Cyclic ureas and processes for their preparation

ES 2 301 554 T3

DESCRIPTION

Cyclic ureas compounds and their preparation procedure.

The subject of the present invention is a new process for the preparation of cyclic urea compounds and new cyclic urea compounds.

The synthesis and applications of substituted ureas have known, for some years, an important development. In particular, cyclic ureas are present in a number of active principles currently under development in the pharmaceutical industry as HIV protease inhibitors, or factor Xa (fXa) inhibitors. The cyclic ureas described in the literature (WO 93/07128, WO 96/29329, WO 97/08150, WO 98/20009) generally have rings of 5, 6, 7 or 8 atoms. These rings can sometimes contain a supplemental heteroatom, such as a nitrogen atom adjacent to the urea function (Sham et al., Journal of Medicinal Chemistry, 1996, 39, 392-397). The urea cycle of the biologically active cyclic ureas described in the literature is used as a platform of limited conformation on which the pharmacophore groups that serve for recognition by the HIV protease are arranged. Therefore, it is important to have a sufficiently flexible synthesis procedure to easily allow the introduction of molecular diversity at the level of the pharmacophore groups as well as at the level of the position of these groups in the ring. The cyclic ureas described in the literature are generally prepared from the corresponding diamines by intramolecular cyclization of said diamines with the aid of a carbonylating agent such as carbonyldiimidazole. The alkylation of N, N'-disubstituted ureas with bis-alkyl halides for the preparation of cyclic ureas has also been described (WO96 / 00708 and WO 93/07128).

In the field of research that envisages developing new compounds with immunomodulatory activity, the applicant has previously developed a simple and effective procedure that allows the preparation of new stable activated derivatives of carbamic acid, from an N-protected amino acid derivative, comprising three stages:

a) a stage of transformation of the -COOH group of the N-protected amino acid derivative (amino acids a, β, γ and δ) into a -CON group₃ to obtain an acyl-azide,

b) a transformation stage of the -CON group₃ of the acyl-azide in the -NCO group to obtain an isocyanate,

c) a step of treating the isocyanate to obtain said stable derivative of carbamic acid.

The term "amino acid derivative" should be interpreted in the broad sense, as understood by the person skilled in the art, and designates in particular a derivative of a peptide, a polypeptide, a protein, a pseudopeptide or an oligourea.

Carbamic acid derivatives are stable and crystalline intermediates that react with amines to form substituted ureas. Carbamic acid derivatives also make it possible to prepare peptides containing urea motifs ("Guichard et al., J. Org. Chem. 1999, 64, 8702-8705", and "Guichard et al., Tetrahedron Letter, 2000, 41 , 1553-1557 ").

One of the aspects of the invention is to propose a new process for the preparation of cyclic urea compounds.

Another aspect of the invention is to propose a new process for the preparation of cyclic urea compounds, which makes it possible to obtain easily and in very few steps a great molecular diversity of cyclic urea compounds.

Another aspect of the invention is to propose new cyclic urea compounds.

In its generality, the invention has as its object a process for the preparation of cyclic ureas compounds from at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function, which comprises a cyclization step by reaction between the primary or secondary amine function and the carbamic acid function of said or said carbamic acid derivatives.

By the expression "activated derivative of carbamic acid" is meant a derivative of carbamic acid, in particular a carbamate, which contains a primary or secondary amine function capable of reacting with primary or secondary amines in the presence or absence of a base in a solvent organic.

By "unprotected" primary or secondary amine function is meant a free primary or secondary amine function, that is to say capable of reacting with another chemical functional group, and in particular with a carbamic acid function. The "unprotected" primary or secondary amine function may also be called, in the continuation of the description, the "released", "free" or "unprotected" primary or secondary amine function.

ES 2 301 554 T3

In the continuation of the description, "activated derivative of carbamic acid containing an unprotected primary or secondary amine function" is also understood:

- a derivative of oligomeric carbamic acid, also named below "activated derivative of homo-oligomeric carbamic acid" or "homo-oligomeric derivative" or "activated derivative of hetero-oligomeric carbamic acid" or "hetero-oligomeric derivative", or

- a monomeric carbamic acid derivative, corresponding to an activated non-homo-oligomeric carbamic acid derivative or a non-hetero-oligomeric carbamic acid derivative.

The activated homo-oligomeric and / or hetero-oligomeric carbamic acid derivative (s) are obtained at the end of one or more homo-oligomerization and / or hetero-oligomerization reactions of at least one activated monomeric carbamic acid derivative. Homo-oligomerization or hetero-oligomerization reactions may also be referred to below as "intermolecular reactions".

By the term "cyclization step" is to be understood an intramolecular cyclization step or an intermolecular cyclization step.

An intramolecular cyclization takes place by the reaction between the unprotected primary or secondary amine function of the activated derivative of carbamic acid and its carbamic acid function.

An intermolecular cyclization takes place through the reaction between:

- the unprotected primary or secondary amine function of an activated derivative of carbamic acid (called derivative 1) and the carbamic acid function of another activated derivative of carbamic acid (called derivative 2), and

- the unprotected primary or secondary amine function of said carbamic acid derivative 2 and the carbamic acid function of said carbamic acid derivative 1.

A cyclic urea compounding process comprising:

- a step of obtaining at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function, from at least one stable activated derivative of carbamic acid containing an amine function protected by a protective group, by means of selective release of said protected amine function from said stable activated derivative (s) of carbamic acid, by cleavage or transformation of said protecting group,

- a cyclization step by reacting between the unprotected primary or secondary amine function of at least one activated derivative obtained at the end of the selective release step and the carbamic acid function of the derivative or derivatives.

According to an advantageous embodiment of the process of the invention, the cyclization step is an intramolecular cyclization between the unprotected primary or secondary amine function of an activated derivative obtained at the end of the selective release step and its carbamic acid function.

By the term "protecting group" is meant a group that protects the amine function of the activated derivative of carbamic acid, in particular to prevent it from reacting with other chemical functional groups, during the synthesis of said derivative.

By the term "stable activated derivative of carbamic acid" is meant an isolatable, purifiable and storable carbamic acid derivative (preferably at 4 ° C) for a period of at least 3 months without noticeable degradation. Stability can be measured, for example, by the following test: high performance liquid chromatography (HPLC), thin layer chromatography (TLC), nuclear magnetic resonance (NMR) or infrared (IR).

By the term "selective release" of the protected amine function, it is to be understood a release that allows the liberation only of the protected amine function of the stable activated derivative of carbamic acid without altering the carbamic acid function of said derivative. In the continuation of the description, the "selective release" step may also be referred to as "selective deprotection".

The step of selective release or deprotection of the amine function protected by a protecting group depends on:

- of the protecting group used to protect the amine function, and

- of the reactive agent used during the deprotection or release of the amine function.

The release of an amine function by cleavage of the protecting group or by transformation of the protecting group is carried out according to the usual procedures described in the literature.

ES 2 301 554 T3

A stable activated derivative of carbamic acid containing an amine function protected by a protecting group can be obtained from an amino acid derivative in which the amino group is protected, by a process as described above, and whose three steps are as follows:

- transformation of the -COOH group of the N-protected amino acid derivative into -CON group₃ to obtain an acyl-azide,

- transformation of the -CON group₃ of the acyl-azide in the -NCO group to obtain an isocyanate,

- treatment of isocyanate -NCO to obtain said stable derivative of carbamic acid.

According to an advantageous embodiment of the preparation process of the invention, the unprotected primary or secondary amine function of the activated derivative of carbamic acid is presented:

(1) in free form and / or, (2) in protonated form, in particular in salt form.

By way of example of an activated derivative of carbamic acid containing a primary or secondary amine function in protonated form, in particular in salt form, mention may be made in particular of an acetate salt, a hydrochloride salt or a trifluoroacetate salt.

The activated derivative of carbamic acid containing an unprotected primary or secondary amine function in protonated form can be isolated, while the activated derivative of carbamic acid containing an unprotected primary or secondary amine function in free form cannot be isolated: in the latter case, the cyclization step takes place immediately after obtaining at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function.

According to an advantageous embodiment of the invention, the process for preparing the cyclic ureas compounds comprises, during or at the end of the selective release step, a homo-oligomerization and / or hetero-oligomerization step:

- between the unprotected primary or secondary amine function of a molecule of the activated derivative of carbamic acid and the carbamic acid function of another molecule of said activated derivative of carbamic acid and / or,

- between the unprotected primary or secondary amine function of a molecule of the activated derivative of carbamic acid and the carbamic acid function of a molecule of another activated derivative of carbamic acid, to obtain at least one homo-oligomeric and / or hetero-oligomeric derivative of carbamic acid containing an unprotected primary or secondary amine function.

