L sodium carbonate. After decantation, the organic phase was washed successively with 3 x 20 ml of water, followed by 20 ml of brine. The organic solution was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a colorless oil in a yield of 72%.

NMR 1 H (CDCl 3, 100 MHz, δ): 2.85 (m, 8H, 4CH ₂ ), 4.15 (s, 2H, N-CH ₂ -S), 7.25 (m, 4H, aroma). H).

SK 286911 Β6

5.6. [4- [2- (3-Thiazolidinyl) ethyl] phenyl] -2-thiophenecarboximidamide (5)

The same experimental procedure as described for Intermediate 2.4 was used. 3- {2- [4-aminophenyl] ethyl} thiazolidine replaced 3- (4-aminobenzyl) thiazolidine. Beige powder. Melting point: 60.5 to 61.5 ° C. NMR 1 H (DMSO, 400 MHz, δ): 2.65 (t, 2H, CH ₂ ), 2.82 (t, 2H, CH ₂ ), 2.91 (t, 2H, CH ₂ ), 3, 13 (t, 2 R _CH2);

4.13 (s, 2H, _N-CH2 -S), 6.93 to 6.95 - 7.19 to 7.21 (4 s, 4 H, arom. H), 7.09 (t, 1 H, H thiophene), 7.44 (m, 2H, thiophene H).

IR: [nu] _C-N (amidine): 1591 cm <-1> ^.

Example 6

N- {4- [2- (1H-Imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide (6)

6.1 1- {2- [4- (tert-Butoxycarbonylamino) phenyl] ethyl} -1H-imidazole

2.5 g (18 mmol) of K ₂ CO ₃ was mixed in a 100 mL flask with 680 mg (10 mmol) of imidazole diluted in 10 mL of acetonitrile. The reaction mixture was heated at 70 ° C before adding dropwise a solution of 2 g (9.2 mmol) of 1-bromomethyl-4-nitrobenzene in a solution of 25 mL of acetonitrile. After shaking for 2 hours at this temperature, the reaction mixture was cooled and filtered to remove insoluble components. The filtrate was concentrated in vacuo and the residue was diluted in 50 mL of dichloromethane. The organic solution was washed successively with 3 x 50 mL water and 50 mL brine. After drying over Na ₂ SO ₄ , filtration, the organic phase was concentrated in vacuo and the residue was purified on a silica gel column (eluent: dichloromethane / methanol: 95/5). Brown oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.50 (s, 9H, tBu), 2.90 (t, 2H, CH ₂ ), 4.10 (t, 2H, CH ₂ ), 6.50 (s, 1H, NH imidazole), 7.05 (m, 4H, aromatic H), 6.85 (m, 1H, H imidazole), 7.03 (s, 1H, H imidazole), 7.32 (m, 1H, H imidazole).

6.2. 1- [2- (4-Aminophenylphethyl) -1H-imidazole

The same experimental procedure as described for Intermediate 5.5, 1- {2- [4- (tert-butoxycarbonylamino) phenyl] ethyl} -1H-imidazole was substituted for 3- {2- [4- (tert-butoxycarbonylamino) phenyl] ethyl} thiazolidine. Colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 2.90 (t, 2H, CH ₂ ), 3.35 (broad s, 2H, NH ₂ ), 4.10 (t, 2H, CH ₂ ), 6 70 (m, 4H, aromatic H), 6.85 (m, 1H, H imidazole), 7.03 (s, 1H, H imidazole), 7.32 (m, 1H, H imidazole).

6.3. N- {4- [2- (1H-Imidazol-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide hydroiodide (6)

The same experimental procedure as described for Intermediate 1.3, 1- [2- (4-aminophenyl) ethyl] -1H-imidazole, was substituted for 1- (4-aminophenyl) -1H-imidazole. Beige powder. Melting point: 214-215 ° C. NMR 1 H (DMSO, 400 MHz, δ): 3.11 (t, 2H, CH ₂ ), 4.33 (t, 2H, CH ₂ ), 7.29 (m, 6H, aromatic H), 7 99 (m, 1 H, arom. H), 8.70 (br s, 2H, _NH2).

IR: [nu] _C-N (amidine): 1597 cm <-1>,

Example 7

N- {4- [2- (1,2,3,6-Tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate (7)

7.1 1- {2- [4- (tert-Butoxycarbonylamino) phenyl] ethyl) -1,2,3,6-tetrahydropyridine

The same experimental procedure as described for Intermediate 6.1, 1,2,3,6-tetrahydropyridine was substituted for thiazolidine. Colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ) 1.57 (s, 9H, tBu), 2.10 (m, 2H, CH ₂ ), 2.70 (m, 6H, 3CH ₂ ), 3.00 ( m, 2H, CH ₂ ),

5.72 (m, 2H, CH-CH), 6.48 (s, 1H, NH), 7.10 (m, 4H, aromatic H).

7.2 1- [2- (4-Aminophenyl) ethyl] -1,2,3,6-tetrahydropyridine

The same experimental procedure as described for Intermediate 5.5, 1- {2- [4- (tert-butoxycarbonylamino) phenyl] ethyl} -1,2,3,6-tetrahydropyridine, was substituted for 3- {2- [4-aminophenyl] ethyl} thiazolidine. Colorless oil.

NMR 1 H (CDCl 3, 100 MHz, δ): 3.20 (m, 2H, CH ₂ ), 3.80 (m, 6H, 3CH ₂ ), 4.10 (m, 2H, CH ₂ ), 4, 57 (br s, 2H, _NH2), 6.90 (m, 2H, CH = CH), 8.00 (m, 4 H, arom. H).

7.3. N- {4- [2- (1,2,3,6-Tetrahydropyridin-1-yl) ethyl] phenyl} -2-thiophenecarboximidamide fumarate (7)

The same experimental procedure as described for Intermediate 1.3, 1- [2- (4-aminophenyl) ethyl] -1,2,3,6-tetrahydropyridine, was substituted for 1- (4-aminophenyl) -1H-imidazole. White powder. Melting point: 128 to 129 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 2.19 (m, 2H, CH ₂ ), 2.83 (m, 6H, 3CH ₂ ), 3.25 (m, 2H, CH ₂ ), 72 (m, 2H, CH-CH), 6.58 (s, 3H, fumaric acid), 6.81 - 6.83 - 7.18 - 7.20 (4s, 4H, aromatic H), 7, 10 (t, 1H, H thiophene),

7.63 (m, 1H, thiophene H), 7.75 (m, 1H, thiophene H).

IR: Vq = n (amidine): 1620 cm ^-1 ,

SK 286911Β6

Example 8 N- [4- (3-Thiazolidinylcarbonylmethyl) phenyl] -2-thiophenecarboximidamide (8)

8.1 3 - [{4- (tert -Butoxycarbonylamino) phenyl} methylcarbonyl] thiazolidine

4- (tert-butoxycarbonylamino) benzeneacetic acid (1.4 g, 5.6 mmol), intermediate 5.1, and carbonyldiimidazole (0.9 g, 5.6 mmol) were dissolved in 15 mL of THF. The reaction mixture was kept at ambient temperature for 1 hour. Thiazolidine (0.5 g, 5.6 mmol) in THF solution (5 mL) was then added to the reaction mixture. The whole mixture was shaken again for 2 hours at ambient temperature. The solvents were evaporated under reduced pressure. Then the residue was dissolved in 25 mL of dichloromethane and washed 3 times with 15 mL of water. The organic phase was dried and concentrated under reduced pressure. 3 - [{4- (tert-Butoxycarbonylamino) phenyl} methylcarbonyl] thiazolidine was obtained as a white powder (1.43 g, 79%) and used in the next steps without further purification. Melting point: 223-224 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.51 (s, 9H, tBu), 3.00 (m, 2H, CH ₂ -S), 3.67 (s, 2H, N-CH ₂ - s), 3.88 (m, 2H, _CH2 N), 4.52 (d, J = 16 Hz, 2H, _CH2 CO), 6.52 (br s, 1H, NH), 7, 26 (m, 4H, aromatic H).

8.2. 3 - [(4-Aminophenyl) methylcarbonyl] thiazolidine

3 - [(4-Aminophenyl) methylcarbonyl] thiazolidine was obtained as a colorless oil in a yield of 44% according to the procedure described for Intermediate 5.5.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.62 (broad s, 2H, NH ₂ ), 2.98 (m, 2H, CH ₂ -S), 3.61 (s, 2H, N-CH) _2-S), 3.80 (m, 2H, _CH2 N), 4.52 (d. J = 16 Hz. 2H, _CH2 CO), 6.61 - 6.69 to 7.01 - 7.09 (4 s, 4H, aromatic H).

8.3. N- [4- (3-Thiazolidinylcarbonylmethyl) phenyl] -2-thiophenecarboximidamide (8)

The same procedure as described for Intermediate 2.4, 3 - [(4-aminophenyl) methylcarbonyl] thiazolidine, was substituted for 3- (4-aminobenzyl) thiazolidine. The free base was obtained with a yield of 64%. Melting point: 163.0-163.5 ° C.

NMR 1 H (CDCl 3, 400 MHz, δ): 3.01 (m, 2H, CH ₂ -S), 3.69 (d, J = 6 Hz, 2H, N-CH ₂ -S), 3.75 - 3.88 (2t, 2H, _CH2 N), 4.55 (d, 2H, _CH2 CO), 4.87 (s, 2H, NH _2), H), 6.95 - 6 97-7.22-7.24 (4 s, 4H, aromatic H), 7.08 (t, 1H, thiophene), 7.43 (m, 2H, thiophene).

IR: in _C20 (amide): 1630 cm @ ^-1 ; Incl. _N (amidine): 1577 cm ^-1

Example 9

N- (4 - {[2-Thiazolidinyl] carbonylaminomethyl} phenyl) -2-thiophenecarboximidamide fumarate (9)

9.1. 3- (tert-butoxycarbonyl) thiazolidine-2-carboxylic acid

Thiazolidine-2-carboxylic acid (2 g, 15 mmol) was shaken in the presence of di-tert-butyl dicarbonate according to the procedure described for Intermediate 5.1. 3- (tert-butoxycarbonyl) thiazolidine-2-carboxylic acid was obtained as a pale yellow oil in a yield of 97% (3.4 g) and was used as in the following steps.

NMR 1 H (CDCl 3, 100 MHz, δ) 1.46 (s, 9H, tBu), 3.10 (m, 3H, CH ₂ -S, CH-S), 3.85 (m, 2H, CH ₂₎ N).

9.2 (4-Nitrobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxamide

3- (tert-butoxycarbonyl) thiazolidine-2-carboxylic acid (1 g, 4.3 mmol) and carbonyldiimidazole (0.7 g,

4.3 mmol) was dissolved in THF (10 mL). The mixture was shaken for 1 hour at ambient temperature. To the previous solution was added 4-nitrobenzylamine (0.81 g, 4.3 mmol) and triethylamine (0.6 mL, 0.43 g, 4.3 mmol) in a suspension of 10 mL of a mixture of THF and DMF (1/1). and the whole mixture was heated under reflux for 5 hours. The solvents were then evaporated under reduced pressure. The residue was dissolved in 25 mL of ethyl acetate and washed 3 times with 15 mL of water. The organic phase was dried and the solvent was evaporated under reduced pressure. The obtained product was purified on silica gel in dichloromethane / methanol (95/5). N- (4-Nitrobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxamide was obtained as a pale yellow oil in a yield of 80% (1.25 g).

NMR 1 H (CDCl 3, 100 MHz, δ): 1.45 (s, 9H, tBu), 3.09 (m, 3H, CH ₂ -S, CH-S), 3.86 (m, 2H, CH ₂ -CH ₂ -N),

4.57 (m, 2H, _CH2 NH), 6.60 (br s, 1H, NH), 7.41 to 7.50 - 8.14 to 8.23 (4 s, 4 H, arom. H) .

9.3 (4-Aminobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxane

A tip of a Raney nickel knife was added to a solution of 1.25 g (3.4 mmol) of N- (4-nitrobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxamide in 2.5 ml of methanol. The whole mixture was refluxed and hydrazine hydrate (1.75 mL) was added dropwise to the medium. The reaction mixture was kept under reflux for 1 hour, then returned to ambient temperature. The catalyst was filtered off and washed extensively with methanol. The solvent was evaporated under reduced pressure. Then the residue was dissolved in dichloromethane (20 mL) and washed 3 times with 15 mL of water. The organic phase was dried and the solvent was evaporated under reduced pressure. N- (4-Aminobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxamide was obtained as an inert yellow solid (0.315 g, 71%); it was used in subsequent steps without further purification.

NMR 1 H (CDCl ₃ 100 MHz, δ): 1.43 (s, 9H, tBu), 3.08 (m, 2H, CH ₂ -S), 3.67 (m, 3H, CH ₂ -CH ₂₎ -N, CH-S),

4.36 (m, 2H, _CH2 NH), 6.05 (br s, 1H, NH), 6.60 to 6.69 - 7.04 to 7.12 (4 s, 4 H, arom. H ).

9.4 [4 - {[3- (tert-Butoxycarbonyl) -2-thiazolidinyl] carbonylaminomethyl} phenyl] -2-thiophenecarboximidamide

The same experimental procedure as described for Intermediate 2.4, N- (4-aminobenzyl) -3- (tert-butoxycarbonyl) thiazolidine-2-carboxamide, was substituted for 3- (4-aminobenzyl) thiazolidine. The expected substance was obtained in a yield of 77%.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.45 (s, 9R, tBu), 3.14 (m, 3H, CH ₂ -S, CH-S), 3.34 (m, 2H, CH) ₂ -CH ₂ -N),

4.46 (m, 2H, _CH2 NH), 4.83 (br s, 2H, N11 _2), 6.27 (br s, 1H, NH), 7.22 (m, 7H, arom. H ).

9.5. N- (4 - {[2-Thiazolidinyl] carbonylaminomethyl} phenyl) -2-thiophenecarboximidamide fumarate (9)

Using the same experimental procedure as described for Intermediate 5.5, [4 - {[3- (tert-butoxycarbonyl) -2-thiazolidinyl] carbonylaminomethyl} -phenyl] -2-thiophenecarboximidamide replaced 3- {2- [4-aminophenyl-ethyl] ) thiazolidine. The expected substance was obtained as the free base in a yield of 34%. It was converted to a salt with fumaric acid equivalent in ethanol under reflux. Melting point: 167-168 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 2.78 (t, 2H, CH ₂ -S), 3.06 (m, 2H, CH ₂ -NCH ₂ -N), 3.28 (broad s, 1 H, CH-S),

4.26 (m, 2H, _CH2 NH), 4.86 (br s, 1H, NH), 6.45 (br s, 2H, _NH2), 6.81 - 6.83 to 7.19 7.21 (4 s, 4H, aromatic H), 7.10 (t, 1H, thiophene), 7.61 (d, 1H, thiophene), 7.74 (m, 1H, thiophene), 8, 53 (t, 1 H, NH-CO).

IR: Voo (amide): 1624 cm ^-1 ; [nu] _C-N (amidine): 1584 cm <-1> ^.

Example 10

N- (3,5-di-tert-Butyl-4-hydroxyphenyl) -5- [4- {imino (2-thienyl) methylamino} phenyl) -2-furancarboxamide hydroiodide (10)

10.1 2,6-Di-tert-Butyl-4-nitrophenol

2,6-di-tert-Butylphenol (8 g, 39 mmol) was dissolved in 25 mL of cyclohexane at 10 ° C. (1/1) nitric acid / acetic acid (5 mL) was added dropwise to the reaction medium maintained at this temperature. Shaking was then performed for 15 minutes at ambient temperature. Then the precipitate formed was filtered off, washed with water and pentane. The obtained 2,6-di-tert-butyl-4-nitrophenol (6.34 g, 65%) was dried in an oven and used in the next steps without further purification. Pale yellow powder. Melting point: 167-168 ° C. NMR δ H (CDCl 3, 100 MHz, δ): 1.48 (s, 18H, 2tBu), 5.93 (s, 1H, OH), 8.13 (s, 2H, aromatic H).

10.2 2,6-Di-tert-Butyl-4-aminophenol

2,6-di-tert-Butyl-4-nitrophenol (6.3 g, 25 mmol) was dissolved in methanol (100 mL), 0.6 g palladium on carbon (10 wt%) was added and the reaction medium was placed under hydrogen atmosphere under a pressure of 0.2 MPa (2 bar). The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in heptane and filtered. There was thus obtained 2,6-di-tert-butyl-4-aminophenol (2.7 g, 48%) which was used in the following steps without further purification. Pink powder. Melting point: 123-124 ° C. NMR ^! H (CDCl 3, 100 MHz, δ): 6.60 (s, 2H, Ph); 4.65 (broad s, 1H, OH); 3.15 (br s, 2H, NH _2); 1.42 (s, 18H, 2tBu).