Thus, according to an advantageous embodiment, the preparation process of the invention comprises, during or at the end of the selective release step:

- a homo-oligomerization step between the unprotected primary or secondary amine function of a molecule of the activated derivative of carbamic acid and the carbamic acid function of another molecule of said activated derivative of carbamic acid, to obtain at least one homo-oligomeric derivative carbamic acid containing an unprotected primary or secondary amine function, or

- at least one homo-oligomerization step between the unprotected primary or secondary amine function of a molecule of an activated derivative of carbamic acid and the carbamic acid function of another molecule of said activated derivative of carbamic acid, and at least one hetero-oligomerization step between the unprotected primary or secondary amine function of a molecule of an activated derivative of carbamic acid and the carbamic acid function of a molecule of another activated derivative of carbamic acid, to obtain at least one derivative homo-oligomeric and at least one hetero-oligomeric derivative of carbamic acid containing an unprotected primary or secondary amine function.

Thus, the bifunctional acyclic precursors obtained during or at the end of the selective release of the protected amine function, that is to say the monomeric activated derivatives of carbamic acid containing a primary or secondary amine function in free or protonated form, can undergo, before the intramolecular cyclization stage, intermolecular homo- and / or hetero-oligomerization reactions in order to form homo-oligomeric and / or hetero-oligomeric bifunctional acyclic precursors. The homo-oligomeric and / or hetero-oligomeric acyclic carbamic acid derivatives thus obtained then undergo, like the non-homo- and / or non-hetero-oligomeric acyclic carbamic acid derivatives, an intramolecular cyclization (or macrocyclization) by the reaction of its primary or secondary amine function not protected with its carbamic acid function, in order to obtain homo-oligomeric and / or hetero-oligomeric cyclic ureas.

ES 2 301 554 T3

However, for intermolecular homo-oligomerization and / or hetero-oligomerization reactions, and intramolecular cyclization reactions to take place, the primary or secondary amine function released from the activated carbamic acid derivative must be in free form and not in protonated form. Indeed, only the primary or secondary amine function in free form can react by intermolecular homo- or hetero-oligomerization reaction, or by intramolecular cyclization.

Thus, when the activated derivative of carbamic acid, obtained at the end of the selective release step, contains a primary or secondary amine function, not protected in free form, the homo- and / or hetero-oligomerization and cyclization reactions intramolecular can take place immediately after the formation of the activated derivative of carbamic acid containing an unprotected primary or secondary amine function in free form, since said amine function in free form can react with the activated carbamic acid group.

When the activated derivative of carbamic acid, obtained at the end of the selective release step, contains an unprotected primary or secondary amine function in protonated form, it will be necessary to previously neutralize said protonated form of the amine in free form so that they can have place the intermolecular homo-oligomerization and / or hetero-oligomerization reactions, and the intramolecular cyclization reactions.

According to an advantageous embodiment of the process for the preparation of cyclic ureas compounds, when the activated derivative of carbamic acid contains a primary or secondary amine function in protonated form, the homo-oligomerization and / or hetero-oligomerization step is carried out neutralizing the primary or secondary amine function in protonated form to primary or secondary amine function in free form, to obtain at least one homo-oligomeric and / or hetero-oligomeric derivative containing an unprotected primary or secondary amine function in free form.

According to another advantageous embodiment of the process for the preparation of cyclic ureas compounds, when the activated derivative of carbamic acid contains a primary or secondary amine function in protonated form, the cyclization step is carried out by neutralizing the primary or secondary amine function in the form protonated in primary or secondary amine function in free form.

The neutralization of said protonated amine function in free form is carried out in particular with the aid of a base selected from the group consisting of diisopropylethylamine, triethylamine, lutidine, pyridine, 2,4,6-collidine, N -methylmorpholine, 2,6-di-tert-butyl-4-methylpyridine, or their mixtures.

On the other hand, in order to carry out the intramolecular cyclization step of the oligomeric or monomeric activated derivatives of carbamic acid containing a primary or secondary amine function, a solvent selected from the group consisting of acetonitrile (MeCN ), toluene, pyridine, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), chloroform, dichloromethane, N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), ethyl acetate, methanol, ethanol, or their mixtures.

The solvent used to carry out the cyclization step is referred to in the following as "reaction solvent" or "cyclization solvent".

Thus, the intramolecular cyclization step of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function in protonated form is carried out in the presence:

- of a base in order to neutralize the protonated form of the amine in free form, and

- of the reaction solvent for intramolecular cyclization, while the intramolecular cyclization step of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function in free form is carried out directly with the aid of a reaction solvent for cyclization intramolecular.

According to an advantageous embodiment of the process of the invention, the intramolecular cyclization step of the activated derivative of carbamic acid containing an unprotected primary or secondary amine function is carried out at a temperature of approximately -40 ° C to approximately 40 ° C, in particular from about -20 ° C to about 40 ° C, and preferably from about 0 ° C to about 20 ° C.

According to another advantageous embodiment of the process of the invention, the concentration of an activated derivative of carbamic acid containing an unprotected primary or secondary amine function in free form, in a solution containing a reaction solvent for intramolecular cyclization, is of about 10^-6M to about 10 M, in particular about 10 ⁵ M to about 1 M, and preferably about 10^-4 at about 1 M.

According to another advantageous embodiment of the process of the invention, the concentration of an activated derivative of carbamic acid containing an unprotected primary or secondary amine function in protonated form, in a solution containing a reaction solvent for intramolecular cyclization and a base, is about 10 ⁶ M to about 10 M, in particular about 10 ⁵ M to about 1 M, and preferably about 10^-4 M to about 1 M.

ES 2 301 554 T3

The concentration of the base in the reaction solvent for intramolecular cyclization is approximately 10 ⁶ M to about 10 M, in particular about 10 ⁵ M to about 1 M, and preferably about 10 ⁴ M to about 1 M.

According to an advantageous embodiment of the process for the preparation of the cyclic ureas compounds, the activated derivative of carbamic acid containing a protected amine function is synthesized on a solid support, and is chemically linked to said solid support or (a) by its amine function, either (b) through its carbamic acid function, or (c) through any other functional group present in said activated derivative of carbamic acid.

By the expression "solid support" is to be understood the matrix on which the chemical reaction is carried out. It is generally a solid insoluble polymer that allows filtration or centrifugation, and therefore the separation of the reactive agents and the product formed on the resin. By way of example of a solid support, mention may be made of polystyrenic resins, polyacrylamide, polyethylene glycol, cellulose, glass, and silica.

According to an advantageous embodiment of the preparation process of the invention, when the activated derivative of carbamic acid containing a protected amine function is chemically bound to a solid support:

- through its amine function, the selective release step entails the cleavage of the amine function of said derivative in relation to the support,

- by means of its carbamic acid function, the cyclization step entails the cleavage of the carbamic acid function of said derivative in relation to the support,

- by means of a functional group other than the amine or carbamic acid function such as a hydroxyl function, an amide function or a carboxyl function, the cleavage of said functional group relative to the support can take place during or at the end of any of the stages of selective release or cyclization.

According to another advantageous embodiment of the process for the preparation of the invention, the amine function of the activated derivative of carbamic acid is protected in the form of a group:

- carbamate (ROCON-) in which R is a group tert-butyl, 9-fluorenylmethyl, benzyl, allyl, tert-butyldimethylsilyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl,

- tertiary amine of formula R'N <when ​​the amine function to be protected is a secondary amine, or of formula R'R "N- when the amine function to be protected is a primary amine, R 'and R" each representing a group protector selected from the group consisting of benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, diphenylmethyl, para-methoxyphenyl, 3,4-dimethoxybenzyl or 9-phenyl-9-fluorenyl,

- amide,

- nitro,

- azide,

- trityl,

- ortho- (or para) -nitrophenylsulfonyl,

- tosyl,

- phthalimide, or

- cyano.

The release of the amine function by cleavage of the protecting group is carried out according to the usual procedures described in the literature. In this regard, mention can be made of the work entitled "Protecting groups" by PJ Kocienski (Thieme edition), which provides an exhaustive list of protecting groups for amine functions and their modes of deprotection.

By way of example, one can cite in particular:

- the deprotection of the tert-butoxycarbonyl group (ROCO- with R = tert-butyl group) (also called Boc group) in acidic condition (trifluoroacetic acid or solution of hydrochloric acid in organic solvent at 3-4 M) leading to obtaining of the corresponding amine in the form of trifluoroacetate or hydrochloride salt,

ES 2 301 554 T3

- the deprotection of the benzyloxycarbonyl group (ROCO- with R = benzyl group) (also called group Z) or of the tertiary amines (of formula R'N <or R'R ”N-) containing one or two benzyl groups, by Catalytic hydrogenation in the presence of Pd / C, with the addition or not of an acid to protonate or not the liberated primary or secondary amine.

The liberation of the amine function by the transformation of a chemical group serving in the occult form of the amine such as a nitro, cyano, amide or azide group, is described in particular in the following examples. However, these examples are not limiting because there are a large number of procedures that allow the transformations described below to be carried out. ("Textbook of Practical Organic Chemistry" by Vogel, (5^to edition), 1989).

The release of the amine function can be effected by the reduction of the nitro or cyano groups in amine, for example, by catalytic hydrogenation in the presence of Pd / C and PtO₂ respectively.

The transformation of an amide group into an amine group can be effected by the Hoffman rearrangement, for example by treating the amide with iodobenzyl bis-trifluoroacetate in a water / acetonitrile mixture.

The reduction of an azide group to an amine group can be carried out by different procedures, for example by catalytic hydrogenation or by treatment with lithium aluminum hydride.

Another subject of the invention is cyclic urea compounds comprising a ring having at least 7 atoms, in particular 7 to 50 atoms, and preferably 7 to 20 atoms, a ring comprising at least one amide function and at least one urea function, each amide or urea function being separated from the closest adjacent amide or urea function by at least one carbon atom, and in particular by 1 to 4 carbon atoms.

The invention relates in particular to cyclic urea compounds comprising a ring having at least 7 atoms, in particular 7 to 20 atoms, and preferably 7 to 10 atoms, which ring comprises a separate amide function and a urea function. to each other by at least one carbon atom, and in particular by 1 to 4 carbon atoms.

To this end, the invention relates to cyclic urea compounds of formula (Ia):

<img file="ES2301554T3_D0001.tif" />

(the)

<img file="ES2301554T3_D0002.tif" />

in which the R groups¹, R², R³, R⁴ and R⁵ can represent each and independently of each other:

a) a hydrogen,

b) a halogen,

c) the side chain, protected or not, of an amino acid selected from natural or unnatural amino acids,

d) a linear or branched (C1-C20) alkyl group, unsubstituted or substituted by one or more substituents, among which: -COOR ,, -CONHR_to, -OR_to, -NHR_to, -NH (CO) R_to, -NHCOOR_to, an aryl or heteroaryl group, including the structure R "'CO-, the group R"' comprising 1 to 10 carbon atoms, a nitrile, guanidino or nitro group,

e) an aryl group whose ring structure contains from 5 to 20 carbon atoms, substituted or not by the substituents mentioned above, as well as by cyano or amidine groups,

f) an alkenyl or alkynyl group (C1-C6),

g) a sulfonyl group (R_cSW₂),

h) an acyl group (R_cCO),

i) an OR group_b,

j) an NH2 group,

ES 2 301 554 T3

k) -COORb,

l) -CONHR_b,

m) -CH₂CONH₂ representing R_to and R_b independently of each other a hydrogen, an allyl group, benzyl, t-butyl, fluorenylmethyl, benzyloxymethyl, tert-butyldimethylsilyl, 2-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyran-2yl, trimethylsilyl, triethylsilyl, 2- (trimethylsilyl, 2- (trimethyls) trilyl, 2,2,2-trichloroethyl, tosyl, ortho- (or para) -nitro-phenylsulfonyl, alkyl having 1 to 20 carbon atoms, or an aryl group whose ring structure contains 5 to 20 carbon atoms , representing R_c an alkyl group having 1 to 20 carbon atoms, or an aryl group whose ring structure contains 5 to 20 carbon atoms, or a heteroaryl, arylalkyl or heteroarylalkyl group, the R groups also being able to¹, R², R³ and R⁴ form the following intramolecular cyclizations:

1 / cyclization between R¹ and R² me,

2 / cyclization between R³ and R⁴Said compounds can be cyclic ureas, when one or more asymmetric carbons are present in formula (Ia), independently, either of the R configuration (rectus) or of the S configuration (sinister).

An advantageous group of cyclic ureas compounds responding to the general formula (Ia) is constituted by cyclic ureas compounds responding more particularly to formulas (Ib), (Ic), (Id), (Ie), (If ), (Ig), (Ih):

<img file="ES2301554T3_D0003.tif" />

in which the R groups¹, R², R⁴ and R⁵ have the meanings indicated above, where the R groups may¹ and R² also form an intramolecular cyclization, said compounds being cyclic ureas, when one or more asymmetric carbons are present in formulas (Ib) to (Ih), independently, either of the R configuration (rectus) or of the S configuration. (sinister).

In the compounds depicted above and below, the bond "-" represents a methyl group, and could also be represented as follows: "-CH3".

ES 2 301 554 T3

The invention also relates to the cyclic urea compounds of formulas (Ila), (Ilb), (Ilc), (Ild):

<img file="ES2301554T3_D0004.tif" />

<img file="ES2301554T3_D0005.tif" />

in which the R groups¹, R², R³, R⁴, R⁵ and R⁶ have the meanings indicated above in relation to the R groups¹ to R⁵, where the R groups¹, R², R³, R⁴, R⁵ also form the following intramolecular cyclizations:

1 / cyclization between R¹ and R², or

2 / cyclization between R² and R³, me

3 / cyclization between R⁴ and R⁵, or

4 / cyclization between R⁵ and R⁶, being able to represent groups d¹, d², d³ and d⁴ each and independently of one another a group: nitro, alkyl comprising 1 to 4 carbon atoms, and in particular a methyl, alkoxy comprising 1 to 7 carbon atoms, and in particular a methoxy, aryloxy comprising of 5 to 10 carbon atoms, and in particular a benzyloxy, halogen such as a fluoro, bromine, chlorine or iodine, CN, guanidino, NHR_to, NHCOOR_to, COOR_to, OR_to, having R_to the meanings indicated above, said compounds being cyclic ureas, when one or more asymmetric carbons are present in formulas (IIa) to (IId), independently, either in the R configuration (rectus) or in the S configuration ( sinister).

The invention also relates to cyclic urea compounds comprising a ring having at least 14 atoms, in particular from 14 to 30, preferably from 14 to 20, said ring comprising two amide functions and two urea functions, each amide function being or urea separated from the nearest adjacent amide or urea function by at least one carbon atom, and in particular by 1 to 4 carbon atoms.

In this regard, the invention relates to the cyclic urea compounds of formula (IIIa):

<img file="ES2301554T3_D0006.tif" />

in which the R groups¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the meanings mentioned above in relation to the R groups¹ to R⁵,

ES 2 301 554 T3 and the R groups can also¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ form the following intramolecular cyclizations:

1 / cyclization between R¹ and R², me

2 / cyclization between R³ and R⁴, me

3 / cyclization between R⁶ and R⁷, me

4 / cyclization between R⁸ and R⁹Said compounds can be cyclic ureas, when one or more asymmetric carbons are present in formula (IIIa), independently, either of the R configuration (rectus) or of the S configuration (sinister).

An advantageous group of cyclic urea compounds responding to the general formula (IIIa) is constituted by cyclic urea compounds responding more particularly to formulas (IIIb), (IIIc), (IIId), (IIIe), (IIIf ) and (IIIg):

<img file="ES2301554T3_D0007.tif" />

(lllb) (lile) (Illd)

<img file="ES2301554T3_D0008.tif" />

in which the R groups², R³, R⁴, R⁵, R⁷, R⁸, R⁹ and R¹⁰ have the meanings mentioned above in relation to the R groups¹ to R⁵, the R groups also being able³, R⁴, R⁷, R⁸ and R⁹ form the intramolecular cyclizations as defined above in relation to the R groups¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ of the compounds of general formula (IIIa), said compounds being cyclic ureas, when one or more asymmetric carbons are present in formulas (IIIb) to (IIIg), independently, or of the R configuration (rectus) or well configuration S (sinister).

Among the cyclic urea compounds, mention may be made of those comprising a ring having 7 atoms and comprising a urea function, of formula (IVa):

<img file="ES2301554T3_D0009.tif" />

(IVa)

ES 2 301 554 T3 in which R¹, R², R³, R⁴, R⁵ and R⁶ have the meanings mentioned above in relation to the R groups¹aR⁵, provided that if R³ = R⁴ = OH then R² must be different from R⁵, the R groups also being able¹, R², R³, R⁴, R⁵ form the following intramolecular cyclizations:

1 / cyclization between R¹ and R², me

2 / cyclization between R² and R³, me

3 / cyclization between R³ and R⁴, me

4 / cyclization between R⁴ and R⁵Said compounds can be cyclic ureas, when one or more asymmetric carbons are present in formula (IVa), independently, either of the R configuration (rectus) or of the S configuration (sinister).