10.3. N- (3,5-di-tert-Butyl-4-hydroxyphenyl) -5- (4-nitrophenyl) -2-furancarboxamide

The same experimental procedure as described for Intermediate 8.1 was used. 2,6-di-tert-Butyl-4-aminophenol and 5- (4-nitrophenyl) -2-furanecarboxylic acid replaced thiazolidine and 4- (tert-butoxycarbonylamino) benzeneacetic acid. The expected substance was obtained as a colorless oil in a yield of 56%. NMR 1 H (DMSO, 100 MHz, δ) 1.41 (s, 18H, 2tBu), 6.91 (s, 1H, OH), 7.42 (m, 4H, aromatic H), 7.54 ( s, 2H, aromatic H), 8.30 (m, 4H, aromatic H), 10.11 (s, 1H, NH).

10.4. N- (3,5-di-tert-Butyl-4-hydroxyphenyl) -5- (4-aminophenyl) -2-furancarboxamide

The same experimental procedure as described for Intermediate 1.2 was used. N- (3,5-di-tert-Butyl-4-hydroxyphenyl) -5- (4-nitrophenyl) -2-furan carboxamide replaced 1- (4-nitrophenyl) -1H-imidazole. The expected substance was obtained as a colorless oil in a yield of 59%.

NMR 1 H (DMSO, 100 MHz, δ): 1.41 (s, 18H, 2 tBu), 4.70 (broad s, 2H, NH ₂ ), 6.91 (s, 1H, OH), 7, 50 (m, 4H, aromatic H), 7.54 (s, 2H, aromatic H), 8.20 (m, 4H, aromatic H).

SK 286911 Β6

10.5. N- (3,5-di-tert-Butyl-4-hydroxyphenyl) -5- [4- (imino (2-thienyl) methylamino} phenyl) -2-furancarboxamide hydroiodide (10)

The same experimental procedure as described for Intermediate 1.3 was used. N- (3,5-di-tert-butyl-4-hydroxyphenyl) -5- (4-aminophenyl) -2-fluorocarboxamide replaced 1- (4-aminophenyl) - H-imidazole. The expected product was obtained as a salt in a yield of 27%. Mp .: 273-274 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 6.90 (s, 1H, OH), 7.45 (m, 5H, aromatic H), 7.54 (s, 2H, aromatic H), 8.15 (m, 4H, aromatic H), 9.05-9.90 (broad 2s, 2H, NH ₂ ), 10.01 (s, 1H, NH- CO), 11.57 (s, 1H, H1). IR: ν _OH : 3423-3242 cm ^-1 ; [nu] C-O (amide): 1646 cm &^lt; -1 &gt; nu N (amidine): 1554 cm ^"first

Example 11

3- (3,5-di-tert-Butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride (11)

11.1 Ethyl (3,5-di-tert-butyl-4-hydroxyphenyl) aminoacetate g (4.5 mmol) 2,6-di-tert-butyl-4-aminophenol (intermediate 10.2) and 0.65 g sodium acetate (7.9 mmol) was suspended in 1 mL of ethanol. Bromoacetate (0.94 g, 5.65 mmol) was then added to the medium and the reaction mixture was heated at 65 ° C for 2 hours. The reaction mixture was poured into 20 mL of ice-cold water and the reaction product was extracted with dichloromethane (3 x 15 mL). The organic phases were dried and the solvent was evaporated under reduced pressure. The residue was passed through silica gel in dichloromethane. A colorless oil is obtained consisting of a mixture of 2 substances: the product of mono- and di-substitution. The mixture of these 2 substances was used without further purification in the following steps.

11.2 Ethyl (3,5-di-tert-butyl-4-hydroxyphenyl) - (4-nitrophenylcarbamoyl) aminoacetate

1.13 g (4.2 mmol) of intermediate 11.1 and 0.69 g (4.23 mmol) of 4-nitrophenyl isocyanate were dissolved in 9 ml of dichloromethane. The reaction mixture was shaken for 2.5 hours at ambient temperature. The solvent was evaporated under reduced pressure and the residue was passed through silica gel in dichloromethane. 0.66 g of pure (3,5-di-tert-butyl-4-hydroxyphenyl) - (4-nitro-phenylcarbamoyl) aminoethyl acetate was isolated in the form of a colorless oil. (Yield in 2 steps: 31%).

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.30 (t, 3H, CH ₃ ), 1.46 (s, 18H, 2tBu), 4.23 (q, 2H, CH ₂ -CH ₃ ) , 4.38 (s, 2H, _CH2 CO), 5.50 (s, 1 H, OH), 6.75 (br s, 1H, NH), 7.28 (s, 2H, arom. H) 7.40 - 7.50 - 8.10 - 8.20 (4s, 4H, aroma H).

11.3 (3,5-di-tert-Butyl-4-hydroxyphenyl) - (4-nitrophenyl) -2,5-imidazolidinedione

0.66 g (1.4 mmol) of intermediate 11.2 was dissolved in 10 ml of ethanol at 50 ° C and the whole mixture was heated at this temperature for 2 hours. The precipitate formed was filtered off and washed with cold ethanol. The obtained compound was used directly in the subsequent steps without further purification.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.47 (s, 18H, 2tBu), 4.51 (s, 2H, N-CH ₂ -CO), 5.27 (s, 1H, OH) 7.33 (s, 2H, aromatic H), 7.77-7.86-8.32-8.41 (4s, 4H, aromatic H).

11.4 (3,5-di-tert-Butyl-4-hydroxyphenyl) -1- (4-aminophenyl) -2,5-imidazolidinedione

The same experimental procedure as described for Intermediate 1.2 was used. 3- (3,5-di-tert-Butyl-4-hydroxyphenyl) -1- (4-nitrophenyl) -2,5-imidazolidinedione replaced by 1- (4-nitrophenyl) -1H-imidazole. The expected material was obtained as a white precipitate in a yield of 87%. It was used in the next step without further purification.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.47 (s, 18H, 2tBu), 4.45 (s, 2H, N-CH ₂ -CO), 5.18 (s, 1H, OH) 6.70-6.80-7.16-7.23 (4s, 4H, aromatic H), 7.39 (s, 2H, aromatic H).

11.5 3- (3,5-di-tert-Butyl-4-hydroxyphenyl) -1- {4- [imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride (11)

The same experimental procedure as described for Intermediate 2.4, 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- (4-aminophenyl) -2,5-imidazolidinedione, was substituted for 3- (4-aminobenzyl). ) thiazolidine. The free base was converted to the salt by treatment with 1 mol / L hydrogen chloride in ether. The hydrochloride was obtained in a yield of 53%. Melting point: 258-265 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.65 (s, 2H, CH ₂ ), 7.08 (s, 1H, OH), 7.40 (m, 3H, aromatic H), 7.61 (s, 4H, aromatic H), 8.21 (m, 2H, aromatic H), 9.20 - 9.95 (broad 2s, 2H, NH) ₂ ), 11.75 (s, 1H, HCl). IR: [ _{nu] OH} : 3637-3437 cm <-1>; v _{c = 0} (imidazolidinedione): 1712 cm ^-1;

[nu] _{C- O} (amidine): 1598 cm <-1>.

Example 12

2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-tiazolidinónhydrochlorid (12)

12.1 2- (3,5-di-tert-Butyl-4-hydroxyphenyl) -3- (4-nitrophenyl) -4-thiazolidinone g 3,5-di-tert-butyl-4-hydroxybenzaldehyde (21 mmol) and 2 95 g of paranitroaniline (21 mmol) were dissolved in 50 ml of anhydrous toluene. 0.5 ml of glacial acetic acid was added and the whole was refluxed for 24 hours. Then 1.96 g of mercaptoacetic acid (21 mmol) was added to the medium and reflux continued for a further 24 hours. Then the reaction mixture was returned to ambient temperature, washed with water (3 times with 30 mL). After decantation, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified on silica gel in ethyl acetate / heptane (1/4) to give 1.33 g of pure 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (4-nitrophenyl) -4 -thiazolidinone as a colorless oil (15%).

NMR 1 H (CDCl 3, 100 MHz, δ): 1.36 (s, 18H, 2tBu), 3.91 (s, 2H, CH-S), 5.28 (s, 1H, CH-S), 6 20 (s, 1H, OH), 7.03 (s, 2H, aromatic H), 7.38-7.48-8.11-8.20 (4s, 4H, aromatic H).

12.2 2- (3,5-di-tert-Butyl-4-hydroxyphenyl) -3- (4-aminophenyl) -4-thiazolidinone

1.3 g of 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (4-nitrophenyl) -4-thiazolidinone (3 mmol) and 3.4 g (15 mmol) of stannous chloride dihydrate are added. dissolved in 25 mL of ethyl acetate. The reaction mixture was maintained at 70 ° C for 2 hours. The mixture was then returned to ambient temperature and poured into saturated sodium bicarbonate solution. The expected product was then extracted from the organic phase and then washed 3 times with 10 ml of water. 2- (3,5-di-tert-Butyl-4-hydroxyphenyl) -3- (4-aminophenyl) -4-thiazolidinone was purified on silica gel in ethyl acetate / heptane (1/1) and obtained as a beige of oil in a yield of 69% (0.82 g).

NMR 1 H (CDCl 3, 100 MHz, δ) 1.37 (s, 18H, 2tBu), 3.64 (broad s, 2H, NH ₂ ), 3.89 (s, 2H, CH ₂ -S), δ 22 (s, 1H, CH-S), 5.91 (s, 1H, OH), 6.51-6.59-6.78-6.86 (4 s, 4H, aromatic H), 7 0.04 (s, 2H, aromatic H).

12.3 2- (3,5-di-tert-Butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride (12)

The same experimental procedure as described for Intermediate 2.4, 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (4-aminophenyl) -4-thiazolidinone, was substituted for 3- (4-aminobenzyl) - thiazolidine. The expected compound was obtained in the form of a salt (hydrochloride) by treatment of the free base with a solution of hydrogen chloride in ether in a yield of 43%. Melting point: 58-61 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.32 (s, 18H, 2tBu), 3.93 (m, 2H, CH-S), 6.57 (s, 1H, CH-S), 7 10.08 (s, 2H, aromatic H), 7.41 (m, 5H, aromatic H), 8.15 (m, 2H, aromatic H), 9.10 - 9.90 (broad 2s, 2H , NH ₂ ), 11.45 (broad s, 1H, HCl).

IR: v _OH : 3624-343 cm ^-1 ; nu 0 (thiazolidinone): 1679-1658 cm ^-1; nu N (amidine): 1568 cm ^'1'

Example 13

5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione fumarate ( 13)

13.1 1-Methyl-3- (4-nitrophenyl) -2,4-imidazolidinedione

0.47 g of sarcosine ethyl ester, HCl (3 mmol) was dissolved in 5 mL of dichloromethane and 0.42 mL (3 mmol) of triethylamine was added. 0.5 g of 4-nitrophenylisocyanate (3 mmol) in a solution of 5 ml of dichloromethane was added dropwise to the previous mixture and the reaction mixture was kept at ambient temperature for 30 minutes. The organic solution was then washed with water (3 x 10 mL), then dried and the solvent was evaporated under reduced pressure.

The residue was dissolved in 10 mL of ethanol and the reaction medium was heated under reflux for 2 hours. The reaction medium was then returned to ambient temperature, and the precipitate formed was filtered off. There was thus obtained 1-methyl-3- (4-nitrophenyl) -2,4-imidazolidinedione in 72% yield (0.5 g) and was used in the next step without further purification.

NMR 1 H (CDCl 3, 100 MHz, δ): 3.11 (s, 3H, CH ₃ ), 4.09 (s, 2H, CH ₂ ), 7.70-7.79-8.27-8, 37 (4 s, 4H, aromatic H).

13.2 5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- (4-nitrophenyl) -2,4-imidazolidinedione

Intermediate 13.1 (0.5 g, 2.13 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (0.5 g, 2.13 mmol) and b-alanine (0.123 g, 1.4 mmol) ) were dissolved in acetic acid (10 mL). The reaction mixture was kept under reflux for 24 hours. The reaction medium was then returned to ambient temperature, 40 ml of water was added to the medium and the whole mixture was shaken for 1 hour. The precipitate formed was filtered off and washed with water. The filtrate was concentrated in vacuo and the evaporation residue was purified on silica gel (eluent: heptane / ethyl acetate: 4/1). Pure fractions were collected and concentrated to dryness to give the expected product in a yield of 32% (03 g).

SK 286911 Β6

NMR δ (CDCl 3, 100 MHz, δ): 1.49 (s, 18H, 2tBu), 3.35 (s, 3H, CH ₃ ), 5.59 (s, 1H, OH), 6.40 (s 1 H, CH = C), 7.75-7.84-8.31-8.40 (4 s, 4H, aromatic H), 7.92 (s, 2H, aromatic H).

13.3 5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- (4-aminophenyl) -2,4-imidazolidinedione

The same experimental procedure as described for Intermediate 12.2 was used. 5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- (4-nitrophenyl) -2,4-imidazolidinedione replaced by 2- (3,5-di-tert- butyl-4-hydroxyphenyl) -3- (4-nitrophenyl) -4-thiazolidinone. The expected substance was obtained with a yield of 45%.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.47 (s, 18H, 2tBu), 3.30 (s, 3H, CH ₃ ), 5.51 (s, 1H, OH), 6.28 (s, 1H, CH = C), 6.69-6.78-7.12-7.21 (4 s, 4H, aromatic H), 7.91 (s, 2H, aromatic H).

13.4 5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione ( 13) fumarate

The same experimental procedure as described for Intermediate 2.4 was used. 5 - [(3,5-di-tert-Butyl-4-hydroxyphenyl) methylene] -1-methyl-3- (4-aminophenyl) -2,4-imidazolidinedione replaced by 3- (4-aminobenzyl) thiazolidine. The expected substance was obtained in the form of a salt (fumarate) by treatment of the free base with an equivalent of filmaric acid in ethanol with a yield of 35%. Mp 54.5-57.5 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 3.22 (s, 3H, CH ₃ ), 6.59 (s, 1H, CH = C), 61 (s, fumaric acid), 6.97 - 6.99 - 7.30 - 7.32 (4 s, 4H, aromatic H), 7.11 (t, 1H, thiophene), 7.64 (d 1H, thiophene), 7.79 (m, 1H, thiophene), 7.96 (s, 2H, aromatic H).

IR: _δH : 3618-3433 cm ^-1 ; v _{c = 0} (imidazolidinedione): 1711 cm ^-1;

[nu] _C-N (amidine): 1585 cm <-1> ^.

Example 14

2- (S) -4- (S) -N- [4-hydroxy-3,5-bis (l, l-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} -prolinamide hydrochloride (14)

14.1 2- (S) -4- (S) -1 - [(1,1-Dimethylethoxy) carbonyl] -4- (4-nitrophenoxy) proline methyl ester

A solution of 4.37 g (30.7 mmol) of 4-nitrophenol in 30 mL of anhydrous N-methyl-2-pyrrolidinone was added slowly to a suspension cooled to 0 ° C, 1.23 g (30.7 mmol) of NaH 60% by weight in a suspension of 30 ml of anhydrous N-methyl-2-pyrrolidinone, under an inert atmosphere. After shaking for one hour at 0 ° C, the proline derivative (6 g, 15 mmol) was added in one portion. The reaction mixture was shaken at 20 ° C for 15 hours, followed by heating to 80 ° C for 2 hours to complete the reaction. Then the reaction mixture was returned to 20 ° C, 200 ml of ethyl acetate and 100 ml of 1M sodium carbonate solution were added to the medium. After decantation, the organic phase was washed successively with dilute sodium carbonate solutions until complete extraction of the unreacted phenol derivative, 2 x 100 ml of water and 100 ml of brine. The organic solution was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give a pale yellow oil which crystallized spontaneously in air. The crystals were collected and washed with 3 x 50 mL of ethyl ether. After drying, colorless crystals are obtained with a yield of 63%. M.p .: 155-157 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.34-1.40 (2s, 9H, tBu); 2.45 (m, 2H, _CH2); 3.60 (m, 2H, _CH2 N); 3.58 to 3.63 (2 s, 3 H, O-CH _3); 4.40 (m, 1H, CH - CO ₂ ); 5.22 (m, 1H, HC-O); 7.63 (m, 4H, Ph).

14.2 2- (S) -4- (S) -1 - [(1,1-Dimethylethoxy) carbonyl] -4- (4-nitrophenoxy) proline

730 mg (approximately 16 mmol) of potassium carbonate diluted in 5 mL of water was added at 20 ° C to a 100 mL flask containing 2.87 g (7.84 mmol) of 14.1 in 40 mL of ethanol. After shaking for 15 hours, the reaction mixture was diluted with 100 mL ethyl acetate, acidified at 0 ° C with 12 M HCl and decanted. The organic phase was washed with 50 ml of water, followed by 50 ml of brine. After drying over sodium sulfate, the organic solution was filtered off and concentrated to dryness under vacuum. 2.67 g of a white powder were obtained, which was used directly in the next step without further purification.

NMR δ (CDCl ₃ , 100 MHz, δ) 1.50 (s, 9H, tBu); 2.60 (m, 2H, _CH2); 3.80 (m, 2H, _CH2 N); 4.60 (m, 1H, CH - CO ₂ ); 5.07 (m, 1 H, HC-O); 7.58 (m, 4H, Ph); 8.95 (br s, 1H, CO ₂ H).