The present invention also relates to a process for the preparation of cyclic urea compounds as defined above, from at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function, comprising:

- a step of obtaining at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function, from at least one stable activated derivative of carbamic acid containing an amine function protected by a protective group, by means of selective release of said protected amine function from said stable activated derivative (s) of carbamic acid, by cleavage or transformation of said protecting group,

- a cyclization step by reaction between the unprotected primary or secondary amine function of at least one activated derivative obtained at the end of the selective release step and the carbamic acid function of the derivative or derivatives, said process being characterized in that the activated derivative of carbamic acid containing an unprotected primary or secondary amine function responds respectively:

- or to one of the following formulas (VIa), (VIb), (VIc) or (VId) (to obtain the compounds of formula (Ia) to (Ih) as defined above):

<img file="ES2301554T3_D0010.tif" />

<img file="ES2301554T3_D0011.tif" />

in which the group X represents a group that confers on the derivative an activated derivative structure of carbamic acid, said group X coming from a compound selected in particular from phenols, optionally substituted by at least one nitro group or at least one halogen , or hydroxylamine derivatives, or benzyl alcohol derivatives grafted on a solid support, and more particularly selected from the following compounds: N-hydroxysuccinimide, phenol, pentafluorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, 2,4-dichloro-6-nitrophenol, hydroxy-1,2,3benzotriazole, 1-oxo- 2-hydroxydihydrobenzotriazine (HODhbt), 7-aza-1-hydroxybenzotriazole (HOAt), 4-aza1-hydroxybenzotriazole (4-HOAt), imidazole, tetrazole, WANG resin,

ES 2 301 554 T3 groups R¹, R², R³ R⁴ and R⁵ have the meanings mentioned above in relation to the R groups¹ to R⁵,

- or to one of the following formulas (VIIa), (VIIb), (VIIc) or (VIId) (to obtain the compounds of formula (IIa) as defined above):

<img file="ES2301554T3_D0012.tif" />

(VIIa)

<img file="ES2301554T3_D0013.tif" />

OR⁴ (VIIb)

<img file="ES2301554T3_D0014.tif" />

(VIIc)

<img file="ES2301554T3_D0015.tif" />

(VIId) in which

X is as defined above the R groups¹, R², R³, R⁴, R⁵ and R⁶ have the meanings mentioned above in relation to the R groups¹ to R⁵,

- or to one of the following formulas (VIIIa), (VIIIb), (VIIIc) or (VIIId) (to obtain the compounds of formulas (IIb) as defined above):

<img file="ES2301554T3_D0016.tif" />

I \ K4 (Villa)

<img file="ES2301554T3_D0017.tif" />

(VlIIb)

<img file="ES2301554T3_D0018.tif" />

(VIIIc)

<img file="ES2301554T3_D0019.tif" />

(VHId) in which

X is as defined above, the groups R¹, R², R³, R⁴, R⁵ and R⁶ have the meanings mentioned above in relation to the R groups¹ to R⁵,

ES 2 301 554 T3

- or to one of the following formulas (IXa), (IXb), (IXc) or (IXd) (to obtain the compounds of formula (IIc) as defined above):

<img file="ES2301554T3_D0020.tif" />

<img file="ES2301554T3_D0021.tif" />

(IXc) (IXd) in which

X is as defined above, the groups R¹, R², R³ and R⁶ have the meanings mentioned above in relation to the R groups¹ to R⁵, groups d¹ , d², d³ and d⁴ have the meanings mentioned above,

- or to one of the following formulas (Xa), (Xb), (Xc) or (Xd) (to obtain the compounds of formulas (IId) as defined above):

<img file="ES2301554T3_D0022.tif" />

<img file="ES2301554T3_D0023.tif" />

in which

X is as defined above, the groups R¹ , R⁴, R⁵ and R⁶ have the meanings mentioned above in relation to the R groups¹ to R⁵, groups d¹ , d², d³ and d⁴ have the meanings mentioned above,

ES 2 301 554 T3

- or to one of the following formulas (XIa), (XIb), (XIc), (XId) (to obtain the compounds of formulas (IIIa) to (IIIg) as defined above):

<img file="ES2301554T3_D0024.tif" />

<img file="ES2301554T3_D0025.tif" />

(XIc) (XId) in which

X is as defined above, the groups R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the meanings mentioned above in relation to the R groups¹ to R⁵.

The compounds of formula (IVa) can be obtained according to the preparation procedure as defined above, from at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function that responds to one of the formulas (XIIa) or (XIIb) following:

<img file="ES2301554T3_D0026.tif" />

X is as defined above, the groups R¹, R², R³, R⁴ and R⁵ have the meanings mentioned above in relation to the R groups¹ to R⁵.

According to an advantageous embodiment of the present invention, the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of the formulas: (VIa), (VIb), (VIc), (VId), (VIIa), (VIIb), (VIIc), (VIId), (VIIIa), (VIIIb), (VIIIc), (VIIId), (IXa ), (IXb), (IXc), (IXd), (Xa), (Xb), (Xc), (Xd), (XIa), (XIb), (XIc), (XId), (XIIa), (XIIb), are obtained by the selective release of the protected amine function of the corresponding stable activated derivatives of carbamic acid under the conditions described below.

Below are given some examples of protecting groups and deprotection solvents used to obtain respectively the compounds (VIIa), (VIIb), (VIIc), (VIId), (VIIIa), (VIIIb), (VIIIc), (VIIId ), (IXa), (IXb), (IXc), (IXd), (Xa), (Xb), (Xc), (Xd), (XIa), (XIb), (XIc), (XId), (XIIa), (XIIb).

The amine function of the stable activated derivatives of carbamic acid will advantageously be protected by oxycarbony groups (such as tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z) groups) or benzyl groups, or it will be hidden in the form of a nitro group, cyano or azide. Two modes of deprotection will be used advantageously according to the process of the invention.

The Boc group will be deprotected by acid hydrolysis (for example with the help of trifluoroacetic acid (TFA), or of a TFA / dichloromethane mixture, or of a solution of hydrochloric acid (HCl) in an organic solvent (dioxane, ether, etc.) )), at a temperature of about 0 ° C to about 40 ° C, in order to obtain the carbamic acid derivatives containing a protonated primary or secondary amine function, in the form of trifluoroacetate or hydrochloride.

Hydrogenation will be used for the cleavage of the Z and benzyl groups, and for the reduction of the nitro, cyano or azide groups. Hydrogenation can be carried out with catalysts of the PtO2, Pd / C type in solvents

ES 2 301 554 T3 such as ethanol, methanol, dimethylformamide (DMF), ethyl acetate, tetrahydrofuran (THF), chloroform or a mixture of these solvents, at a temperature of from about 0 ° C to about 40 ° C, and at a pressure of about 1 bar to about 100 bar. In the absence of acid added during hydrogenation (HCl or acetic acid), deprotection leads exclusively to carbamic acid derivatives that contain a primary or secondary amine function in free form. The addition of one equivalent of HCl or acetic acid makes it possible to obtain carbamic acid derivatives containing a protonated primary or secondary amine function, in the form of acetate or hydrochloride.

The cyclization of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function in protonated form of formulas:

- (Via), (VIb), (VIc), (VId),

- (VIIa), (VIIb), (VIIc), (VIId),

- (VIIIa), (VIIIb), (VIIIc), (VIIId),

- (IXa), (IXb), (IXc), (IXd),

- (Xa), (Xb), (Xc), (Xd),

- (XIa), (XIb), (XIc), (XId),

- (XIIa), (XIIb), to respectively obtain the activated derivatives of carbamic acid containing the compounds of formula:

- (Ia) to (Ih),

- (IIa),

- (IIb),

- (IIc),

- (IId),

- (IIIa) to (IIIg),

- (IVa), is carried out respectively under the conditions described above.

The carbamic acid derivative containing a primary or secondary amine function in protonated form, namely the derivative of formula (VIc), (VId), (VIIc), (VIId), (VIIIc), (VIIId), (IXc) , (IXd), (Xc), (Xd), (XIc), (XId) or (XIIb):

- is solubilized in the particular cyclization solvent selected from the group consisting of acetonitrile (MeCN), toluene, pyridine, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), chloroform, dichloromethane , N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), ethyl acetate, methanol, ethanol, or mixtures thereof, and then

- is added dropwise to a solution containing a base, in particular selected from the group consisting of diisopropylethylamine, triethylamine, lutidine, pyridine, 2,4,6-collidine, N-methylmorpholine, 2,6-di-tert-4-methylpyridine, or mixtures thereof, and the reaction solvent as defined above, at a temperature of approximately -20 ° C to approximately 20 ° C, and in particular of approximately 0 ° C to 20 ° C.

The concentration of the carbamic acid derivative containing a primary or secondary amine function in protonated form in the cyclizing solvent is about 10^-4 M to about 1 M, and in particular from about 10 ³ M to about 1 M.

The concentration of the base in the cyclizing solvent is approximately 10^-6 M to about 10 M, in particular about 10^-5 to about 1 M, preferably about 10^-4 M to about 1 M.

ES 2 301 554 T3

The cyclization conditions of the carbamic acid derivative containing a primary or secondary amine function in free form, namely the derivative of formula (VIa), (VIb), (VIIa), (VIIb), (VIIIa), (VIIIb) , (IXa), (IXb), (Xa), (Xb), (XIa), (XIb) or (XIIa), differ only from those listed above with regard to carbamic acid derivatives containing a primary amine function or secondary in protonated form, because it is not necessary to operate in the presence of a base.

According to another advantageous embodiment, the invention relates to a preparation process as defined above, of cyclic urea compounds of formula (IIIa) to (IIIg) as defined above, characterized in that said compounds (IIIa ) to (IIIg) are obtained at the end of a homo-oligomerization or hetero-oligomerization reaction, from at least one activated derivative of carbamic acid containing a primary or secondary amine function, which responds to at least one of the formulas (VIa), (VIb), (VIc) or (VId) as defined above.

The homo-oligomerization or hetero-oligomerization reaction of the activated derivatives of carbamic acid containing a primary or secondary amine function of formula (VIa), (VIb), (VIc) or (VId), as well as the cyclization of the homo- or hetero-oligomers thus obtained in cyclic ureas compounds of formula (IIIa) to (IIIg), is favored by carbamic acid derivatives of formula (VIa), (VIb), (VIc) or (VId), in which the -CONR link³ mostly adopts a trans conformation.

The homo-oligomerization or hetero-oligomerization reaction is advantageously carried out at low concentrations of the activated derivatives of carbamic acid of formula (VIa), (VIb), (VIc) or (VId) in the cyclization solvent, namely concentrations of approximately 10^-3 M to about 10 ⁵ M, at a temperature of about 0 ° C to about 20 ° C.

According to an advantageous embodiment, the method of preparation of the invention is characterized in that it comprises:

• a cyclization step of the activated derivatives of carbamic acid that contain an unprotected primary or secondary amine function, leading to cyclic urea compounds that comprise in their cycle a urea function of the formula -NH-CO-N &lt;or -NH -CO-NH-, • a step of alkylating the hydrogen of the -NH- group or groups comprised in the urea function of the cyclic urea compound obtained at the end of the previous cyclization step.

The step of alkylating the hydrogen of the -NH- group or groups comprised in the urea function of the cyclic urea compound obtained at the end of the cyclization step consists in reacting an alkylating agent on the NH function (s) of the cyclic urea in presence of an adapted base.

As an example of an alkylating agent, mention may be made in particular of a halogenated derivative, the halogen group generally being a chlorine, a bromine or an iodine.

As an example of a database, the one selected from the group consisting of:

- a metal hydride, such as a sodium hydride (NaH),

- a metal alcoholate, such as sodium methanolate or potassium t-butanolate,

- sodium, lithium or potassium bis (trimethylsilyl) amide,

- potassium fluoride on alumina (KF / Al₂OR₃), in non-protic solvents such as tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethoxyethane (DME), or under phase transfer conditions with potassium carbonate (K₂CO₃), sodium carbonate (Na₂CO₃) or potash (KOH).

According to an advantageous embodiment, the process for preparing the cyclic urea compounds of formula (Ia), (Ib), (Ic), (Ie), (If), (Ig) and (Ih) as they have described above, is more particularly characterized in that it comprises:

• a cyclization stage:

_- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIa) or (VIc), or _- of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIb) or (VId),

ES 2 301 554 T3 leading respectively to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or

- compounds of cyclic ureas that comprise in their cycle a urea function of formula -R⁵NCO-NH-, • an alkylation step respectively:

- from the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁵, or

- from the hydrogen of the urea function of formula -R⁵N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹, in order to obtain the cyclic ureas compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih) that comprise in their cycle the function urea - (R⁵N-CO-NR¹) -, where the groups R¹ and R⁵ as previously described.

According to an advantageous embodiment, the process for preparing the cyclic urea compounds of formula (IIa) is more particularly characterized in that it comprises:

• a cyclization stage:

_- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIIa) or (VIIc), or _- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIIb) or (VIId), leading respectively to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or

- compounds of cyclic ureas that comprise in their cycle a urea function of formula -R⁶NCO-NH-, • an alkylation step respectively:

- from the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁶, or

- from the hydrogen of the urea function of formula -R⁶N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹, in order to obtain the cyclic urea compounds of formula (IIa) that comprise in their cycle the urea function - (R⁶N-CO-NR¹) -, where the groups R¹ and R⁶ as previously described.

According to an advantageous embodiment, the process for preparing the cyclic urea compounds of formula (IIb) is more particularly characterized in that it comprises:

• a cyclization stage:

_- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIIIa) or (VIIIc), or _- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (VIIIb) or (VIIId), leading respectively to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or

- compounds of cyclic ureas that comprise in their cycle a urea function of formula -R⁶NCO-NH-,

ES 2 301 554 T3 • an alkylation step respectively:

_- of the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁶, or

- from the hydrogen of the urea function of formula -R⁶N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹, in order to obtain the cyclic urea compounds of formula (IIb) that comprise in their cycle the urea function - (R⁶N-CO-NR¹)-.

According to an advantageous embodiment, the process for preparing the cyclic ureas compounds of formula (IIc) is more particularly characterized in that it comprises:

• a cyclization stage:

_- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (IXa) or (IXc), or _- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (IXb) or (IXd), leading respectively to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or _- cyclic ureas compounds that comprise in their cycle a urea function of formula -R⁶NCO-NH-, • an alkylation step respectively:

_- of the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁶, or _- of the hydrogen of the urea function of formula -R⁶N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹, in order to obtain the cyclic ureas compounds of formula (IIc) that comprise in their cycle the urea function - (R⁶N-CO-NR¹)-.

According to an advantageous embodiment, the process for preparing the cyclic urea compounds of formula (IId) is more particularly characterized in that it comprises:

• a cyclization stage:

_- of the activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (Xa) or (Xc), or _- of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (Xb) or (Xd), respectively leading to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or

- compounds of cyclic ureas that comprise in their cycle a urea function of formula -R⁶NCO-NH-, • an alkylation step respectively:

_- of the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁶, or

- from the hydrogen of the urea function of formula -R⁶N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹, in order to obtain the cyclic ureas compounds of formula (IId) that comprise in their cycle the urea function - (R⁶N-CO-NR¹)-.

ES 2 301 554 T3

According to an advantageous embodiment, the process for preparing the cyclic urea compounds of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) and (IIIg), is characterized more particularly because it comprises:

• a cyclization stage:

_- of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (XIa) or (XIc), or _- of activated derivatives of carbamic acid containing an unprotected primary or secondary amine function of formula (XIb) or (XId), leading respectively to:

_- cyclic urea compounds that comprise in their cycle a urea function of the formula -NHCO-NR¹-, or

- compounds of cyclic ureas that comprise in their cycle a urea function of formula -R¹⁰NCO-NH-, • an alkylation step respectively:

- from the hydrogen of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹⁰, or

- from the hydrogen of the urea function of formula -R¹⁰N-CO-NH-, obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group¹ , in order to obtain the cyclic ureas compounds of formula (Illa), (IlIb), (IlIc), (IlId), (lile), (IlIf) and (IlIg), which comprise in their cycle the urea function - ( R¹⁰N-CO-NR¹) -, where the groups R¹ to R¹⁰ as previously described.