14.3 2- (S) -4- (S) -1 - [(1,1-Dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis- (1,1-dimethyl-ethyl) -phenyl ] -4- (4-nitrophenoxy) -prolinamide

1.28 g (6.20 mmol) of dicyclohexylcarbodiimide was added at 0 ° C to a solution of 1.99 g (5.64 mmol) of intermediate 14.2, 1.25 g (5.64 mmol) of intermediate 10.2 and 845 mg (6, 20 mmol) of hydroxybenzotriazole in 25 ml of DMF. After shaking for 24 hours at 20 ° C, the reaction mixture was filtered off and the precipitate was washed with ethyl acetate. The filtrate was diluted with 100 mL of ethyl acetate and washed successively with 2 x 40 mL of 1M sodium carbonate solution, 2 x 40 mL of water and 40 mL of brine. After drying over sodium sulfate, the organic solution was filtered off and concentrated to dryness in vacuo to give a brown oil which was purified on a silica gel column (eluent heptane / ethyl acetate: 1/1). Pure fractions were collected and then concentrated in vacuo. 1.35 g were obtained

286 (43%) beige powder. Melting point: 117-120 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.20-1.70 (m, 27 H, 3x tBu); 2.68 (m, 2H, _CH2); 3.80 (m, 2H, _CH2 N);

4.58 (m, 1H, CH - CO ₂ ); 5.10 (m, 2H, OH, HC-O); 7.25 - 7.28 (2s, 2H, Ph - OH); 7.51 (m, 4H, _Ph-NO2); 8.00 (broad s, 1H, NHCO).

14.4 2- (S) -4- (S) -1 - [(1,1-Dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis- (1,1-dimethyl-ethyl) phenyl] 4- (4-aminophenoxy) -prolinamide

Intermediate 14.3 (1.35 g, 2.4 mmol) in ethanol (30 mL) was dissolved in an autoclave equipped with a magnetic stirrer in the presence of a 1/2 wt% Pd / C spatula. The reaction mixture was shaken under 1.5 bar of hydrogen for 3 hours. After filtration through Celite, the filtrate was concentrated in vacuo. The residue was dissolved in 1/1 ethyl ether / heptane and after crystallization was filtered and washed using heptane. A beige powder was obtained with a yield of 60%. Melting point: 112-113 ° C.

NMR 1 H (CDCl ₃ , 100 MHz, δ) 1.20-1.70 (m, 27H, 3x tBu); 2.55 (m, 2H, _CH2); 3.50 (br s, 2H, NH _2);

3.75 (m, 2H, _CH2 N); 4.48 (m, 1H, CH - CO ₂ ); 4.80 (m, 1H, HC - O); 5.10 (s, 1 H, OH); 6.65 (m, 4H, _Ph-NH2);

7.28 (m, 2H, Ph - OH); 8.00 (broad s, 1H, NHCO).

14.5 2- (S) -4- (S) -N- [4-Hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -4- [4 - [(imino (2-thienyl) - methyl) amino] phenoxy} proline amide hydrochloride (14)

A mixture of 694 mg (1.32 mmol) of intermediate 14.4 was heated at 50 ° C for 48 hours in the presence of 376 mg (1.32 mmol) of S-methyl-2-thiophenethiocarboximide hydroiodide in a solution of 15 mL of isopropanol. The reaction mixture was then concentrated to dryness under vacuum and the evaporation residue was suspended in 50 mL of ethyl acetate. After addition of 50 ml of saturated Na ₂ CO ₃ solution, the organic phase was decanted and washed successively with 25 ml of saturated Na ₂ CO ₃ solution, 50 ml of water and 50 ml of brine. After drying over sodium sulfate, the organic solution was filtered off and concentrated to dryness in vacuo to give a yellow powder which was purified on a silica gel column (eluent: ethyl acetate). Pure fractions were collected and then concentrated in vacuo. 686 mg (82%) of a beige powder were obtained, which was immediately dissolved in 5 ml of a 4 mol / L solution of HCl in 1,4-dioxane. After shaking for 15 hours at 20 ° C, 20 mL of dry ethyl ether was added to the reaction mixture. The precipitate which formed was then filtered off, washed with 2 x 25 ml dry ethyl ether and dried in an oven to give 270 mg of beige powder. Mp: 233.5-235 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2 x tBu); 2.61 (m, 2H, _CH2); 3.60 (m, 2H, _CH2 N); 4.56 (m, 1H, CH - CO ₂ ); 5.25 (m, 1 H, HC-O); 6.92 (s, 1 H, OH); 7.21 (m, 4H, Ph - N); 7.38 (m, 1H, thiophene); 7.45 (s, 2H, Ph - OH); 8.18 (m, 2H, thiophene); 8.78 (br s, 1 H, NH ^4); 9.09 (br s, 1 H, NH ^4); 9.80 (br s, 1 H, NH ^4);

10.68 (c, 1H, CONH); 11.42 (br s, 1 H, NH ^4).

IR: v _OH : 3624-3420 cm ^-1 ; [Nu] C-O (amide): 1653 cm <^4>; ν _c -n (amidine): 1610 cm ^4.

Example 15

5,6-Dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1- (2H) -pyridinecarboxamide hydrochloride (15)

15.1 5,6-Dihydro-N- (4-nitrophenyl) -1- (2H) -pyridinecarboxamide

900 mg (5 mmol) of 4-nitrophenylisocyanate was dissolved under argon in a 100 mL three neck flask in 17 mL of dry DMF. 0.45 ml (5 mmol) of 1,2,3,6-tetrahydropyridine was added to this solution at once and the shaking was maintained for 15 hours. The reaction mixture was then concentrated to dryness in vacuo and the evaporation residue was placed on a silica gel column. After elution with heptane / ethyl acetate: 4/6, the pure fractions were collected and concentrated under reduced pressure to give 860 mg (70%) of a sharp yellow powder. Melting point: 169-170 ° C.

NMR 1 H (DMSO, 100 MHz, δ): 2.29 (m, 2H, CH-CH ₂ ); 3.69 (m, 2H, _CH2 N); 4.10 (m, 2H, = _CH-CH2-N);

5.91 (m, 2H, CH-CH); 8.09 (m, 4H, Ph); 9.32 (broad s, 1H, NHCO).

15.2 N- (4-Aminophenyl) -5,6-dihydro-1- (2H) -pyridinecarboxamide

The same experimental procedure as described for Intermediate 12.2, 5,6-dihydro-N- (4-nitrophenyl) -1- (2H) -pyridinecarboxamide was used to replace 2- (3,5-di-tert-butyl-4-hydroxyphenyl). ) -3- (4-nitrophenyl) -4-thiazolidinone. A brown oil was obtained with a yield of 36%.

NMR 1 H (CDCl ₃ + D ₂ O, 400 MHz, δ): 2.20 (m, 2H, = CH-CH ₂ ); 3.59 (m, 2H, _CH2 N); 3.95 (m, 2H, = _CH-CH2-N); 5.84 (m, 2H, CH-CH); 6.90 (m, 4H, Ph); 9.32 (broad s, 1H, NHCO).

15.3 5,6-Dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1- (2H) -pyridinecarboxamide hydrochloride (15)

The same experimental procedure as described for Intermediate 14.5 was used. N- (4-aminophenyl) -5,6-dihydro-1- (2H) -pyridinecarboxamide replaced 2- (S) -4- (S) -1 - [( l, l-dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis (l, l-dimethylethyl) phenyl] -4- (4-aminophenoxy) -prolinamide. After salt formation and using a 1 mol / L HCl solution in ethyl ether, a pale yellow powder was obtained in a yield of 55%. Melting point: 230-231 ° C.

SK 286911 Β6

NMR 1 H (DMSO, 400 MHz, δ): 2.16 (m, 2H, = CH-CH ₂ ); 3.59 (m, 2H, _CH2 N); 3.98 (m, 2H, = _CH-CH2-N);

5.80 (m, 2H, CH-CH); 7.52 (m, 4H, Ph); 7.38 (s, 1H, thiophene); 8.16 (m, 2H, thiophene); 8.78 (broad s, 1H, NH ⁺ );

8.81 (s, 1 H, CONH); 9.73 (broad s, 1H, NH ⁺ ); 11.41 (broad s, 1H, NH ⁺ ).

IR nu (urea): 1637 cm ^-1, [nu] _C-N (amidine): 1583 cm <-1> ^.

Example 16 N- [4-Hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2- (R, S) - {4 - [(imino (2-thienyl) methyl) amino] phenyl } -4- (R) -thiazolidinecarboxamide fumarate (16)

16.1. 2- (R, S) - (4-Nitrophenyl) -4- (R) -thiazolidinecarboxylic acid (17.08 mmol) of L-cysteine hydrochloride and 2.18 g (22.2 mmol) of sodium acetate were dissolved in 75 ml water. The solution was shaken vigorously during the addition of 3.10 g (20.5 mmol) of 4-nitrobenzaldehyde in a solution of 80 mL of 95% ethanol in portions. A white precipitate rapidly appears in this pale yellow solution, which is formed. Shaking was maintained for one hour, then the reaction mixture was cooled to 0 ° C and filtered. The precipitate was washed successively with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying, a white powder was obtained in a yield of 87%. Melting point: 120-121 ° C.

NMR 1 H (Acetone D 6, 100 MHz, δ): 3.50 (m, 2H, CH ₂ -S); 4.25 (m, 1H, CH - CO); 4.75 (hump 2H, CO ₂ H + + NH); 5.86 (s, 1H, N - CH - S); 8.20 (m, 4H, Ph).

16.2. 3 - [(1,1-Dimethylethoxy) carbonyl] -2- (R, S) - (4-nitrophenyl) -4- (R) -thiazolidine carboxylic acid

The same experimental procedure as described for Intermediate 5.1 was used, 2- (R, S) - (4-nitrophenyl) -4- (R) -thiazolidinecarboxylic acid replaced 4- (tert-butoxycarbonylamino) -benzeneacetic acid. A pale yellow powder was obtained with a yield of 59%. Melting point: 145-146 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.35 (m, 9H, tBu); 3.40 (m, 2H, _CH2 S); 4.95 (m, 1H, CH - CO); 6.10 (m, 1H, N - CH - S); 8.00 (m, 4H, Ph); 10.00 (broad s, 1H, CO ₂ H).

16.3 3 - [(1,1-Dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2- (R, S) - (4-nitrophenyl) -4 (R) -thiazolidinecarboxamide

The same experimental procedure as described for Intermediate 14.3 was used, 3 - [(1,1-dimethylethoxy) carbonyl] -2- (R, S) - (4-nitrophenyl) -4- (R) -thiazolidinecarboxylic acid replaced 2- (S) -4- (S) -1 - [(1,1-dimethylethoxy) carbonyl] -4- (4-nitrophenoxy) prolm. A white powder was obtained with a yield of 41%. Melting point: 226-227 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.45 (m, 27H, 3x tBu); 3.52 (m, 2H, _CH2 S); 5.00 (m, 1H, CH - CO); 5.15 (s, 1H, OH); 6.10 (broad s, 1H, N-CH-S); 7.30 (s, 2H, Ph - OH); 7.92 (m., 4H, _Ph-NO2); 8.60 (broad s, 1H, CONH).

16.4 3 - [(1,1-Dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2- (R, S) - (4-aminophenyl) -4 (R) -thiazolidinecarboxamide

The same experimental procedure as described for Intermediate 12.2, 3 - [(1,1-dimethylethoxy) carbonyl] -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2 was used. - (R, S) - (4-Nitrophenyl) -4- (R) -thiazolidinecarboxamide replaced 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- (4-nitrophenyl) -4-thiazolidine . The expected product was obtained as a pale yellow powder in a yield of 21%. Melting point: 196-198 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.40 (m, 27H, 3x tBu); 3.50 (m, 4H, _{CH2-S-NH 2);} 5.00 (m, 1H, CH - CO); 5.10 (s, 1 H, OH); 6.01 (broad s, 1H, N-CH-S); 6.98 (m, 4H, _Ph-NH2); 7.25 (s, 2H, Ph - OH); 8.50 (broad s, 1H, CONH).

16.5 N- [4-Hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -2- (R, S) - (4 - [(imino (2-thienyl) methyl) amino] phenyl} -4- (R) -thiazolidinecarboxamide fumarate (16)

The same experimental procedure was used as described for Intermediate 14.5, Intermediate 16.4 replaced 2- (S) -4- (S) -1 - [(1,1-dimethylethoxy) carbonyl] -N- (4-hydroxy-3, 4- 5-Bis- (1,1-dimethylethyl) phenyl] -4- (4-aminophenoxy) proline amide 16.5 was obtained as the free base then converted to the salt in the presence of filmaric acid under reflux in ethanol for 30 minutes. The powder was obtained in a total yield of 30% Melting point: 201-204 ° C.

NMR 1 H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2 x tBu); 3.17 (m, 2H, _CH2 S); 3.29 (broad s, 1H, NH thiazolidine); 3.91 (m, H, -CH-CO); 4.31 (m, -H, CH-CO); 5.59 (s, 1H N-CH-S); 5.67 (s, -H, N-CH-S); 6.61 (s, 2H, fum,); 6.74 (m, 2H, NH ₂ amidine); 7.11 (m, 1H, thiophene); 7.19 (m, 4H, Ph - N); 7.42 (s, 2H, Ph - OH); 7.62 (m, 1H, thiophene); 7.73 (broad s, 1H, thiophene); 9.69 (s, H, CON H); 9.95 (s, H, CONH).

IR: [ _{nu] OH} : 3625-341 cm <-1>; Vc = ₀ (amide): 1652 cm ^-1, v _{c- N} (amidine): 1604 cm ^-1

Example 17 N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -2- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -4-thiazolecarboxamide hydroiodide (17)

17.1 4-Nitrobenzene-carbothioamide

6.06 g (15 mmol) of Lawesson's reagent was added to a solution of 4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxane. The reaction mixture was heated under reflux for two hours. The solution was then returned to ambient temperature, poured into 150 ml of water and extracted 5 times with 100 ml of ethyl acetate. The organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow oil which was purified on a silica gel column (eluent: heptane / ethyl acetate 1/1). Pure fractions were collected and concentrated in vacuo. 3.26 g of a yellow powder were obtained in a yield of 72%. Melting point: 165-167 ° C.

17.2 Ethyl 2- (4-nitrophenyl) -4-thiazolecarboxylate

Intermediate 17.1 (3.26 g, 17.9 mmol) and ethyl bromopyruvate (2.26 ml, 18 mmol) were introduced successively into a flask containing 100 ml DMF. After shaking the reaction mixture at 23 ° C for 1 hour, the solution was concentrated in vacuo. The evaporation residue was dissolved in 150 ml of dichloromethane and washed successively with 100 ml of water and 100 ml of brine. After drying over magnesium sulfate and filtering, the organic solution was concentrated in vacuo. The obtained powder was then shaken in the presence of 100 ml (3/1) of toluene / ethanol, filtered and washed with 25 ml of the same solvent mixture. 3.2 g (60%) of a beige powder were obtained. Melting point: 156-158 ° C.

17.3 2- (4-Nitrophenyl) -4-thiazolecarboxylic acid

A solution of 0.82 g (14.5 mmol) of KOH in 5 mL of water was added dropwise at 23 ° C to the intermediate solution.

17.2 (2.15 g, 7.25 mmol) in 100 mL acetone. After shaking overnight, the precipitate formed was filtered off and washed with 10 ml of acetone. This precipitate was dissolved in a mixture of 100 mL of ethyl acetate and 100 mL of a 1 mol / L HCl solution. After decantation, the aqueous phase was re-extracted with 25 ml of ethyl acetate. The organic phases were collected and washed successively with 25 ml of water and 50 ml of brine. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow powder in 93% yield. Melting point: 250-252 ° C.

17.4N- [3,5-bis (l, l-dimethylethyl) -4-hydroxyphenyl] -2- (4-nitrophenyl) -4-thiazolecarboxamide

The same experimental procedure as described for Intermediate 14.3 was used, Intermediate 17.3 replaced Intermediate 14.2. The expected substance was obtained as a yellow powder in a yield of 51%. Melting point: 262-264 ° C.

NMR 1 H (acetone d6.100 MHz, δ) 1.60 (s, 18H, 2tBu), 6.12 (s, 1H, OH), 8.21 (m, 2H, aromatic H), 8.50 (s, 4H, aromatic H), 8.60 (s, 1H, thiazole), 9.93 (broad s, 1H, CO-NH).

17.5 N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -2- (4-aminophenyl) -4-thiazolecarboxamide

3.59 g (16 mmol) of SnCl ₂ , 2H ₂ O was introduced into a solution of intermediate 17.4 (1.50 g, 3.18 mmol) in 50 mL of ethyl acetate / ethanol / acetone (2/1/2). The reaction mixture was heated to reflux for 5 hours and finally, after cooling, half-concentration was carried out in vacuo. The evaporation residue was then poured into 50 ml of cold water; the precipitate that formed was diluted with 100 mL of ethyl acetate and 25 mL of saturated NaHCO ₃ solution. The cloudy mixture was filtered through Celite and the filtrate was decanted. The organic phase was washed successively with 50 ml of water and 50 ml of brine. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo to give a pale yellow powder, which was purified by washing with Et ₂ O / Heptane (90/10). The expected substance was obtained as a pale yellow powder in a yield of 55%. Melting point: 267-268 ° C.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.49 (s, 18H, 2 tBu), 4.00 (broad s, 2H, NH ₂ ), 5.11 (s, 1H, OH), 6, 72 (m, 2H, aromatic H), 7.60 (s, 2H, aromatic H), 7.81 (m, 2H, aromatic H), 8.05 (s, 1H, thiazole), 9, 10 (broad s, 1H, CO-NH).