The process for preparing the cyclic ureas compounds of formula (IVa) is more particularly characterized in that it comprises:

• a cyclization step of the activated derivatives of carbamic acid that contain an unprotected primary or secondary amine function of formula (XIIa) or (XIIb), leading to cyclic urea compounds that comprise in their cycle a urea function of formula - NH-CO-NR¹-, • a hydrogen alkylation step of the urea function of formula -NH-CO-NR¹ - obtained at the end of the cyclization stage with the help of an alkylating agent comprising the R group⁶, in order to obtain the cyclic urea compounds of formula (IVa) that comprise in their cycle the urea function - (R⁶N-CO-NR¹) The alkylation step of the process for preparing the cyclic ureas compounds as described above, may be carried out in particular under the particular conditions described below. A solution of a cyclic urea compound (10 mmol) in THF (10 ml) is added dropwise to a suspension of NaH (1-1.2 equivalents if an NH is to be alkylated, 2-2.4 equivalents if they must rent two NHs) in THF (with Argon and at 0 ° C). The reaction medium is stirred at 0 ° C for 60 minutes, and then the alkylating agent (11.5 equivalents if one NH must be alkylated, 2-3 equivalents if two NH must be alkylated) dissolved in THF at 0 ° C. C. The reaction is allowed to work for 12 hours and then the reaction medium is diluted with ethyl acetate and with a NH solution.₄Saturated Cl. The organic phase is washed with a saturated solution of KHSO₄ 1N, H₂Or, a NaHCO solution₃ saturated, H₂O. The organic phase is dried over MgSO₄ and the solvent is concentrated by rotary evaporation.

The preparation process as defined above can be used to obtain cyclic urea compounds comprising a 6-atom ring and comprising a urea function, of formula (Va):

ES 2 301 554 T3

<img file="ES2301554T3_D0027.tif" />

in which R¹, R², R³, R⁴ and R⁵ can represent each and independently of each other:

a) a hydrogen,

b) a halogen,

c) the side chain, protected or not, of an amino acid selected from natural or unnatural amino acids,

d) a linear or branched (C1-C20) alkyl group, unsubstituted or substituted by one or more substituents among which: -COOR_to, -CONHR_to, -OR_to, -NHR_to, -NH (CO) R_to, -NHCOOR_to, an aryl or heteroaryl group, whose cyclic structure contains from 5 to 20 carbon atoms, a halogen atom, a group R "'CO-, the group R"' comprising from 1 to 10 carbon atoms, a nitrile group, guanidino or nitro,

e) an aryl group whose ring structure contains from 5 to 20 carbon atoms, substituted or not by the substituents mentioned above, as well as by cyano or amidine groups,

f) an alkenyl or alkynyl group (C1-C6),

g) a sulfonyl group (R_cSO2),

h) an acyl group (R_cCO),

i) an OR group_b,

j) an NH2 group,

k) -COORb,

l) -CONHRb,

m) -CH2CONH2, Ra and Rb representing independently of each other a hydrogen, an allyl group, benzyl, t-butyl, fluorenylmethyl, benzyloxymethyl, tert-butyldimethylsilyl, 2-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyran-2yl, trimethylsil triethylsilyl, 2- (trimethylsilyl) ethyl, trityl, 2,2,2-trichloroethyl, tosyl, ortho- (or para) -nitro-phenylsulfonyl, alkyl having 1 to 20 carbon atoms, an aryl group whose ring structure contains 5 to 20 carbon atoms, Rc representing an alkyl group having 1 to 20 carbon atoms, or an aryl group whose ring structure contains 5 to 20 carbon atoms, or a heteroaryl, arylalkyl or heteroarylalkyl group, the R groups being able¹, R², R³ and R⁴ form the following intramolecular cyclizations:

1 / cyclization between R¹ and R², me,

2 / cyclization between R³ and R⁴Said compounds can be cyclic ureas, when one or more asymmetric carbons are present in formula (Va), independently, either of the R configuration (rectus) or of the S configuration (sinister),

ES 2 301 554 T3 from an activated derivative of carbamic acid containing a primary or secondary amine function corresponding to one of the following formulas (XIIIa) or (XIIIb):

<img file="ES2301554T3_D0028.tif" />

(XlIJa) (XlUb) in which the group X represents a group that confers on the derivative a structure of an activated derivative of carbamic acid, said group X proceeding from a compound selected in particular from among phenols, optionally substituted by at least one group nitro or at least one halogen, or hydroxylamine derivatives, or benzylic alcohol derivatives grafted on a solid support, and more particularly selected from the following compounds: N-hydroxysuccinimide, phenol, pentafluorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, 2,4-dichloro-6-nitrophenol, hydroxy-1,2,3-benzotriazole, 1- oxo-2-hydroxydihydrobenzotriazine (HODhbt), 7-aza-1-hydroxybenzotriazole (HOAt), 4-aza-1-hydroxybenzotriazole (4-HOAt), imidazole, tetrazole, WANG resin, and the R groups¹ , R², R³ and R⁴ they are as defined above.

The preparation process as defined above can be used to obtain cyclic urea compounds comprising a ring having at least 8 atoms, a ring comprising at least two urea functions separated from each other by at least one carbon atom. and in particular by 1 to 4 carbon atoms.

In this regard, the preparation process as defined above can be used to obtain cyclic urea compounds comprising a ring having at least 8 atoms and comprising at least two urea functions separated from each other by 2 carbon atoms. , which respond to the formulas (XIV), (XV) and (XVIa):

<img file="ES2301554T3_D0029.tif" />

in which the R groups¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ have the meanings mentioned above in relation to the R groups¹ to R⁵, where the R groups¹, R², R⁵, R⁶, R⁹, R¹⁰, R¹³ and R¹⁴ also form the following intramolecular cyclizations:

1 / cyclization between R¹ and R², me

2 / cyclization between R⁵ and R⁶, me

3 / cyclization between R⁹ and R¹⁰, me

4 / cyclization between R¹³ and R¹⁴,

ES 2 301 554 T3 from activated carbamic acid derivatives, respectively, containing a primary or secondary amine function, and corresponding to the following formulas (XXIII), (XXIV) and (XXV):

<img file="ES2301554T3_D0030.tif" />

XXIIi

<img file="ES2301554T3_D0031.tif" />

<img file="ES2301554T3_D0032.tif" />

XXV in which the R groups¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶above, they are as defined, the group X is as defined above, and said carbamic acid derivatives can also be in protonated form.

The preparation process as defined above can be used to obtain cyclic urea compounds comprising at least four urea functions, of formulas (XVIb), (XVIc), (vid) and (XVIe):

<img file="ES2301554T3_D0033.tif" />

<img file="ES2301554T3_D0034.tif" />

(XVIe)

ES 2 301 554 T3 in which the R groups², R³, R⁶, R⁷, R⁶, R¹⁰, R¹¹, R¹⁴ and R¹⁵ have the meanings mentioned above in relation to the R groups¹ to R⁵.

The preparation process as defined above can be used to obtain compounds of formula (XVIb), in which:

- the R substituents², R⁶, R¹⁰ and R¹⁴ are selected from:

• a hydrogen atom, • a C1-C6 alkyl chain, straight or branched, substituted or not by:

i) an amine function protected or not, ii) an acid function protected or not, iii) an alcohol function protected or not, iv) an aryl or heteroaryl group, • the side chain protected or not of an amino acid selected from amino acids natural or unnatural

- the R substituents³, R⁷, R¹¹ and R¹⁵ represent a hydrogen atom, from activated derivatives of carbamic acid of formula (XXV), as mentioned above, in which:

i) the R substituents², R⁶ and R¹⁴ have the same definition as above, and the substituents R¹, R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹¹, R¹², R¹⁵ and R¹⁶ represent a hydrogen atom, or

- the R substituents³, R⁷, R¹¹ and R¹⁵ have the meanings mentioned above for R², R⁶, R¹⁰ and R¹⁴, and the substituents R¹, R², R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹², R¹⁴ and R¹⁶ represent a hydrogen atom, and ii) the R group¹³ is an arylalkyl or heteroarylalkyl group, which can be linked to a solid support, and which allows the formation, before the final deprotection step, of a synthetic intermediate having the formula (XVIa) as mentioned above, in which the different substituents R¹ to R¹⁶ they have the same meanings as those mentioned above for the compound of formula (XXV).