17.6 N- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -2- (4 - [(imino (2-thienyl) methyl) amino] phenyl) -4-thiazolecarboxamide hydroiodide (17)

The same experimental procedure was used as described for Intermediate 1.3, Intermediate 17.5 replaced Intermediate 1.2. A yellow powder was obtained with a yield of 27%. Melting point: 270-272 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.40 (s, 18H, 2H), 6.89 (s, 1H, OH), 7.41 (m, 1H, aromatic H), 7, 63 (m, 4H, aromatic H), 8.11 (m, 1H, aromatic H), 8.20 (m, 1H, aromatic H), 8.36 (m, 2H, aromatic H), 8.48 (s, 1H, aromatic H),

9.19 (broad s, 1H, NH ⁺ ), 9.90 (broad s, IH, NH ⁺ ), 10.02 (s, IH, CO-NH), 1.15 (s, IH, NH ⁺⁾ ).

LR: the _{C = 0} (amide): 1660 cm ^-1; [nu] _C-N (amidine): 1646 cm <-1> ^.

SK 286911Β6

Example 18 N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4- (S) - (4 - [(imino (2-thienyl) methyl) amino] phenoxy} -pyrrolidine- 2- (R) -carboxamide dihydrochloride (18)

18.1 1- (1,1-Dimethylethyl) - and 2-methyl-4- (S) - (4-nitrophenoxy) -1,2- (R) -pyrrolidine dicarboxylate

4.38 g (31.5 mmol) of 4-nitrophenol in a solution of 40 ml of anhydrous N-methyl-2-pyrrolidinone was added dropwise to a suspension of 1.26 g (31.5 mmol) of NaH as 60% by weight in 60 ml of anhydrous N-methyl-2-pyrrolidinone in a three-necked flask cooled to 0 ° C under an inert atmosphere. The reaction was accompanied by a significant release of hydrogen. After shaking for one hour at 0 ° C, 6 g (15 mmol) of 1- (1,1-dimethylethyl) - and 2-methyl-4- (R) - {[(4-methylphenyl) sulfonyl] -oxy were added in one portion. } -1,2- (R) -pyrrolidine dicarboxylate, shaking was maintained for an additional 15 hours at 23 ° C and the reaction was completed at reflux for 5 hours. The reaction mixture was then returned to 23 ° C, diluted with 150 mL of ethyl acetate and 100 mL of a 1 mol / L sodium carbonate solution. After decantation, the aqueous phase was re-extracted twice with 50 ml of ethyl acetate. The organic phases were separated and washed successively with sodium carbonate (until the excess 4-nitrophenol was lost from the organic phase), with water until neutrality was achieved and finally with 100 ml of brine. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo to give an oily brown residue which was purified on a silica gel column (eluent: heptane / ethyl acetate: 8/2). Pure fractions were collected and concentrated in vacuo to give a pale yellow oil in a yield of 83%.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.41 (s, 9H, tBu), 2.40 (m, 2H, CH ₂ ), 3.80 (s, 5H, CH ₃ + CH ₂ ) 4.50 (m, 1H, CH-N), 5.03 (m, 1H, CH-O), 6.95 (m, 2H, aromatic H), 8.22 (m, 2H, aroma). H).

18.21.1-Dimethylethyl 2- (R) -carboxy-4- (S) - (4-nitrophenoxy) -1-pyrrolidinecarboxylate

A solution of 2.14 g (38 mmol) of K.OH in 15 ml of water was added dropwise at 0 ° C to a solution of 7 g (19 mmol) of intermediate 18.1 in 100 ml of methanol. The reaction mixture was shaken at 23 ° C for 15 hours and finally concentrated half under vacuum. After dilution with 50 ml of ethyl acetate and 50 ml of sodium carbonate, the mixture was decanted. The organic phase was separated and the aqueous phase was acidified with cold 1N HCl solution, then the product was extracted with 100 mL of ethyl acetate. The organic solution was then washed with 50 ml of water and 50 ml of brine. After drying over magnesium sulfate and filtration, the solution was concentrated in vacuo. A pale yellow oil was obtained with a yield of 66%.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.52 (m, 2H, CH ₂ ), 3.80 (m, 2H, CH ₂ ), 4.48 (m, 1H, CH-N), 5.03 (m, 1H, CH-O), 5.92 (broad s, CO ₂ H), 6.92 (m, 2H, aromatic H), 8, 20 (m, 2H, aromatic H).

18.3 1,1-Dimethylethyl-2- (R) - {[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] amino] carbonyl} -4- (S) - (4-nitrophenoxy) pyrrolidine -1-carboxylate

The same experimental procedure as described for Intermediate 14.3 was used, Intermediate 18.2 replaced Intermediate 14.2. A beige powder was obtained with a yield of 43%. Melting point: 140-142 ° C. NMR δ (CDCl ₃ , 100 MHz, δ): 1.45 (s, 18H, 2 tBu), 1.50 (s, 9H, tBu), 2.30 (m, 1H, 1/2 CH ₂ ), 2.95 (m, 1H, 1/2 CH ₂ ), 3.75 (m, 2H, CH ₂ ), 4.65 (m, 1H, CH-N), 5.10 (m, 2H, CH- O + OH), 6.98 (m, 2H, aromatic H), 7.31 (s, 2H, aromatic H), 8.22 (m, 2H, aromatic H), 9.10 (broad S (1H, CO - NH).

18.4 1,1-Dimethylethyl-2- (R) - {[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] amino] carbonyl} -4- (S) - (4-aminophenoxy) - pyrrolidine-1-carboxylate

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 18.3 replaced Intermediate 14.3. After purification on a silica gel column (eluent: heptane / ethyl acetate: 1/1) and concentration of the pure fractions, the expected compound is obtained in the form of a beige powder in a yield of 70%. Melting point: 104-106 ° C.

1 H (CDCl ₃ , 100 MHz, δ) 1.45 (s, 18H, 2Bu), 1.50 (s, 9H, tBu), 1.60 (s, 2H, NH ₂ ), 2.10 ( m, 1H, 1/2 CH ₂ ), 2.80 (m, 1H, 1/2 CH ₂ ), 3.60 (m, 2H, CH ₂ ), 4.60 (m, 1H, CH-N) 4.85 (m, 1H, CH-O), 5.04 (s, 1H, OH), 6.70 (m, 4H, aromatic H), 7.34 (s, 2H, aromatic H) 9.10 (broad s, 1H, CO-NH).

18.5 N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4- (S) - (4 - [(imino (2-thienyl) methyl) amino] phenoxy} pyrrolidine-2- (R) -carboxamide dihydrochloride (18)

The same experimental procedure as described for Intermediate 2.4 was used, Intermediate 18.4 replaced 3- (4-aminobenzyl) -thiazolidine. The free base obtained as a pale yellow powder is directly deprotected in the presence of 10 equivalents of a 4 mol / L solution of anhydrous HCl in 1,4-dioxane. After shaking for 15 hours, the precipitate formed was filtered off, the crystals were washed with acetone followed by ethyl ether. The expected product was obtained as a pale yellow powder in a yield of 53%. Mp 245-247 ° C. NMR 1 H (DMSO d 6, 400 MHz, δ): 1.36 (s, 18H, 2tBu), 2.29 (m, 1H, 1/2 CH 2), 2.71 (m, 1H, 1/2 CH ₂ ), 3.42 (m, 1H, 1/2 CH ₂ ), 3.77 (m, 1H, 1/2 CH ₂ ), 4.57 (m, 1H, CH-N), 5.26 ( m, 1H, CH-O), 6.93 (s, 1H, OH), 7.17 (m, 2H, aromatic H), 7.37 (m, 1H, aromatic H), 7.42 ( m, 2H, aromatic H), 7.48 (s, 2H, aromatic H), 8.17 (m, 2H, aromatic.

SK 286911Β6

H), 8.81 (broad s, 1H, NH ⁴ ), 9.03 (broad s, 1H, NH ⁴ ), 9.78 (broad s, 1H, NH ⁴ ), 10.70 (s, 1H, CO-NH);

10.84 (broad s, 1H, NH ⁴ ), 11.50 (broad s, 1H, NH ⁴ ).

IR: _c . _δ (amide): 1681 cm ^-1 ; the _C _ _N (amidine): 1652 cm ^"first

Example 19 Methyl-1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H- [1] -benzopyran-2-yl) carbonyl] -4- (S) ) - {4 - [(imino- (2-thienyl) methyl) amino] phenoxy} pyrrolidine-2- (S) -carboxylate hydrochloride (19)

19.1 1- (1,1-Dimethylethyl) - and 2-methyl-4- (S) - (4-nitrophenoxy) -1,2- (S) -pyrrolidine dicarboxylate

The same experimental procedure as described for Intermediate 18.1, 1- (1,1-dimethylethyl) and 2-methyl-4- (S) - {[(4-methylphenyl) sulfonyl] oxy) -1,2- (R) was used. The pyrrolidine dicarboxylate derivative was used instead

1- (1,1-dimethylethyl) - and 2-methyl-4- (R) - {[(4-methylphenyl) sulfonyl] oxy} -1,2- (R) -pyrrolidine dicarboxylate derivative. The expected product was obtained as a white powder in a yield of 63%. M.p .: 155-157 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.37 (25, 9H, tBu), 2.22 (m, 1H, 1/2 CH ₂ ), 2.62 (m, 1H, 1H) 2 CH ₂ ), 3.45 (m, 1H, 1/2 CH ₂ ), 3.62 (2 s, 3H, OCH ₃ ), 3.78 (m, 1H, 1/2 CH ₂ ), 4, 42 (m, 1H, CH-N), 5.20 (m, 1H, CH-O), 7.07 (m, 2H, aromatic H), 8.20 (m, 2H, aromatic H).

19.2. Methyl 4- (S) - (4-nitrophenoxy) -pyrrolidine-2- (S) -carboxylate ml (94 mmol) of trifluoroacetic acid diluted with 10 ml of dichloromethane was added to the solution at 0 ° C.

3.45 g (9.4 mmol) of intermediate 19.1 in 15 ml of dichloromethane. The reaction mixture was then shaken for 2 hours at 23 ° C and finally concentrated in vacuo. The evaporation residue was diluted with 100 ml of dichloromethane and the organic solution was washed successively 3 times with 20 ml of saturated Na ₂ CO ₃ solution, twice with 20 ml of water and finally with 20 ml of brine. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo to give a pale yellow oil in 78% yield.

19.3 Methyl-1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H- [1] -benzopyran-2-yl) carbonyl] -4- (S) - (4-nitro-phenoxy) -pyrrolidine-2 (S) -carboxylate

1.3 g (8.06 mmol) of 1,1'-carbonyldiimidazole was added to a solution of 1.83 g (7.33 mmol) of Trolox in 20 mL of dry THF. After shaking for one hour at 23 ° C, a solution of 1.95 g (7.33 mmol) of intermediate 19.2 diluted in 10 mL of dry THF was added dropwise. The reaction mixture was shaken at 23 ° C for 15 hours and finally concentrated to dryness under vacuum. The residue was diluted with 100 mL of ethyl acetate and the organic solution was washed twice with 50 mL of water and 50 mL of brine. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo. The evaporation residue was purified on a silica gel column (eluent: heptane / ethyl acetate: 6/4). Pure fractions were collected and evaporated in vacuo to give a yellow powder in 61% yield. Melting point: 103-105 ° C.

1 H NMR (CDCl ₃ , 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.63 (m, 2H, CH ₂ ), 3.60-3.71 (2 s) , 3H, _OCH3), 3.85 (m, 2H, _CH2), 4.70 to 4.88 (2m, 1H, CH-N), 5.02 (m, 1H, CH-O); 6.82 (m, 2H, aromatic H), 8.20 (m, 2H, aromatic H).

19.4 Methyl-1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H- [1] -benzopyran-2-yl) carbonyl] -4- (S) - (4-amino-phenoxy) -pyrrolidine-2 (S) -carboxylate

The same procedure as described for Intermediate 14.4 was used, Intermediate 19.3 replaced Intermediate 14.3. The expected product was obtained as a white powder in a yield of 95%. Melting point: 110-112 ° C.

19.5 Methyl-1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H- [1] -benzopyran-2-yl) carbonyl] -4- (S) - {4 - [(imino (2-thienyl) methyl) amino] phenoxy} pyrrolidine-2- (S) -carboxylate hydrochloride (19)

The same procedure as described for Intermediate 2.4 was used, Intermediate 19.4 replaced Intermediate 2.3. The condensation reaction is carried out only in 2-propanol. After salt formation, the expected product was obtained as a pale yellow powder in a yield of 75%. Mp: 203-206 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.45 (m, 2H, CH ₂ ), 3.45-3.60 (2 s) , 3H, _OCH3), 3.70 (m, 2H, _CH2), 4.51 (m, 1H, CH-N), 5.02 (m, 1 H, CHO), 7.00 (m, 2H , aromatic H), 7.39 (m, 3H, aromatic H), 8.16 (m, 2H, aromatic H), 8.80 (broad S, 1H, NH ⁴ ), 9.75 (broad s, 1H, NH ⁴ ), 11.36 (broad s, 1H, NH ⁴ ).

IR: _c _ ₀ (amide): 1650 cm ^-1, [nu] _C - _N (amidine): 1611 cm <-1> ^.

Example 20 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- (S) - (4) - [(imino (2-thienyl) methyl) amino] phenoxy} pyrrolidine hydrochloride (20)

SK 286911Β6

20.1 1,1-Dimethylethyl 3- (R) - {[(4-methylphenyl) sulfonyl] oxy} -1-pyrrolidinecarboxylate

21.6 g (114 mmol) of p-toluenesulfonyl chloride were added to a solution of 10 g (57 mmol) of (R) -N-boc-3-pyrrolidinol (prepared in a standard manner starting from commercial (R) -3-pyrrolidinol) and 13, 7 ml (171 mmol) of pyridine in 150 ml of dichloromethane. After shaking for 24 hours at 23 ° C, the reaction mixture was washed 3 times with 50 mL of 1 M HCl solution. After decantation, the organic phase was washed with 50 ml of water, followed by 50 ml of brine and finally dried over magnesium sulfate, filtered and concentrated in vacuo. The evaporation residue was purified rapidly on a silica gel column (eluent: heptane / ethyl acetate: 8/2) to give a pale yellow oil in a yield of 67%.

20.2 1,1-Dimethylethyl 3- (S) - (4-nitrophenoxy) -1-pyrrolidine carboxylate

The same experimental procedure as described for Intermediate 18.1 was used, Intermediate 20.1 replaced 1- (1,1-dimethylethyl) - and 2-methyl-4- (R) - {[(4-methylphenyl) sulfonyl] oxy} -1, 2- (R) -pyrrolidine dicarboxylate derivative. The expected product was obtained as a pale yellow powder in a yield of 77%. Melting point: 112-114 ° C.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH ₂ ), 3.60 (m, 4H, CH ₂ -CH ₂ ) 5.00 (m, 1H, CH-O), 6.94 (m, 2H, aromatic H), 8.20 (m, 2H, aromatic H).

20.3 3- (S) - (4-Nitrophenoxy) pyrrolidine

The same experimental procedure as described for Intermediate 19.2 was used, Intermediate 20.2 replaced Intermediate 19.1, brown oil was obtained in quantitative yield.

20.4 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- (S) - (4-nitrophenoxy) ) pyrrolidine

The same experimental procedure as described for Intermediate 19.3 was used, Intermediate 20.3 replaced Intermediate 19.2. The expected product was obtained after chromatography on a silica gel column (eluent: heptane / ethyl acetate: 7/3). The pure fractions after evaporation produced a beige powder in a yield of 23%. Melting point: 176-178 ° C.

NMR 1 H (CDCl ₃₎ 400 MHz, δ): 1.52-2.60 (m, 16H, Trolox), 2.62 (m, 2H, CH ₂ ), 3.50-4.40 (m, 4H, _{CH2 CH2),} 4.80 (m, 1H, CH-O), 6.89 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

20.5 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- (S) - (4-aminophenoxy) ) pyrrolidine

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 20.4 replaced Intermediate 14.3, a white powder was obtained with a yield of 78%. Melting point: 98-100 ° C.

20.6 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- (S) - {4- [20] (imino (2-thienyl) methyl) amino] phenoxy} pyrrolidine hydrochloride (20)

The same procedure was used as described for Intermediate 2.4, Intermediate 20.5 replaced Intermediate 2.3. The condensation reaction is carried out only in 2-propanol. After salt formation, the expected product was obtained as a pale yellow powder in a yield of 85%. M.p .: 195-197 ° C.