The preparation procedure as defined above can be used to obtain compounds of formula (XV), in which:

- the R substituents², R⁶ and R¹⁰ are selected from:

• a hydrogen atom, • a C1-C7 alkyl chain, straight or branched, substituted or not by:

i) an amine function protected or not, ii) an acid function protected or not, iii) an alcohol function protected or not, iv) an aryl or heteroaryl group, • the side chain protected or not of an amino acid selected from amino acids natural or unnatural

- the R substituents¹, R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹¹ and R¹² represent a hydrogen atom, from activated derivatives of carbamic acid of formula (XXIV), as mentioned above, in which:

ES 2 301 554 T3 ⁱ⁾ the R substituents², R⁶ and R¹⁰ have the meanings mentioned above, and the substituents R¹, R³, R⁴, R⁵, R⁷, R⁸, R¹¹ and R¹² represent a hydrogen atom, or

- the R substituents³, R⁷ and R¹¹ have the meanings mentioned above for R², R⁶ and R¹⁰, and the substituents R¹, R², R⁴, R⁵, R⁶, R⁸, R¹⁰ and R¹² represent a hydrogen atom, and ⁱⁱ⁾ group R⁹ is an arylalkyl or heteroarylalkyl group, which can be linked to a solid support, and which allows the formation, before the final deprotection step, of a synthetic intermediate having the formula (XV), as mentioned above, in which the different substituents R¹ to R¹² they have the same meanings as those mentioned above for the compound of formula (XXIV).

Among the cyclic ureas compounds, mention may be made of compounds of formula (XV) or (XVIa) as mentioned above, in which the substituents R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ represent:

- either a hydrogen atom,

- either the protected or unprotected side chain of an amino acid selected from natural or non-natural amino acids, and in particular in which:

• R¹, R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁵ and R¹⁶ represent a hydrogen atom, and • R², R⁶, R¹⁰ and R¹⁴ represent a group selected from the groups methyl, isopropyl, isobutyl, sec-butyl, benzyl, alkyl acetate and hydroxybenzyl (ortho, meta or para), provided that the compounds of formula (XV) or (XVIa) are other than the following compounds of formulas (VIII bis / 1), (VIII bis / 2), (VIII bis / 3) and (VIII bis / 4)

<img file="ES2301554T3_D0035.tif" />

<img file="ES2301554T3_D0036.tif" />

<img file="ES2301554T3_D0037.tif" />

(HIV bis / 1)

<img file="ES2301554T3_D0038.tif" />

(VIII bis / 2)

<img file="ES2301554T3_D0039.tif" />

(Vni bis / 3) (VIII bis / 4)

ES 2 301 554 T3

Mention may also be made of compounds as defined above, which correspond to the following formulas:

<img file="ES2301554T3_D0040.tif" />

<img file="ES2301554T3_D0041.tif" />

<img file="ES2301554T3_D0042.tif" />

<img file="ES2301554T3_D0043.tif" />

ES 2 301 554 T3

<img file="ES2301554T3_D0044.tif" />

<img file="ES2301554T3_D0045.tif" />

<img file="ES2301554T3_D0046.tif" />

in which Alloc represents an allyloxycarbonyl group, and

<img file="ES2301554T3_D0047.tif" />

ES 2 301 554 T3

According to an advantageous embodiment, the preparation process of the present invention makes it possible in particular to obtain new cyclic urea compounds that would have been difficult to obtain by prior art preparation processes that generally require the preparation of diamines. The preparation process of the present invention allows the cyclization of carbamic acid derivatives obtained from derivatives of N-protected amino acids (α, β, γ and δ acids), and therefore allows to obtain easily and in very few steps a great molecular diversity on the side chains used. The process of the invention is also applied to the cyclization of carbamic acid derivatives obtained in only three stages, namely:

a) a stage of transformation of the -COOH group of the N-protected amino acid derivative (α, β, γ and δ acids), into the -CON group₃ to obtain an acyl-azide,

b) a step of transformation of the -CON3 group of the acyl-azide into -NCO group to obtain an isocyanate,

c) a step of treating the isocyanate to obtain said stable derivative of carbamic acid, and this from very simple molecules, such as N-protected dipeptides, to give extremely functionalized and asymmetric cyclic ureas molecules.

It is recalled that the term "amino acid derivative" is to be interpreted in the broad sense, as understood by the person skilled in the art, and designates in particular a derivative of a peptide, a polypeptide, a protein, a pseudopeptide or an oligourea.

Description of the figures

Figures 1A and 1B represent the two-dimensional structure of the compound of formula (Ij). Figure 1A corresponds to the top view of the urea cycle.

Figure 1B corresponds to the view along the axis formed by the carbons C^to, noted C (1) and C (4).

For the sake of clarity, the atoms have been numbered. The following tables indicate certain interatomic distances (in A) and certain angular values.

Lengths of certain bonds in the compound of formula (Ij)

<td>Link</td><td>Length (A)</td>

<td>N (1) -C (3)</td><td> 1,32</td>

<td>N (2) -C (12)</td><td> 1,32</td>

<td>C (12) -N (3)</td><td> 1,38</td>

Values ​​of certain angles in the compound of formula (Ij)

<td>Angle</td><td>Value (A)</td>

<td>C (3) - N (1) -C (1)</td><td> 120</td>

<td>N (1) - C (3) - C (4)</td><td> 119</td>

<td>C (12) - N (2) - C (4)</td><td> 132</td>

<td>N (2) - C (12) - N (3)</td><td> 119</td>

<td>C (12) - N (3) - C (1)</td><td> 126</td>

Values ​​of certain torsion angles in the compound of formula (Ij)

<td>Angle</td><td>Value (A)</td>

<td>N (3) - 0 (12) - N (2) - 0 (4)</td><td> 0,47</td>

<td>C81) - N (3) - C (12) - N (2)</td><td> -3,43</td>

<td>0 (4) - C (3) - N (1) - C (1)</td><td> -1,07</td>

The following examples illustrate the invention. They do not limit it in any way.

ES 2 301 554 T3

Example 1

Intermolecular and intramolecular reactions that can occur during the preparation of cyclic urea compounds

The macrocyclization process from bifunctional acyclic precursors (activated derivatives of carbamic acid containing a primary or secondary amine function) homo-oligomeric and / or hetero-oligomeric, can lead to obtaining homo-oligomeric and / or cyclic ureas compounds. or hetero-oligomeric, whose size distribution depends on the dilution of the reaction medium and the effective molarity of the different linear precursors. It is the competition that exists between the intermolecular and intramolecular reaction processes, which leads to obtaining a reaction mixture that can be more or less complex.

1) Use of a stable activated derivative of carbamic acid

When the activated derivative of carbamic acid containing a primary or secondary amine function in protonated form (precursor) is reacted in the presence of a base, it is possible to obtain homooligomeric cyclic ureas of variable sizes, and in variable proportions.

Scheme 1 below represents the homo-oligomeric cyclic urea compounds obtained at the end of intermolecular and intramolecular reactions.

<img file="ES2301554T3_D0048.tif" />

<img file="ES2301554T3_D0049.tif" />

xxu

In this scheme, the secondary amine functions of the activated derivatives of carbamic acid (acyclic bifunctional precursors) are represented in protonated form (VIc-1) and in free form (VIa-1).

When the starting compound is the bifunctional acyclic precursor (VIa-1) (activated derivative of carbamic acid containing a secondary amine function in free form) obtained at the end of the release step, the intermolecular homo-oligomerization reaction can take place. directly after said release step, without the addition of a base.

When the starting compound is the bifunctional acyclic precursor (VIc-1) (activated derivative of carbamic acid containing a secondary amine function in protonated form) the intermolecular homo-oligomerization reaction takes place in the presence of a base, in order to neutralize the protonated secondary amine function to secondary amine function in free form (VIa-1). At the end of the intermolecular homo-oligomerization reaction, a homo-oligomeric acyclic bifunctional precursor is obtained that contains a secondary amine function in free form (XXI), which undergoes intramolecular cyclization to form a homo-oligomeric cyclic urea (XXII) .

Thus, in the case in which the precursor is the molecule (VIc-1) or (VIa-1), or the homo-oligomer (XXI), the mass spectrometry of the reaction medium allows to detect cyclic ureas (XXII) of variable sizes, ranging from monomer to octamer, and which are represented with the help of the integer n (n = integer between 0 and 7). When n is equal to 0, there is no homo-oligomer formation, and the intramolecular cyclization step b) takes place immediately after the formation of the compound (VIa-1).

Generally, for this family of precursors, among the cyclic ureas present in the reaction medium, the cyclic dimer (n = 1) is the major product.

Therefore, it is possible from a single precursor (a stable activated derivative of carbamic acid that contains a primary or secondary amine function in free or protonated form) to obtain a mixture of homo-oligomeric cyclic ureas that present cycles of different sizes. The cyclic ureas thus obtained can be characterized by mass spectrometry and can be purified by chromatography.

ES 2 301 554 T3

2) Use of two stable activated derivatives of carbamic acid

Likewise, it is possible, starting from a mixture of several precursors of the same family, to obtain a statistical distribution, for the different cycle sizes, of hetero-oligomeric and homo-oligomeric cyclic ureas .