NMR 1 H (pyridine d 6, 400 MHz, δ): 1.52-2.48 (m, 16H, Trolox), 2.60-3.05 (m, 2H, CH ₂ ), 3.58-4, 42 (m, 4H, _{CH2 CH2),} from 4.59 to 4.90 (m, 1H, CH-O), 6.65 (m, 1 H, arom. H), 6.89 (m, 2H , aromatic H), 7.01 (m, 1H, aromatic H), 7.15 (m, 1H, aromatic H), 7.30 (m, 1H, NH ⁺ ), 7.41 (m, 1 H, NH ^4), 7.74 (m, 2H, aromatic H), 8.95 (m, 1 H, NH ^+). IR Vc = o (amide): 1650 cm ^-1, vc = n (amidine): 1610 tin ¹

Example 21

3 - {[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [l] benzopyran-2-yl) carbonyl] amino} -l- {4 - [( imino (2-thienyl) methyl) amino] phenyl} pyrrolidine (21)

21.1 3 - {[(1,1-Dimethylethoxy) carbonyl] amino} -1- (4-nitrophenyl) pyrrolidine

The same experimental procedure as described for Intermediate 1.1, 3- (tert-butoxycarbonylamino) pyrrolidine, was substituted for imidazole.

NMR 1 H (CDCl ₃ , 100 MHz, δ) 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH 2), 3.50 (m, 4H, 2 x CH ₂ -N), 4.35 (m, 1H, CH-N), 4.75 (m, 1H, NH), 6.45 (m, 2H, aromatic H), 8.10 (m, 2H, aromatic H).

21.2 3-Amino-1- (4-nitrophenyl) pyrrolidine

The same experimental procedure as described for Intermediate 19.2 was used, Intermediate 21.1 replaced Intermediate 19.1.

NMR 1 H (CDCl ₃ , 100 MHz, δ) 1.50 (broad s, 2H, NH ₂ ), 2.10 (m, 2H, CH ₂ ), 3.10 (m, 1H, CH), 3, 50 (m, 4H, 2 * _CH2), 6.40 (m, 2H, arom. H), 8.10 (m, 2H, arom. H).

SK 286911 Β6

21.3 3 - {[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] amino} -1- (4-nitrophenyl) pyrrolidine

The same experimental procedure as described for Intermediate 19.3 was used, Intermediate 21.2 replaced Intermediate 19.2. A yellow solid was obtained which was used directly in the next step without further purification.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.50-2.20 (m, 18H, Trolox + CH ₂ ), 3.45 (m, 4H, 2 x CH ₂ ), 4.40 (m, 1H, CH), 4.50 (broad s, 1H, NH), 8.15 (m, 2H, aromatic H), 8.35 (m, 2H, aromatic H).

21.4 3 - {[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] amino} -1- (4-aminophenyl) pyrrolidine

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 21.3 replaced Intermediate 14.3.

NMR 1 H (CDCl 3, 100 MHz, δ) 1.50-2.50 (m, 18H, Trolox + CH ₂ ), 3.15 (m, 4H, 2 x CH ₂ ), 4.50 (m, 2H) , CH + NH), 6.40 (m, 4H, aromatic H).

21.5 3 - {[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] amino} -1- {4 - [( imino (2-thienyl) methyl) amino] phenyl} pyrrolidine (21)

The same experimental procedure as described for Intermediate 2.4 was used, Intermediate 21.4 replaced Intermediate 2.3. The expected product was obtained as a yellow powder (free base) in a yield of 81%. Melting point: 135-138 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ) 1.39-2.50 (m, 18H, Trolox + CH ₂ ), 2.85-3.43 (m, 4H, 2 x CH ₂ ), 4, 37 (m, 1 H, CH), 6.23 (br s, 2H, _NH2), 6.46 (m, 2H, arom. H), 6.73 (m, 2H, arom. H), 7, 07 (m, 1H, aromatic H),

7.17 (d, 1 / 2H, 1/2 CONH, J = 7.6 Hz), 7.34 (d, 1 / 2H, 1/2 CONH, J = 7.6 Hz), 7.56 ( m, 1H, aromatic H), 7.68 (m, 1H, aromatic H).

IR: [nu] _C- O (amide): 1657 cm <^4>; v _c . _N (amidine): 1626 cm ^{&lt; 4 &gt;.}

Example 22

4- [3,5-bis (l, l-dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] benzoyl} -N-methyl-lH-imidazole -2-methanamine hydrochloride (22)

22.1 {[3,5-bis- (1,1-Dimethyl-ethyl) -4-hydroxy-phenyl] -a-carbonyl} -methyl-N-methyl-N - [(phenylmethoxy) -carbonyl] -glycinate

This intermediate was obtained in a standard manner starting from Cbz-Sarcosine and 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -2-bromoethanone in the presence of cesium carbonate in DMF.

NMR 1 H (CDCl ₃ , 100 MHz, δ): 1.46 (s, 18H, 2Bu), 3.00 (s, 3H, N-CH ₃ ), 4.20 (m, 2H, O-CH ₂ -Ph), 5.10-5.40 (m, 4H, CH ₂ -N (CH ₃ ) + CO-CH ₂ -O-CO), 5.80 (s, 1H, OH), 7.30 (m, 5H, aromatic H), 7.70 (s, 2H, aromatic H).

22.2 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-N - [(phenylmethoxy) carbonyl] -1H-imidazole-2-methanamine

This intermediate was obtained starting from intermediate 22.1, using the same experimental procedure as described in TetrahedronLett ,. 1993,34,1901. A pale green powder was obtained with a yield of 81%. Melting point: 200-207 ° C.

NMR 1 H (CDCl ₃ , 400 MHz, δ) 1.40 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH ₃ ), 4.50 (m, 2H, O-CH ₂₎ Ph), 5.10 (s, 2H, CH ₂ -N-CO-O), 5.20 (s, 1 H, OH), 7.00 (s, 1 H, imidazole), 7.20 to 7.50 ( m, 7H, aromatic H), 9.90 (s, 1H, NH).

22.3 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-N - [(phenylmethoxy) carbonyl] -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H imidazole-2-methanamine

7.1 g (51.2 mmol) of potassium carbonate were added portionwise to a mixture of 9.96 ml (56.3 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride and 23 g (51.2 ml) of intermediate 22.2 in 200 ml of DMF. When the addition was complete, the reaction mixture was shaken for 3 hours at 50 ° C. The solvent was then removed in vacuo and the residue was diluted with 200 mL of ethyl acetate. The organic solution was washed twice with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The evaporation residue was purified on a silica gel column (eluent heptane / ethyl acetate: 1/1). Pure fractions were evaporated to give a green oil in 53% yield. NMR 1 H (CDCl ₃ , 400 MHz, δ): 0.0 (s, 9H, Si (CH ₃ ) ₃ ), 0.9 (m, 2H, CH ₂ -Si), 1.50 (s, 18H) 2 tBu), 3.00 (s, 3H, _N-CH3), 3.30 to 3.50 (m, 2H, O-CH ₂ -CH ₂ -Si), 4.70 (s, 2H CH _2-N-CO-O), 5.10 (s, 2H, _O-CH2-Ph), 5.20 (s, 2H, _{CH2-imidazole} -OSEM), 5.30 (s, 1H, OH); 7.20 (s, 1H, imidazole), 7.35 (m, 5H, aromatic H), 7.60 (s, 2H, aromatic H).

SK 286911 Β6

22.4 4- [3,5-Bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-2-methanamine

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 22.3 replaced Intermediate 14.3, a brown oil was obtained in a yield of 98%.

H NMR (CDCl, 100 MHz, δ): 0.0 (s, 9 H, Si _{(CH3) 3),} 0.9 (m, 2H, C H _r Si), 1.50 (s, 18H, 2 tBu), 2.50 (s, 3H, N-CH ₃ ), 3.50 (m, 2H, O-CH ₂ -CH ₂ -Si), 4.00 (s, 2H, N-CH ₂ -imidazole ), 5.20 (s, 1 H, OH), 5.40 (s, 2H, _{CH2-imidazole} -OSEM), 7.10 (s, 1 H, imidazole), 7.50 (s, 2H, arom. H).

22.5 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-nitrobenzoyl) -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1 H-imidazole-2-methanamine

A solution of 2.67 g (14.4 mmol) of 4-nitrobenzoic acid chloride in 50 mL of dry THF was added dropwise to a solution of 5.34 g (11.9 mmol) of intermediate 22.4 and 2 mL (14.4 mmol) of triethylamine in 50 ml dichloromethane. After agitation for 2 hours at 23 ^Q C, the mixture was diluted with 100 mL of dichloromethane and the organic solution was washed twice with 100 ml of brine. After drying over magnesium sulfate, the organic phase was filtered and concentrated in vacuo to give a yellow oil which was used as it was in the next step. NMR ¹ H (CDCl ₃ , 400 MHz, δ): 0.0 (s, 9H, Si (CH ₃ ) ₃ ), 0.9 (m, 2H, CH ₂ -Si), 1.50 (s, 18H) 2 tBu), 3.15 (s, 3H, _N-CH3), 3.50 (m, 2H, O-CH ₂ -CH ₂ -Si), 4.80 (s, 2H, _N-CH2 imidazole), 5.20 (s, 2H, _{CH2-imidazole} -OSEM).

5.30 (s, 1H, OH), 6.90 (m, 2H, aromatic H), 7.15 (s, 1H, imidazole), 7.60 (s, 2H, aromatic H), 8.10 ( m, 2H, aromatic H).

22.6 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-nitrobenzoyl) -1H-imidazole-2-methanamine

Intermediate 22.5 (7.42 g, 12.5 mmol) was dissolved in 62.4 mL (62.4 mmol) of a 1 M tetrabutylammonium fluoride solution in the presence of 1.12 g (18.7 mmol) of ethylenediamine. The reaction mixture was heated to reflux for 5 hours and finally poured directly into 200 mL of brine and diluted with 200 mL of ethyl acetate. The organic phase was decanted, washed with 100 ml of brine and finally dried over magnesium sulfate, filtered and concentrated in vacuo. The evaporation residue was purified on a silica gel column (eluent: dichloromethane + 5% ethanol). The expected product was obtained in the form of a red foam in a yield of 37%.

NMR 1 H (CDCl ₃ , 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N-CH ₃ ), 4.70 (s, 2H, N-CH) _2- imidazole),

5.20 (s, 1H, OH), 7.10 (s, 1H, imidazole), 7.40-7.60 (m, 4H, aromatic H), 8.30 (m, 2H, aromatic H) 10.10 (broad s, 1H, NH).

22.7 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-aminobenzoyl) -1H-imidazole-2-methanamine

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 22.6 replaced Intermediate 14.3. An orange solid was obtained in a yield of 52%. Melting point: 129-131 ° C. NMR 1 H (CDCl 3, 400 MHz, δ): 1.50 (s, 18H, 2Bu), 3.10 (s, 3H, N-CH ₃ ), 3.90 (s, 2H, N-CH ₂₎ imidazole)

4.70 (s, 2H, _NH2), 5.20 (s, 1 H, OH), 6.60 (m, 2H, arom. H), 7.10 (s, 1 H, imidazole), 7.30 7.60 (m, 4H, aromatic H), 10.30 (broad s, 1H, NH).

22.8 4- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] benzoyl} -N-methyl-1H- imidazole-2-methanamine hydrochloride (22)

The same experimental procedure as described for Intermediate 4.3 was used, Intermediate 22.7 replaced Intermediate 4.2. A light beige solid was obtained with a yield of 54%. Melting point: 250-260 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H, N-CH ₃ ), 5.00 (s, 2H, N-CH _2- imidazole),

7.30 (s, 1H, OH), 7.35 (m, 1H, thiophene), 7.50 (m, 4H, aromatic H), 7.70 (s, 2H, a. H), 8.00 ( s, 1H, imidazole), 8.20 (m, 2H, thiophene), 9.20 (s, 1H, NH *), 10.00 (s, 1H, NH *), 11.8 (s, 1H, NH *), 14.8 (s, 1H, NH *), 15.2 (s, 1H, NH *).

IR: Voo (amide): 1635 cm ^{@ -1} ; [nu] _C -N (amidine): 1601 cm <-1> ^.

Example 23

N- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -1- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1H-pyrrole-2- carboxamide hydroiodide (23)

23.1 Ethyl 1- (4-nitrophenyl) -1H-pyrrole-2-carboxylate

0.9 g (7.2 mmol) of pyrrole-2-carboxylic acid methyl ester (prepared by a standard method by esterification of commercial pyrrole-2-carboxylic acid) diluted with 10 ml of dry DMF was added dropwise at 0 ° C under an inert atmosphere to a suspension of 0.3 g (7.4 mmol) of NaH 60% in 15 ml of dry DMF. After shaking for one hour at 23 ° C, a solution of 1.01 g (7.2 mmol) of 4-fluoronitrobenzene in 10 mL of dry DMF was added dropwise. The reaction mixture was then heated at 80 ° C for 3 hours. Then the reaction medium was returned to 23 ° C, poured onto a mixture of 100 ml ice + water and finally

The mixture was diluted with 200 ml of ethyl acetate. After decantation, the organic phase was washed 3 times with 100 ml of water, followed by 100 ml of salt water. The organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo. The evaporation residue was purified on a silica gel column (eluent: heptane / ethyl acetate: 9/1). Pure fractions were collected and evaporated in vacuo to give a pale yellow powder in 49% yield.

23.2 1- (4-Nitrophenyl) -1H-pyrrole-2-carboxylic acid

A solution of 0.5 g (7.1 mmol) of KOH in 5 mL of water was added to a flask containing a solution of 0.87 g (3.5 mmol) of intermediate 23.1 in 20 mL of THF cooled to 0 ° C. The reaction mixture was shaken for 24 hours at 23 ° C and finally diluted with 100 mL of ethyl acetate. After decantation, the organic phase was separated and the aqueous phase was cooled using an ice bath before acidification with a concentrated HCl solution. The precipitate formed was then filtered off and washed twice with 20 ml of water. After drying, the expected product was obtained in a yield of 66%.

23.3N- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -1- (4-nitrophenyl) -1H-pyrrole-2-carboxamide

The same experimental procedure as described for Intermediate 14.3 was used, Intermediate 23.2 replaced Intermediate 14.2. The expected substance was obtained as a greenish powder with a crude yield of 25%. The product was used as it was in the next step.

23.4 N- (3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl) -1- (4-aminophenyl) -1H-pyrrole-2-carboxamide

The experimental procedure used was similar to that described for Intermediate 14.4, Intermediate

23.3 replaced intermediate 14.3. The reaction is carried out in dichloromethane / ethanol (1/1). A white powder was obtained with a yield of 61%. Melting point: 218-219 ° C.

23.5 N- [3,5-bis- (1,1-Dimethylethyl) -4-hydroxyphenyl] -1- [4 - [(imino (2-thienyl) methyl) amino] phenyl] -1H-pyrrole-2- carboxamide hydroiodide (23)

The experimental procedure used was similar to that described for Intermediate 1.3, Intermediate

23.4 replaced intermediate 1.2. A pale yellow powder was obtained with a yield of 73%. Melting point: 271-272 ° C. NMR 1 H (DMSO d 6, 400 MHz, δ) 1.35 (s, 18H, 2 tBu), 6.36 (s, 1H, OH), 6.78 (s, 1H, aromatic H), 7, Δ (s, 1H, aromatic H), 7.16 (s, 1H, aromatic H), 7.45 (m, 7H, aromatic H), 8.10 (m, 1H, aromatic H), 8.19 (m, 1H, aromatic H), 9.16 (broad s, 1H, NH ⁺ ), 9.89 (broad s, 2H, CONH ⁴ ), 11.39 (broad s, 1H, NH ⁴⁾ ).

IR Vc = o (amide): 1633 cm ^-1, [nu] _C-N (amidine): 1609 cm ^&lt; -1 & gt ^;.

Example 24:

1- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -3 - {[4 - [[imino (2-thienyl) methyl] amino] phenyl] carbonyl} -2-imidazolidinone hydroiodide ( 24)

24.1 N- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -N '- (2-chloroethyl) urea

0.17 ml (2 mmol) of chloroethyl isocyanate was added to a flask containing a solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml of DMF. The reaction mixture was shaken for 2 hours at 23 ° C and finally diluted with 100 mL of ethyl acetate and 25 mL of water. After decantation, the organic solution was washed with 25 ml of water, twice with 25 ml of brine and finally dried over magnesium sulfate. After filtration and evaporation, the residue was dissolved in isopentane to finally produce the expected product as a pink solid in a yield of 83%. Mp: 169-171 ° C;

NMR 1 H (DMSO d 6.400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.35 (t, 2H, CH ₂ -NH, J = 6.0 Hz), 3.60 ( t, 2H, CH ₂ -C 1, J = 6.0 Hz), 6.20 (t, 1 H, _NH-CH2, J = 5.6 Hz), 6.60 (s, 1 H, OH), 7 10 (s, 2H, aromatic H), 8.30 (s, 1H, NH-Ph).

24.2 1- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -2-imidazolidinone

A solution of 0.22 g (1.93 mmol) of tBuOK in 2 ml of dry DMF was added to a solution of 0.56 g (1.93 mmol) of intermediate 24.1 in 10 ml of dry DMF. After shaking for 3 hours at 23 ° C, the reaction mixture was diluted with 50 mL of water and 100 mL of ethyl acetate. The organic phase was decanted, washed successively with 50 ml of water and 50 ml of brine, dried over magnesium sulfate, filtered and finally concentrated in vacuo. The brown oil thus obtained was dissolved in isopropyl ether to give a white powder in a yield of 51%. Mp .: 205-207 ° C.

NMR 1 H (DMSO d 6, 100 MHz, δ): 1.40 (s, 18H, 2H), 4.60 (m, 2H, CH ₂ ), 4.90 (m, 2H, CH ₂ ), 90 (broad s, 1H, NH), 5.00 (s, 1H, OH), 7.15 (s, 2H, aromatic H).

24.3 1- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -3 - [(4-nitrophenyl) carbonyl] -2-imidazolidinone

1.28 g (6.9 mmol) of 4-nitrobenzoic acid chloride was added portionwise to a solution of 1.0 g (3.45 mmol) of intermediate 24.2 in a mixture of 20 ml of acetonitrile and 10 ml of THF, followed by 0.71 g. (5.15 mmol) of potassium carbonate. After shaking for 3 hours at 23 ° C, the reaction mixture was diluted with 100 mL of dichloromethane and 50 mL of brine. After decanting, the organic phase was washed with 50 ml of brine and dried over sulfate

SK 286911 Β6. After filtration and concentration in vacuo, the evaporation residue was dissolved in isopropyl ether to give, after drying, a yellow solid in 83% yield. Mp > 260 ° C.

NMR 1 H (CDCl ₃₎ 400 MHz, δ): 1.40 (s, 18H, 2'Bu), 3.95-4.20 (m, 4H, 2 CH ₂ ), 5.20 (s, 1H, OH), 7.20 (s, 2H, aromatic H), 7.80 (m, 2H, aromatic H), 8.25 (m, 2H, t and H).

24.4 1- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -3 - [(4-aminophenyl) carbonyl] -2-imidazolidinone

The experimental procedure used was similar to that described for Intermediate 14.4, Intermediate

24.3 replaced intermediate 14.3. The expected product was obtained as a white powder in a yield of 45%. Mp > 260 ° C.

NMR 1 H (CDCl ₃ , 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.90-4.00 (m, 4H, 2 CH ₂ ), 5.15 (s, 1H, OH), 6.60 (m, 2H, aromatic H), 7.13 (s, 2H, aromatic H), 7.60 (m, 2H, aromatic H).

24.5 1- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -3 - {[4 - [[imino (2-thienyl) methyl] amino] phenyl] carbonyl} -2-imidazolidinone hydroiodide (24)

The experimental procedure used was identical to that described for Intermediate 1.3, Intermediate

24.4 replaced intermediate 1.2. The expected product was obtained as a light beige solid in a yield of 79%. Melting point: 220-260 ° C.

NMR 1 H (DMSO d 6.400 MHz, δ); 1.30 (s, 18H, 2 t Bu), 4.00 (m, 4H, 2 _CH2), 6.95 (s, 1 H, OH), 7.20 (s, 2H, arom. H), 7 40 (m, 1H, thiophene), 7.50 (m, 2H, aromatic H), 7.70 (m, 2H, aromatic H), 8.20 (m, 2H, thiophene), 9.20 (m, 2H, aromatic H) broad s, 1H, NH ⁴ ), 9.90 (broad s, 1H, NH ⁴ ), 11.60 (broad s, 1H, NH ⁴ ).

IR: Vo ₀ (urea): 1735 cm ^-1 ; vc_0 (amide): 1649 cm ^-1 ; [nu] _C-N (amidine): 1595 cm <^-1>

Example 25:

3- [3,5-bis (l, l-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -5-izoxazolacetamid hydroiodide (25)

25.1 3,5-bis- (1,1-Dimethylethyl) -N, 4-dihydroxy-benzenecarboxime

This intermediate was prepared according to the experimental procedure described in J. Med. Chem., 1997, 40, 50-60, starting from commercial 3,5-di-tert-butyl-4-hydroxybenzaldehyde. A red foam with a quantitative yield was obtained.

25.2 3,5-Bis- (1,1-dimethylethyl) -N, 4-dihydroxybenzenecarboximidoyl chloride

The same experimental procedure was used as described in Tetrahedron Lett., 1996, 37 (26), 4455 starting from intermediate 25.1, a beige solid was obtained with a crude yield of 77%. This product was used directly in the next step without further purification.

25.3 Methyl 3- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5-isoxazole acetate

The reaction of intermediate 25.2 with 3-butenoic acid methyl ester was performed under the same conditions as described in Tetrahedron Lett. 1996, 37 (26), 4455. The expected substance was obtained as a brown oil in a yield of 49%.

NMR 1 H (CDCl ₃ , 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (dd, 1H, 1/2 CH ₂ -C =N, J = 16.0 Hz and J = 7.8 Hz)

2.90 (dd, 1H, 1/2 CH ₂ -C = N, J = 16.0 Hz and J = 5.8 Hz), 3.10 (dd, 1H, 1/2 CH ₂ -C = O , J = 16.6 Hz and J = 6.9 Hz), 3.60 (d. 1H, 1/2 CH ₂ -C = O, J = 16.6 Hz and J = 10.2 Hz), 5 19 (m, 1H, CH), 5.50 (s, 1H, OH), 7.50 (s, 2H, aromatic H).

25.4. 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5-isoxazoleacetic acid

This intermediate was obtained by saponification of intermediate 25.3 according to the experimental procedure described in J. Med. Chem. 1997, 40, 50-60. A white solid was obtained with a yield of 74%. Melting point: 229-231 ° C.

NMR 1 H (CDCl 3, 400 MHz, δ), 2.90 (dd, 1H, 1/2 CH ₂ -C = N, J = 16.3 Hz and J = 6.0 Hz), 3.10 (dd) 1 H, 1/2 CH ₂ -C = O, J = 16.6 Hz and J = 6.9 Hz), 3.50 (dd, 1H, 1/2 CH ₂ -C = O, J = 16, 6 Hz and J = 10.2 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH), 7.45 (s, 2H, aromatic H).

25.5 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-N- (4-nitrophenyl) -5-isoxazolacetamide

The same experimental procedure as described in Org. Prep. Proced. Int. (1975), 7, 215, starting from intermediate 25.4 and 4-nitroaniline. A white solid was obtained with a yield of 45%. M.p .: 149-151 ° C.

NMR 1 H (CDCl 3, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.70 (m, 1H, 1/2 CH ₂ -C =N), 2.85 (dd, 1H) , 1/2 CH ₂ -C = N, J = 15.1 Hz and J = 7.5 Hz), 3.20 (dd, 1H, 1/2 CH ₂ -C = O, J = 16.7 Hz and J = 7.0 Hz), 3.70 (dd, 1H, 1/2)

SK 286911 Β6

CH ₂ -C = O, J = 16.7 Hz and J = 10.1 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH), 7.45 (s, 2H, aromatic H), 7.70 (m, 2H, aromatic H), 8.20 (m, 2H, aromatic H), 8.50 (s, 1H, NH-CO).

25.6 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-N- (4-aminophenyl) -5-isoxazolacetaniid

The same experimental procedure as described for Intermediate 17.5 was used, Intermediate 25.5 replaced Intermediate 17.4, a colorless oil was obtained with a yield of 80%.

NMR δ (CDCl ₃ , 400 MHz, δ): 1.40 (s, 18R, 2 tBu), 2.60 (dd, 1H, 1/2 CH ₂ -C =N, J = 15.0 Hz and J = 5.7 Hz),

2.80 (dd, 1H, 1/2 CH ₂ -C = N, J = 15.0 Hz and J = 6.7 Hz), 3.15 (dd, IH, 1/2 CH ₂ -C = O J = 16.7 Hz and J = 7.2 Hz), 3.50 (dd, 1H, 1/2 CH ₂ -C = O, J = 16.7 Hz and J = 10.1 Hz), 3 70 (2H, _NH2), 5.10 (m, IH, CH), 5.60 (s, IH, OH), 6.60 (m, 2H, arom. H), 7.20 (m, 2H, aromatic H), 7.50 (s, 2H, aromatic H), 8.10 (s, 1H, NH-CO).

25.7 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -5 -isoxazolacetamide hydroiodide (25)

The experimental procedure used was identical to that described for Intermediate 1.3, Intermediate 25.6 replaced Intermediate 1.2. The expected product was obtained in the form of a pale yellow powder in a yield of 72%. Mp > 260 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.70 (m, 2H, CH ₂ -C =N), 3.20 (dd, 1H, 1 H); / 2 CH ₂ -C = O, J = 16.8 Hz and J = 6.8 Hz), 3.60 (dd, 1H, 1/2 CH ₂ -C = O, J = 16.8 Hz and J = 10.2 Hz), 5.00 (m, 1H, CH),

7.35 (m, 6H, aromatic H + OH), 7.80 (m, 2H, aromatic H), 8.20 (m, 2H, thiophene), 8.70 (broad s, 1H, NH4 ⁾ ), 9.70 (br s, IH, NH), 10.30 (s, IH, NH-CO), 11.20 (br s, IH, NH ^4).

IR: _C = O (amide): 1650 cm ^-1, [nu] _C-N (amidine): 1603 cm <-1> ^.

Example 26

4- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-2-thiazolmethanamine hydrochloride (26)

26.1 2 - {[(1,1-Dimethylethoxy) carbonyl] methyl} aminoethanethioamide

The experimental procedure used was identical to that described for Intermediate 17.1, N-Boc-sarcosamide (obtained in a standard manner starting from commercial sarcosamide and BocOBoc) was used as the starting product instead of 4-nitrobenzamide. A white paste was obtained which was used directly in the next step.

26.2 4- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N - [(1,1-dimethylethoxy) carbonyl] -N-methyl-2-thiazolmethanamine

The same experimental procedure as described in J. Org. Chem. (1995), 60, 5638 to 5642, starting from intermediate 26.1 and 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -2-bromoethanone. A brown oil was obtained.

NMR 1 H (CDCl ₃₎ 400 MHz, δ) 1.50 (m, 27H, 3 tBu), 3.00 (s, 3H, N-CH ₃ ), 4.70 (s, 2H, CH ₂ ), 5.30 (s, 1H, OH), 7.25 (s, 1H, thiazole), 7.70 (s, 2H, aromatic H).

26.3 4- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-2-thiazolmethanamine

2.3 ml (29 mmol) of TFA was added dropwise at 0 ° C to a solution of 2.5 g (5.8 mmol) of intermediate 26.2 and 2 ml (1.6 mmol) of triethylsilane in 50 ml of dichloromethane. After shaking for one hour, the reaction mixture was concentrated in vacuo and the residue was diluted with 100 mL ethyl acetate and 50 mL saturated NaHCO ₃ solution. After shaking and decanting, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in heptane to give a white solid after drying to yield 73%. M.p .: 136 ° C. NMR 1 H (CDCl ₃ , 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (s, 3H, N-CH ₃ ), 4.20 (s, 2H, CH ₂ ) 5.30 (s, 1H, OH), 7.20 (s, 1H, thiazole), 7.70 (s, 2H, aromatic H).

26.4 4- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-nitrophenyl) -2-thiazolmethanamine

The same experimental procedure was used as described for Intermediate 1.1, Intermediate 26.3 replaced imidazole. A yellow solid was obtained with a yield of 23%. Melting point: 199 - 201 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.25 (s, 3H, N-CH ₃ ), 5.10 (s, 2H, CH ₂ ) 6.95 (m, 2H, aromatic H), 7.10 (s, 1H, OH), 7.60 (s, 2H, aromatic H), 7.80 (s, 1H, thiazole), 8 0.05 (m, 2H, aromatic H).

26.5 4- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-aminophenyl) -2-thiazolmethanamine

The same experimental procedure as described for Intermediate 17.5 was used, Intermediate 26.4 replaced Intermediate 17.4. The expected product was obtained in the form of a beige foam in a yield of 71%.

NMR 1 H (DMSO d 6.400 MHz, δ): 1.40 (s, 18H, 2Bu), 2.90 (s, 3H, N-CH ₃ ), 4.50 (broad s, 2H, NH ₂₎ ), 4.60 (s, 2H, _CH2), 6.50 (m, 2H, arom. H), 6.60 (m, 2H, arom. H), 7.10 (s, 1H, OH) 7.60 (s, 2H, aromatic H), 7.70 (s, 1H, thiazole).

26.6 4- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-2-thiazolmethanamine hydrochloride (26)

The same experimental procedure was used as described for Intermediate 4.3, Intermediate 26.5 replaced Intermediate 4.2. A white powder was obtained with a yield of 67%. Melting point: 157-160 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N-CH ₃ ), 5.00 (s, 2H, CH ₂ ) 6.95 (m, 2H, aromatic H), 7.15 (s, 1H, OH), 7.20 (m, 2H, aromatic H), 7.40 (m, 1H, thiophene), 7 65 (s, 2H, aromatic H), 7.75 (s, 1H, thiazole), 8.15 (m, 2H, thiophene), 8.70 (broad / s, 1H, NH ⁺ ), 9, 70 (broad s, 1H, NH ⁴ ), 11.30 (broad s, 1H, NH ⁺ ). IR: [nu] C-O (amide): 1648 cm <^-1>; v <> N (amidine): 1611 cm ^-1 .

Example 27

4- [3,5-bis (l, l-dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-lH-imidazole 2-Methanamine hydrochloride (27)

27.1 4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-nitrophenyl) -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H- imidazol-2-methanamine

The same experimental procedure was used as described for Intermediate 1.1, Intermediate 22.4 replaced the imidazole. A yellow solid was obtained with a yield of 53%. M.p .: 149-151 ° C.

NMR 1 H (CDCl ₃ , 400 MHz, δ): 0.0 (s, 9H, Si (CH ₃ ) ₃ ), 0.9 (t, 2H, CH ₂ -Si, J = 8.4 Hz), 1.50 (s, 18H, 2 tBu),

3.15 (s, 3H, _NCH3), 3.50 (t, 2H, _{O-CH2-CH2-Si,} J = 8.4 Hz), 4.80 (s, 2H, _NCH2 imidazole ), 5.20 (s, 2H, _{CH2-imidazole} -OSEM), 5.25 (s, 1 H, OH), 6.90 (m, 2H, arom. H), 7.10 (s, 1 H, imidazole). 7.60 (s, 2H, aromatic H),

8.15 (m, 2H, aromatic H).

27.2 4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-nitrophenyl) -1H-imidazole-2-methanamine

The same experimental procedure as described for Intermediate 22.6 was used, Intermediate 27.1 replaced Intermediate 22.5. A yellow solid was obtained with a yield of 44%. Mp 209-211 ° C. NMR 1 H (CDCl 3, 400 MHz, δ): 1.40 (s, 18H, 2Bu), 3.20 (s, 3H, N-CH ₃ ), 4.70 (s, 2H, CH ₂ ), 6.80-7.10 (m, 3H, aromatic H), 7.20-7.60 (m, 3H, aromatic H + OH), 8.10 (m, 2H, aromatic H), 12 .00 (s, 1H, NH).

27.3 4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N-methyl-N- (4-aminophenyl) -1H-imidazole-2-methanamine

The same experimental procedure as described for Intermediate 14.4 was used, Intermediate 27.2 replaced Intermediate 14.3. A beige foam was obtained with a yield of 67%.

NMR 1 H (CDCl ₃ , 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.80 (s, 3H, N-CH ₃ ), 4.20 (s, 2H, CH ₂ ) , 4.30 to 4.70 (m, 3 H, NH ₂ NH + imidazole), 5.00 (s, 1 H, OH), 6.50 (m, 2H, arom. H), 6.70 (m, 2H, aromatic H), 6.80 (s, 1H, imidazole), 7.40 (s, 2H, aromatic H).

27.4 4- [3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-1H-imidazole -2-methanamine hydrochloride (27)

The same experimental procedure as described for Intermediate 4.3 was used, Intermediate 27.3 replaced Intermediate 4.2. A yellow powder was obtained with a yield of 86%. Mp .: 195-200 ° C.

NMR 1 H (DMSO d 6.400 MHz, δ): 150 (s, 18H, 2 tBu), 3.20 (s, 3H, N-CH ₃ ), 5.00 (s, 2H, CH ₂ ), 7 00 (m, 2H, aromatic H), 7.20 (m, 2H, aromatic H), 7.40 (m, 2H, thiophene + OH), 7.60 (s, 2H, aromatic H) 7.90 (s, 1H, imidazole),

8.20 (m, 2H, thiophene), 8.70 (br s, 1 H, NH ^+), 9.70 (br s, 1 H, NH ^4), 11.40 (br s, 1 H, NH ^4), 14.60 (broad s, 1H, NH ⁴ ), 15.60 (broad s, 1H, NH ⁴ ). IR: [nu] C-O (amide): 1646 cm &^lt; -1 &gt; vc-N (amidine): 1612 cm ^"first

Example 28

3- [3,5-bis (l, l-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5- {2- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} ethyl} isoxazole (28)

28.1 3- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5-isoxazoletanol

0.09 g (2.4 mmol) of LiAlH ₄ was added in small portions to a solution of 0.69 g (2.1 mmol) of intermediate

25.3 in 15 ml dry THF cooled to 0 ° C. After shaking for one hour at 23 ° C, the reaction mixture was cooled using an ice bath and the excess hydride was quenched by the addition of water (5 mL). The product was extracted twice with 25 mL of ethyl ether. The organic phase was washed twice with 10 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (eluent: heptane / ethyl acetate: 1/1). A white foam was obtained with a yield of 58%.

SK 286911Β6

NMR 1 H (DMSO d 6, 100 MHz, δ): 1.40 (s, 18H, 2 tBu), 1.60-1.80 (m, 2H, CH) -CH ₂ -O), 3.05 ( m, 1, 1/2 _CH2 isoxazoline), 3.40 (m, 1H, 1/2 _CH2 isoxazoline), 3.50 (m, 2H, CH ₂ CH ₂ O), 4.60 (s 1H, OH), 4.70 (m, 1H, CH isoxazoline), 7.40 (broad s, 3H, aromatic H + OH).

28.2 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5- [2- (4-nitrophenoxy) ethyl] isoxazole

A mixture of 0.37 g (1.58 mmol) of intermediate 28.1, 0.5 ml of Aliquat 336, 0.18 g (1.27 mmol) of 4-fluoronitrobenzene and 0.071 g (1.27 mmol) of KOH in 2 ml of toluene. was heated at 80 ° C for 2 hours. The reaction mixture was then returned to 23 ° C, partitioned between 50 mL of dichloromethane and 20 mL of water. After decantation, the organic phase was washed with 20 ml of water, followed by 20 ml of brine. The organic solution was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The evaporation residue was purified on a silica gel column (eluent: heptane / ethyl acetate: gradient from 10/0 to 0/10). A white powder was obtained with a yield of 60%. Melting point: 151-153 ° C.

H NMR (COC1 _3, 400 MHz, δ): 1.50 (s, 18H, 2 t Bu), 2.15 (m, 2H, CH ₂ CH ₂ O), 3.10 (dd, 1 H, 1/2 CH ₂ isoxazoline, J = 16.3 Hz and J = 6.65 Hz), 3.50 (dd, 1H, 1/2 CH ₂ isoxazoline, J = 16.3 Hz and J = 10.4 Hz ), 4.10 to 4.30 (m, 2H, CH ₂ CH ₂ O), 5.00 (m, 1 H, CH isoxazoline), 5.50 (s, 1 H, OH), 6.90 ( m, 2H, aromatic H), 7.50 (s, 2H, aromatic H), 8.20 (m, 2H, aromatic H).

28.3 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5- [2- (4-aminophenoxy) ethyl] isoxazole

The same experimental procedure as described for Intermediate 17.5 was used, Intermediate 28.2 replaced Intermediate 17.4. A white powder was obtained with a yield of 60%. Melting point: 129-131 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.35 (s, 18H, 2Bu), 2.00 (m, 2H, CH ₂ -CH ₂ -O), 3.15 (dd, 1H, 1/2 CH ₂ isoxazoline, J = 16.7 Hz and J = 7.5 Hz), 3.40 (dd, 1H, 1/2 CH ₂ isoxazoline, J = 16.7 Hz and J = 10.5 Hz ), 3.90 (m, 2H, CH ₂ CH ₂ O), 4.60 (s, 2H, _NH2), 4.70 (m, 1 H, CH isoxazoline), 6.50 (m, 2H , aromatic H), 6.70 (m, 2H, aromatic H), 7.40 (s, 3H, H + OH).

28.4 3- [3,5-Bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5- {2- {4 - [(imino (2-thienyl) methyl) amino] phenoxy } ethyl} isoxazole (28)

The same experimental procedure as described for Intermediate 4.3 was used, Intermediate 28.3 replaced Intermediate 4.2. A white solid was obtained with a yield of 32%. Mp .: 240-245 ° C. NMR 1 H (DMSO d 6, 400 MHz, δ): 1.40 (s, 18H, 2Bu), 2.15 (m, 2H, CH ₂ -CH ₂ -O), 3.20 (dd, 1H, 1/2 CH ₂ isoxazoline, J = 16.65 Hz and J = 7.35 Hz), 3.50 (dd, 1H, 1/2 CH ₂ isoxazoline, J = 16.65 Hz and J = 10.3 Hz ), 4.20 (br, 2H, CH ₂ CH ₂ O), 4.90 (m, 1 H, CH isoxazoline), 7.20 (m, 2H, arom. H), 7.40 (m 6H, aromatic H + + OH), 8.20 (m, 2H, thiophene), 8.80 (broad s, 1H, NH), 9.80 (broad s, 1H, NH ⁺ ), 11.40 (broad s, 1H, NH &lt; ^{+ &gt;} ). IR: v00 (amide): 1655 cm @ ^-1 ; Von (amidine): 1618 cm ^-1 .

Example 29 1 - {[3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] amino} -carbonyl-3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride (29)

29.1 1- (Diphenylmethyl) -3- (4-nitrophenoxy) azetidine

0.5 g (2 mmol) of 1- (diphenylmethyl) -3-hydroxyazetidine was added under an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of NaH in 20 ml of dry THF. After shaking for one hour at 23 ° C, a solution of 0.29 g (2.1 mmol) of 4-thiometrobenzene in 5 mL of dry THF was added dropwise to the reaction mixture. Shaking was continued for a further 2 hours at 23 ° C and the whole mixture was finally poured into 25 ml of water. The product was extracted twice with 25 ml of ethyl acetate, the organic phase was then washed twice with 25 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel column (eluent: 12% ethyl acetate in heptane). Pure fractions were evaporated to give a colorless oil in 40% yield.

NMR 1 H (CDCl 3, 400 MHz, δ): 3.20 (m, 2H, azetidine), 4.50 (s, 1H, CH- (Ph) ₂ ), 4.80 (m, 2H, azetidine), 4.90 (m, 1H, CH-O), 6.80 (m, 2H, aromatic H), 7.20-7.50 (m, 10H, aromatic H), 8.20 (m, 2H , aroma, H).

29.2 1- (Diphenylmethyl) -3- (4-aminophenoxy) azetidine

The same experimental procedure as described for Intermediate 17.5 was used, Intermediate 29.1 replaced Intermediate 17.4. A colorless oil was obtained with a yield of 75%.

NMR 1 H (CDCl 3, 400 MHz, δ): 3.10 (m, 2H, azetidine), 3.40 (broad s, 2H, NH ₂ ), 4.40 (s, 1H, CH- (Ph) ₂₎ 4.70 (m, 2H, azetidine), 4.75 (m, 1H, CH-O), 6.60 (s, 4H, aromatic H), 7.10-7.40 (m, 10H) , aroma, H).

29.3 1- (Diphenylmethyl) -3- {4 - [(1,1-dimethylethoxy) carbonyl] aminophenoxy} azetidine

Protection of the amine is carried out in a standard manner with BocOBoc in the presence of triethylamine in dichloromethane. A white solid was obtained with a yield of 77%. M.p .: 149-151 ° C.

SK 286911 Β6

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.40 (s, 9H, tBu), 2.90 (broad s, 2H, azetidine), 3.60 (broad s, 2H, azetidine), 4, 50 (s, 1H, CH - (Ph) ₂ ), 4.70 (m, 1H, CH - O), 6.70 (m, 2H, aromatic H), 7.10 - 7.60 (m, 12H, aromatic H), 9.10 (s, 1H, NH).

29.4 3- {4 - [(1,1-Dimethylethoxy) carbonyl] aminophenoxy} azetidine

The same experimental procedure as described for Intermediate 14.4 was used except that the hydrogenation catalyst was replaced with Pd (OH) ₂ . A white solid was obtained with a yield of 78%. Mp 184-186 ° C.

NMR ¹ H (DMSO d 6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.50 (m, 2H, azetidine), 3.70 (m, 2H, azetidine), 4.90 ( m, 1H, CH-O), 6.70 (m, 2H, aromatic H), 7.30 (m, 2H, aromatic H), 9.10 (s, 1H, NH).

29.5 1 - {[3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] amino} carbonyl} -3- {4 - [(1,1-dimethylethoxy) carbonyl] aminophenoxy} azetidine

A solution of intermediate 10.2 (0.6 g, 2.7 mmol) in dichloromethane (10 ml) was added dropwise to a solution of triphosgene (0.27 g, 0.9 mmol) in dichloromethane (6 ml) over 1 hour. After shaking for 5 minutes at 23 ° C, a solution of 0.72 g (2.7 mmol) of intermediate 29.4 and 0.52 ml (3 mmol) of diisopropylethylamine in 6 ml of dichloromethane was added in one portion. The reaction mixture was shaken for 2 hours at 23 ° C and finally evaporated to dryness under vacuum. The residue was diluted in 50 mL of ethyl acetate and this organic solution was washed twice with 25 mL of water, followed by 25 mL of brine. After drying over magnesium sulfate and filtration, the organic solution was concentrated in vacuo. The residue was purified on a silica gel column (eluent: heptane / ethyl acetate: 7/3). A white solid was obtained with a yield of 61%. Melting point: 224-226 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ) 1.35 (s, 18H, 2 tBu), 1.45 (s, 9H, tBu), 3.80 (m, 2H, azetidine), 4.30 (s) m, 2H, azetidine), 4.90 (m, 1H, CH-O), 6.60 (s, 1H, OH), 6.70 (m, 2H, aromatic H), 7.20 (s, 2H, aromatic H), 7.35 (m, 2H, aromatic H), 8.20 (s, 1H, NH urea), 9.10 (s, 1H, NH).

29.6 1 - {[3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] amino} carbonyl} -3- (4-aminophenoxy) azetidine

The same experimental procedure as described for Intermediate 26.3 was used, Intermediate 29.5 replaced Intermediate 26.2. A white solid was obtained with a yield of 93%. Melting point: 225-227 ° C. NMR 1 H (DMSO d 6.400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.80 (m, 2H, azetidine), 4.30 (m, 2H, azetidine), 4.70 (br s, 2H, _NH2), 4.85 (m, 1H, CH-O), 6.40 to 6.70 (m, 5H, arom. H and OH), 7.25 (s, 2H, aromatic H), 8.20 (s, 1H, NH urea).

29.7 1 - {[3,5-bis (1,1-Dimethylethyl) -4-hydroxyphenyl] amino} carbonyl} -3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride (29) )

The same experimental procedure was used as described for Intermediate 4.3, Intermediate 29.6 replaced Intermediate 4.2. A white solid was obtained with a yield of 16%. Melting point: 235-240 ° C. NMR 1 H (DMSO d 6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.90 (m, 2H, azetidine), 4.40 (m, 2H, azetidine), 5.10 (m, 1H, CH-O), 6.60 (s, 1H, OH), 6.90-7.50 (m, 7H, aromatic H), 8.20 (m, 2H, thiophene), 8 30 (s, 1H, NH urea), 8.80 (s, 1H, NH ⁴ ), 9.80 (s, 1H, NH ⁴ ), 11.50 (s, 1H, NH ⁴ ). IR Vc = o (urea): 1660 cm ^-1; [nu] C- _N (amidine): 1640 cm <-1> ^.

Example 30

- (2-Hydroxy-5-methoxybenzoyl) -3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride (30)

30.1 1- (2-Hydroxy-5-methoxybenzoyl) -3- {4 - [(1,1-dimethylethoxy) carbonyl] aminophenoxy} azetidine

The condensation of 2-hydroxy-5-methoxybenzoic acid and intermediate 29.4 is carried out under the same experimental conditions as described for intermediate 8.1. A white solid was obtained with a yield of 62%. Melting point: 152-153 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.70 (s, 3H, OCH ₃ ), 4.00-4.80 (m, 4H, azetidine) 5.00 (m, 1H, CH-O), 6.70-6.90 (m, 5H, aromatic H), 7.30 (m, 2H, aromatic H), 9.1 (s, 1 H, OH), 10.65 (s, 1 H, NH).

30.2 1- (2-Hydroxy-5-methoxybenzoyl) -3-aminophenoxy-azetidine

The same experimental procedure as described for Intermediate 26.3 was used, Intermediate 30.1 replaced Intermediate 26.2. A yellow oil was obtained with a yield of 90%.

NMR 1 H (DMSO d 6, 400 MHz, δ): 3.25 (br s, 2H, NH ₂ ), 3.80 (s, 3H, OCH ₃ ), 4.20-4.90 (m, 4H, azetidine), 4.95 (m, 1H, CH-O), 6.60-7.00 (m, 7H, aromatic H), 11.35 (broad s, 1H, OH).

SK 286911 Β6

30.3 1- (2-Hydroxy-5-methoxybenzoyl) -3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride (30)

The same experimental procedure was used as described for Intermediate 4.3, Intermediate 30.2 replaced Intermediate 4.2. A white powder was obtained with a yield of 44%. Melting point: 165-166 ° C.

NMR δ (DMSO d 6, 400 MHz, δ): 3.70 (s, 3H, OCH ₃ ), 4.00-4.80 (m, 4H, azetidine), 5.15 (m, 1H, CH-O) )

6.80-7.10 (m, 5H, aromatic H), 7.40 (m, 3H, aromatic H), 8.20 (m, 2H, thiophene), 8.75 (broad s, 1H, NH ⁴ ), 9.80 (broad s, 1H, NH ⁴ ), 10.60 (s, 1H, OH), 11.50 (broad s, 1H, NH ⁴ ). IR Vc = o (amide): 1655 cm ^-1; _VC-N (amidine): 1612 cm ^'1'

Example 31 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -4- {4 - [(imino ( 2-thienyl) methyl) amino] phenoxy} -piperidine hydrochloride (31)

31.1 1,1-Dimethylethyl 4- (4-nitrophenoxy) -1-piperidinecarboxylate

A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard manner starting from commercial 4-hydroxypiperidine) in 10 mL of dry THF was added dropwise to a solution of 1.23 g (11 mmol) of tBuO'K ^+. in 10 mL dry THF in a three necked flask under an inert atmosphere cooled with an ice bath. After shaking for 30 min at 0 ° C, a solution of 1.06 mL (10 mmol) of 4-fluoronitrobenzene in 10 mL of dry THF was added dropwise. The reaction mixture was shaken for 5 hours at 23 ° C and finally poured into 25 mL of water + ice. The product was extracted using 50 mL of ethyl acetate. After decantation, the organic phase was washed twice with 25 ml of water and 25 ml of brine. The organic solution was dried over magnesium sulfate, followed by filtration and concentration of the filtrate under vacuum to form a residue which was purified on a silica gel column (eluent: heptane / ethyl acetate: 8/2). Pure fractions were collected and evaporated in vacuo. The expected product was obtained in the form of a pale yellow powder in a yield of 47%. Melting point: 97-98 ° C.

31.2 4- (4-Nitrophenoxy) piperidine

The same experimental procedure as described for Intermediate 19.2 was used, Intermediate 31.1 replaced Intermediate 19.1. A yellow oil was obtained in a yield of 87%.

NMR 1 H (CDCl 3, 100 MHz, δ): 1.58 (s, 1H, NH), 1.59-2.19 (m, 4H, CH ₂ -CH ₂ ), 2.65-3.30 ( m, 4H, _{CH2 CH2),} 4.51 (m, 1H, CH-O), 6.98 (m, 2H, arom. H), 8.21 (m, 2H, arom. H).

31.3 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -4- (4-nitrophenyl) piperidine

The same experimental procedure as described for Intermediate 19.3 was used, Intermediate 31.2 replaced Intermediate 19.2. A pale yellow powder was obtained with a crude yield of 83%. The product was pure enough to be used directly in the next step.

31.4 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -4- (4-aminophenyl) piperidine

The experimental procedure used was similar to that described for Intermediate 14.4, Intermediate

31.3 replaced intermediate 14.3. The reaction is carried out in dichloromethane / ethanol (1/1). A white powder was obtained with a yield of 77%. Mp: 153-154 ° C.

NMR ¹ H (CDCl ₃ + D ₂ O, 400 MHz, δ): 1.60-2.18 (m, 18H, CH ₂ + Trolox), 2.52-2.81 (m, 2H, CH ₂ ) , 3.41 to 4.28 (m, 5H, 2 * _CH2-CH-O), 6.63 (m, 2H, arom. H), 6.74 (m, 2H, arom. H).

31.5 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -4- [4 - [(imino (2 thienyl) methyl] amino] phenoxy] azetidine hydrochloride (31)

The same procedure as described for Intermediate 2.4 was used, Intermediate 31.4 replaced Intermediate 2.3. The condensation reaction is carried out only in 2-propanol. After salt formation, the expected product was obtained as a yellow powder in 25% yield. Melting point: decomposition from 170 ° C.

NMR 1 H (DMSO d 6.400 MHz, δ): 1.50-2.10 (m, 18H, CH ₂ + Trolox), 2.40-2.65 (m, 2H, CH ₂ ), 3.13 - 4.37 (m, 4H, 2 * _CH2), 4.64 (m, 1H, CH-O), 7.11 (m, 2H, arom. H), 7.35 (m, 2H, aromatic H, 7.57 (s, 1H, aromatic H),

8.17 (m, 2H, aromatic H), 8.74 (broad s, 1H, NH ⁴ ), 9.76 (broad s, 1H, NH ⁴ ), 11.42 (broad s, 1H, NH ⁴⁾ ).

IR: _C-N (amidine): 1611 cm ^"first

Example 32 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- {4 - [(imino ( 2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride (32)

SK 286911Β6

32.1 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- {4 - [(1,1 dimethylethoxy) carbonyl] aminophenoxy} azetidine

The condensation of Trolox and intermediate 29.4 is carried out under the same experimental conditions as described for intermediate 8.1. A white solid was obtained with a yield of 98%. Melting point: 182-183 ° C.

1 H (CDCl 3, 400 MHz, δ): 1.50 (s, 9H, tBu), 1.60-2.60 (m, 16H, Trolox), 3.90-4.90 (m, 5H, azetidine), 6.40 (s, 1H, OH), 6.65 (m, 2H, aromatic H), 7.20-7.30 (m, 3H, aromatic H + NH).

32.2 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3-aminophenoxyazetidine

The same experimental procedure as described for Intermediate 26.3 was used, Intermediate 32.1 replaced Intermediate 26.2. A white foam was obtained with a yield of 43%.

NMR 1 H (CDCl 3, 400 MHz, δ): 1.60-2.60 (m, 16H, Trolox), 3.50 (broad s, 2H, NH ₂ ), 3.90-4.90 (m, 5H, azetidine), 6.50-6.70 (m, 4H, aromatic H).

32.3 1 - [(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- {4 - [(imino (2 thienyl) methyl) amino] phenoxy} azetidine hydrochloride (32)

The same experimental procedure was used as described for Intermediate 4.3, Intermediate 32.2 replaced Intermediate 4.2. A white powder was obtained in a yield of 56%. Melting point: 190-195 ° C.

NMR 1 H (DMSO d 6, 400 MHz, δ): 1.60 - 2.50 (m, 16H, Trolox), 3.60 - 5.00 (m, 5H, azetidine), 6.90 (m, 2H , aromatic H), 7.30 (m, 3H, aromatic H), 8.15 (m, 2H, thiophene), 8.80 (broad s, 1H, NH ⁺ ), 9.80 (broad s, 1 H, NH ¹ ),

11.50 (broad s, 1H, NH ¹ ). IR: _{C = 0} (amide): 1647 cm ^-1, Vc = n (amidine): 1611 cm ^@ -1

Pharmacological Study of Products of the Invention

Study of effects on neuronal constitutive NO-synthase of rat cerebellum

The inhibitory activity of the products of the invention was determined by measuring their effects on the conversion of [ ³ H] -L-arginine to [ ³ H] -L-citrulline by NO-synthase according to a modified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87 682-685). Sprague-Dawley rat cerebella (300 g - Charles River) was quickly collected, dissected at 4 ° C and homogenized in one volume of extraction buffer (HEPES 50 mmol / l, EDTA 1 mmol / l, pH 7.4, pepstatin A 10 mg) / ml, leupeptin 10 mg / ml). The homogenates were then centrifuged at 21,000 g for 15 minutes at 4 ° C. Dosing was performed in glass tubes in which 100 μΐ of incubation buffer containing 100 mmol / l HEPES (pH 7.4), 2 mmol / l EDTA, 2.5 mmol / l CaCl ₂ , 2 mmol ·! dithiothreitol, 2 mmol / l reduced NADPH and 10 μg / ml calmodulin. 25 μΐ of a solution containing 100 nmol / L [ ³ H] -L-argimine (specific activity: 208.7.10 ¹ ° Bq / mmol (56.4 Ci / mmol), Amersham) and 40 pmol / l of non-radioactive L-arginine were added. . The reaction was started by adding 50 μΐ of homogenate, the final volume being 200 μΐ (the missing 25 μΐ is either water or the test product). After 15 minutes, the reaction was stopped with 1 ml of stop buffer (20 mM HEPES, pH 5.5, 2 mM EDTA). After placing the samples on a 1 ml DOWEX ion exchanger column, radioactivity was quantitated by a liquid scintillation spectrometer. The compounds of Examples 1, 6, 7 and 8 described above had an IC _{50 (} nižšie _{) of} less than 3.5 pmol / L. The compound of the example has an IC ₅ of less than 5 pmol / L.

Study of effects on lipid peroxidation of rat cerebral cortex

The inhibitory activity of the products of this invention was determined by measuring their effects on the degree of lipid peroxidation as determined by the concentration of malondialdehyde (MDA). MDA produced by peroxidation of unsaturated fatty acids is a good indicator of lipid peroxidation (H. Esterbauer and KH Cheeseman, Meth. Enzymol. (1990) 186 407-421). Male Sprague Dawley rats 200-250 g (Charles River) were sacrificed by decapitation. The cerebral cortex was removed, then homogenized using a Thomas crucible in 20 mM Tris-HCl buffer, pH = 7.4, the homogenate was centrifuged twice at 50,000 g for 10 minutes at 4 ° C. The pellet was stored at -80 ° C. On the day of the experiment, the pellet was suspended in a 1 g / 15 ml suspension and centrifuged at 515 g for 10 minutes at 4 ° C. The supernatant was used immediately to determine lipid peroxidation. Rat cerebral cortex homogenate (500 μΐ) was incubated at 37 ° C for 15 minutes in the presence of test substance or solvent (10 μΐ). The lipid peroxidation reaction was initiated by the addition of 50 μΐ FeCl ₂ at a concentration of 1 mmol / l, EDTA 1 mmol / l and ascorbic acid 4 mmol / l. After incubation for 30 minutes at 37 ° C, the reaction was stopped by the addition of 50 μ hydrox of a solution of hydroxylated di-tert-butyltoluene (BHT, 0.2%). MDA was quantified using a colorimetric assay, by reacting the chromogenic reagent (R), N-methyl-2-phenylindole (650 μΐ) with 200 μΐ of homogenate for 1 hour at 45 ° C. The condensation of the MDA molecule with the two molecules of reagent R forms a stable chromophore whose wavelength of maximum absorption is 586 nm. (Caldwell et al. European J. Pharmacol. (1995) 235, 203-206). The compounds of Examples 3, 11, 12, 13, 14 and 15 described above had an IC ₅ of less than 30 pmol / L.

Claims (14)

PATENT CLAIMS 2- (Iminomethyl) aminophenyl derivatives of general formula (I) (D (i)) in which: A is an aroma that corresponds to the structure in which R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having from 1 to 6 carbon atoms, or B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and in particular: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from a linear or branched alkyl radical having from 1 to 6 carbon atoms; an alkoxy tadical having from 1 to 6 carbon atoms or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n wherein n is an integer from 0 to 6; Y is -Y ¹ -, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y-, Y'-CO, -N (R ³ ) -Y'-, -Y'- N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -ΟΥ'-, -Y'-O-, -S-Y'-, -Υ'-S-, -Y '-O-Y'-,-Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazinone, thiazole, thiazoline, thiazole, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole- 3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; it is understood that when A is a hydrogen atom, Het is not a piperidine, pyrrolidine or morpholine radical. SK 286911Β6 2- (Iminomethyl) aminophenyl derivatives according to claim 1, wherein A is an aroma which corresponds to the structure in which R ¹ and R ² are, independently, a linear or branched alkyl radical having 1 to 6 carbon atoms or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; B is a 5 membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons of which are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 up to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or halogen; X is -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -Υ'-ΝΗ-CO-, -Y'-CO-, -Υ'-O-, -Y'-O-Y'-, -Y'-N (R ³ ) - Y'- or bond, Y 'is - (CH ₂ ) n wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-thio, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazol-3-one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine. 2- (Iminomethyl) aminophenyl derivatives according to claim 2, wherein B represents a thiophene ring, the carbons of which are optionally substituted by one or more groups selected from linear or branched alkyls having from 1 to 6 carbon atoms, alkoxy radicals having from 1 to 6 carbon atoms. 1 to 6 carbon atoms or halogen. 2- (Iminomethyl) aminophenyl derivatives according to one of claims 1 to 3, selected from the group consisting of: N- (3,5-di-tert-butyl-4-hydroxyphenyl) -5- [4- {imino (2-thienyl) methylamino} phenyl] -2-furan carboxamide hydroiodide; 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {imino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride; 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) methylamino} phenyl] -4-thiazolidinone hydrochloride; - 5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione fumarate; 2- (S) -4- (S) -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl)] methyl) amino] phenoxy} -prolinamide hydrochloride; N- [4-hydroxy-3,5-bis (l, l-dimethylethyl) phenyl] -2- (R, S) - {4 - [(imino (2-thienyl) methyl) amino] phenyl} - 4- (R) -thiazolidinecarboxamide fumarate; N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -2- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -4-thiazolecarboxamide hydroiodide; - N- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4- (S) - {4 - [(imino (2-thienyl) methyl) amino] -phenoxy} -pyrrolidin-2 - (R) -carboxamide dihydrochloride; - methyl-1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H- [1] -benzopyran-2-yl) carbonyl] -4- (S) - {4 - [(imino (2-thienyl) methyl) amino] -phenoxy} -pyrrolidine-2- (S) -carboxylate hydrochloride; 1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- (S) - {4- [(imino (2-thienyl) methyl) amino] phenoxy} pyrrolidine hydrochloride; -3 - {[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] amino} -1- {4- [ (imino (2-thienyl) methyl) amino] phenyl} pyrrolidine; -4- [3,5-bis- (1,1-dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] benzoyl} -N-methyl-1H- imidazole-2-methanamine hydrochloride; - N- [3,5-bis- (1,1-dimethylethyl) -4-hydroxyphenyl] -1- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -1H-pyrrole-2- carboxamide hydroiodide; -1- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -3 - {[4 - [[imino (2-thienyl) methyl] amino] phenyl] carbonyl} -2-imidazolidinone hydroiodide ; SK 286911 Β6 -3- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -5 -isoxazolacetamide hydroiodide; -4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-2- thiazolmethanamine hydrochloride; -4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -N- {4 - [(imino (2-thienyl) methyl) amino] phenyl} -N-methyl-1H- imidazole-2-methanamine hydrochloride; -3- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] -4,5-dihydro-5- {2- {4 - [(imino (2-thienyl) methyl) amino] phenoxy ethylisoxazole; - 1 - {[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] amino} -carbonyl-3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride; 1- (2-hydroxy-5-methoxybenzoyl) -3- {4 - [(imino (2-thienyl) methyl) amino] phenoxy} azetidine hydrochloride; - 1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -4- [4 - [(iinino (2 (thienyl) methyl) amino] phenoxy} piperidine hydrochloride; 1 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H- [1] -benzopyran-2-yl) carbonyl] -3- {4 - [(imino (2 -thienyl) methyl) amino] phenoxy} azetidine hydrochloride; or salts or enantiomers thereof. 2- (Iminomethyl) aminophenyl derivatives according to any one of claims 1 to 4, selected from: - 3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1- [4- {amino (2-thienyl) methylamino} phenyl] -2,5-imidazolidinedione hydrochloride; 2- (3,5-di-tert-butyl-4-hydroxyphenyl) -3- [4- {imino (2-thienyl) -methyl-amino] phenyl] -4-tiazolidinónhydrochlorid; 5 - [(3,5-di-tert-butyl-4-hydroxyphenyl) methylene] -1-methyl-3- [4- {imino (2-thienyl) methylamino} phenyl] -2,4-imidazolidinedione fumarate; - 2- (S) -4- (S) -N- [4-hydroxy-3,5-bis- (1,1-dimethylethyl) phenyl] -4- {4 - [(imino (2-thienyl)] methyl) amino] phenoxy} -prolinamide hydrochloride; N - [4-hydroxy-3,5-bis- (1,1-dimethyl) ethylphenyl] -2- {4 - [(imino (2-thienyl) methyl) amino) phenyl} -4-thiazolecarboxamide hydrochloride; or salts or enantiomers thereof. 6. Intermediates of compounds of formula (I), compounds of formula (V), (VI) and (VII) in which: A is an aroma which corresponds to the structure: in which R ¹ and R ² independently represent a hydrogen atom, a halogen, an OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having from 1 to 6 carbon atoms, or SK 286911 Β6 CH ₃ R ³ O h ₃ c ch ₃ ch ₃ B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms; an alkoxy radical having from 1 to 6 carbon atoms or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, Y'-CO, -N (R ³ ) -Y'-, -Y' -N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O-, -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazole, thiazole, thiazole, thiazole, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole-3- one, tetrazole, tetrahydropyridine, azetidine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; G _p - represents a group protecting the amine function preferably cleavable in an anhydrous acid medium. Process for the preparation of 2- (iminomethyl) aminophenyl derivatives of general formula (I) according to claim 1, characterized in that it consists of condensation, preferably in a mixture of isopropanol and DMF and at ambient temperature, of aniline derivatives of general formula (III) A-X-Het NH ₂ with S-alkylthioimidate derivatives of general formula (IV) B (III) NH.HI to form the final compounds of formula (I), wherein in compounds of formulas (I), (III) and (IV): A is a hydrogen atom or aromatic which corresponds to structures (iv), or SK 286911 Β6 B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and in particular: thiophene, firane, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -SY-, -Υ'-S-, -Y' -OY ¹ -, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted with one or more substituents X'-OR ³ , X'-NR ³ , X'SR ³ and such as: oxetane, pyrrole , pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidine, thiazolidone, thiazolidine, thiazolidine 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazol-3-one , tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine. A process for the preparation of 2- (iminomethyl) aminophenyl derivatives of formula (I) according to claim 1, characterized in that it comprises condensation, preferably in a mixture of isopropanol and DMF and at ambient temperature, of the aniline derivatives of formula (III) S-alkylthioimidate type derivatives of formula (IV) B h ₃ c With NH.HI to produce the final compound of formula (I), wherein in compounds of formulas (I), (III) and (IV), A is: a hydrogen atom or aromatic, which corresponds to the structure: or in which B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more specifically: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from a linear or branched alkyl radical having from 1 to 6 carbon atoms; an alkoxy radical having from 1 to 6 carbon atoms or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is (CH ₂ ) _n wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, Y'-CO, -N (R ³ ) -Y'-, -Y' -N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O-, -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X'-SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazole, thiazole, thiazole, thiazole, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole-3- one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine. A process for the preparation of 2- (iminomethyl) aminophenyl derivatives of general formula (I) according to claim 1, wherein the Het heterocycle contains at least one nitrogen atom, characterized in that it comprises the following two steps: condensation, preferably in a mixture of isopropanol and DMF and at ambient temperature, of the compounds of formula (VI) with a compound of formula (IV) (VI) (IV) to form a compound of formula (VII), formula (I), in the compounds of formula (I), (IV), (VI) and (VII) means: A is a hydrogen atom or aromatic which corresponds to the structure J in which R ¹ and R ² represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, linear or branched alkoxy radical having from 1 to 6 carbon atoms, R ³ represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR ⁴ radical, R ⁴ represents an alkyl radical having 1 to 6 carbon atoms, or SK 286911Β6 B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms selected from O, S, N and more particularly: thiophene, furan, pyrrole or thiazole, the carbons are optionally substituted with one or more groups selected from linear or branched alkyl having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, or halogen; X is -CO-N (R ³ ) -X'-, -NH-CO-X'-, -CH =, -CO- or a bond, X 'is - (CH ₂ ) _n -, wherein n is an integer from 0 to 6; Y is -Y'-, -CO-NH-Y ', -Υ'-ΝΗ-CO-, -CO-Y'-, -Y'-CO, -N (R ³ ) -Y'-, -Y '-N (R ³ ) -, Y'-CH 2 -N (R ³ ) -CO-, -O-Y'-, -Y'-O- -S-Y'-, -Υ'-S-, -Y'-O-Y'-, -Y'-N (R ³ ) -Y'- or a bond, Y 'is - (CH 2) _n -, wherein n is an integer from 0 to 6; Het means a heterocycle containing from 1 to 5 heteroatoms selected from O, N, S, which may be substituted by one or more substituents X'-OR ³ , X'-NR ³ , X''SR ³ and such as: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, imidazole, imidazoline, dihydroimidazol-2-one, dihydroimidazol-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazole, thiazole, thiazole, hydantoin, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxide-1,2,5-thiadiazolidine, 1,2,4-triazole-3- one, tetrazole, tetrahydropyridine, with the exception of the following heterocycles: piperazines, homopiperazines, 4-aminopiperidine; G _p - represents a protective group of an amine function, preferably cleavable in an anhydrous acidic medium, such as the tert-butyl, trichloroethyl or trimethylsilylethyl carbamates, or also trityl. A 2- (iminomethyl) aminophenyl derivative of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a medicament. Pharmaceutical preparation, characterized in that it contains as an active ingredient at least one 2- (iminomethyl) aminophenyl derivative according to claims 1 to 5. Use of a 2- (iminomethyl) aminophenyl derivative of general formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting NO synthase. Use of a 2- (iminomethyl) aminophenyl derivative of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting lipid peroxidation. Use of a 2- (iminomethyl) aminophenyl derivative of general formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament having both NO synthase inhibition activity and lipid peroxidation inhibition activity.