Scheme 2 below represents homodimeric (IIIf1) and (IIIf3) and heterodimeric (IIIf2) cyclic urea compounds obtained at the end of intermolecular and intramolecular reactions.

<img file="ES2301554T3_D0050.tif" />

The secondary amine functions of the bifunctional acyclic precursors are represented in protonated form (VIc-1) and (VIc-2) and in free form (VIa-1) and (VIa-2).

The two bifunctional acyclic precursors (VIc-1) and (VIc-2) (activated derivatives of carbamic acid containing a secondary amine function in protonated form) each undergo, in the presence of a base, a homodimerization to respectively form two acyclic precursors homodimeric bifunctional (XIa-1) and (XIa-

3) containing a secondary amine function in free form, as well as hetero-dimerization to form a dimeric bifunctional precursor (XIa-2) containing a secondary amine function in free form.

Said homo-dimeric (XIa-1), (XIa-3) and heterodimeric (XIa-2) derivatives thus obtained undergo intramolecular cyclization to form respectively homodimeric cyclic ureas (IIIf1) and (IIIf3) and a heterodimeric cyclic urea (IIIf2 ).

Thus, if the reaction is carried out on a mixture of two precursors (VIc-1), (VIc-2) or (VIa-1), (VIa-2), a heterodimer (IIIf2) and two homodimers (IIIf1) and (IIIf3).

ES 2 301 554 T3

Example 3

Cleavage of the activated derivative of carbamic acid containing a protected amine function relative to the solid support

Scheme 3 below represents the cleavage, relative to a solid support (a resin), of an activated derivative of carbamic acid of formula:

BA-NH-CO-X in which

X represents a group that confers on said derivative an activated carbamic acid function,

B represents the protected amine function,

A represents the part of the molecule that separates the activated carbamic acid function and the protected amine function, represents the solid support (resin).

<img file="ES2301554T3_D0051.tif" />

<img file="ES2301554T3_D0052.tif" />

<img file="ES2301554T3_D0053.tif" />

<img file="ES2301554T3_D0054.tif" />

H

<img file="ES2301554T3_D0055.tif" />

<img file="ES2301554T3_D0056.tif" />

The activated derivative of carbamic acid is chemically bound to the resin either (1) through its amine function (the resin and the resin arm serving as the protecting group) [case n ° 1], or (2) through its function activated carbamic acid [case n ° 2], or (3) by means of another functional group present in said activated derivative of carbamic acid [case n ° 3].

Depending on the mode of binding of the activated derivative of carbamic acid to the resin, the cleavage can be carried out either before the intramolecular cyclization step (the cyclization step will therefore be carried out in solution after the cleavage) [case n 1, case no 2, case no 3-1 and case no 3-3] or after the cyclization step (which will then take place on the solid support) [case no 3-2].

ES 2 301 554 T3

Example 4

Procedure for the preparation of cyclic ureas compounds from protected N-Boc carbamic acid derivatives (XVII) and (XIX)

The selectivity of deprotection of the amine function depends on the type of protecting group used for the amine and the activated carbamic acid group. Said example of orthogonality (i.e. the selective release of the amine function in order not to alter the carbamic acid function of the activated derivative of carbamic acid) is shown below by the selective deprotection of the Boc (tert-butoxycarbonyl) group that does not alter the integrity of the O-succinimidyl carbamate (XVII) and (XIX). Indeed, O-succinimidyl carbamate does not degrade in the presence of trifluoroacetic acid or hydrochloric acid in organic solvent: the step of liberation of the amine function (through the deprotection of the Boc group) is, therefore, completely selective.

This example is in no way limiting. Other types of orthogonality can be imagined such as the use of the benzyloxycarbonyl group with the O-succinimidyl carbamate.

1) Stage of liberation or deprotection of the protected amine function of the stable activated derivatives of carbamic acid (XVII) and (XIX) leading respectively to the derivatives of carbamic acid containing a primary or secondary amine function in protonated form (XVIIIa ) and (VIc-3), or in free form (XVIIIb) or (VIa-3).

Studies have shown that N-hydroxysuccinimide carbamate was stable in an acid medium (treatment with trifluoroacetic acid (TFA) for example). The carbamic acid derivatives of N-hydroxysuccinimide (XVII) and (XIX) represented in Scheme 4 below have been synthesized as described above, that is by:

- a step of transformation of the -COOH group of the corresponding N-protected amino acid derivative into -CON3 group to obtain an acyl-azide,

- a transformation stage of the -CON group₃ of the corresponding acyl-azide in the -NCO group to obtain an isocyanate,

- a step of treating the corresponding isocyanate to obtain the carbamic acid derivative of Nhydroxysuccinimide of formula (XVII) or (XIX).

The synthesis schemes of the activated carbamic acid derivatives of N-hydroxysuccinimide (XVII) and (XIX) are represented respectively below:

<img file="ES2301554T3_D0057.tif" />

The experimental conditions of the different stages of obtaining the carbamic acid derivative (XVII) are described in the publication by Guichard et al. "J. Org. Chem., 1999, 8702-8705 ".

<img file="ES2301554T3_D0058.tif" />

ES 2 301 554 T3

The experimental conditions of the different stages of obtaining the carbamic acid derivative (XIX) are identical to those described for compound (XVII).

Scheme 4 below depicts the selective trifluoroacetic acid (TFA) deprotection of the Boc group of the N-protected succinimidyl carbamic acid derivatives (XVII) and (XIX).

<img file="ES2301554T3_D0059.tif" />

Treatment of the TFA-protected N-Boc carbamates (XVII) and (XIX) allows to obtain intermediate compounds (XVIIIa) and (VIc-3) (trifluoroacetate salts that can be isolated), or (XVIIIb) and (VIa- 3) (non-isolatable) that represent interesting precursors for the synthesis of cyclic ureas compounds.

The protected N-Boc carbamic acid derivatives (XVII) and (XIX) are each dissolved in a solution of trifluoroacetic acid (CF3COOH or TFA) (deprotection solvent) containing methylene chloride (CH2Cl2) (50/50 v / v for example), or in a pure TFA solution. After 30 minutes, the TFA is evaporated or coevaporated in the presence of ether (Et2O) or hexane. In a number of cases, the addition of ether or hexane leads to a precipitate which is filtered and dried under vacuum. Otherwise, the residual oil after evaporation of the TFA is dried under vacuum.

2) Stage of intramolecular cyclization of the precursor compounds (XVIIIb) and (VIa-3)

The previously isolated TFA salts (XVIIIa) and (VIc-3) are each dissolved or suspended in a volume of solvent (e.g. acetonitrile (MeCN)) (cyclization solvent) to achieve a dilution of between about 0.0001 M and approximately 0.1 M. A tertiary base is added (at least one equivalent to neutralize the amine salt formed during the deprotection step) for example diisopropylethylamine, N-methylmorpholine, triethylamine (Et₃N), lutidine or collidine (pure or diluted in an organic solvent such as MeCN) (either dropwise or directly) to the solution of the trifluoroacetate salt for a period of time that can reach 24 hours.

The compounds (XVIIIb) and (VIa-3) thus obtained react intramolecularly to lead to the corresponding cyclic urea compounds having different cycle sizes.

The reaction is monitored by high performance liquid chromatography (HPLC). When the reaction is no longer progressing, the solvent is evaporated and the residue is purified either by reverse phase HPLC, or by flash chromatography on silica, or by recrystallization from an appropriate solvent to give the expected cyclic urea compound (s). .

The following diagrams 5 to 11 represent respectively:

- the step of releasing the protected amine function of a stable activated derivative of carbamic acid that responds to the general formula (XVII) or (XIX), and

- the intramolecular cyclization step from the carbamic acid derivative thus obtained containing an amine function in free form.

ES 2 301 554 T3

Scheme 5

Preparation of the cyclic urea compound (XX)

<img file="ES2301554T3_D0060.tif" />

1) Compound (XVIIa) (323 mg, 0.8 mmol) is dissolved in 10 ml of a TFA / CH mixture₂Cl₂ (50/50 v / v), and the solution is stirred at room temperature for 30 minutes. The solvent is then concentrated and the TFA salt (XVIIIa-1) is precipitated by addition of hexane. The precipitate is filtered and dried with a paddle pump for 12 hours to give a white solid (XVIIIa-1) (300 mg, 93%).

2) Compound (XVIIIa-1) (300 mg, 0.72 mmol) is dissolved in MeCN (10 ml), and a solution of diisopropylethylamine (130 µl, 0.73 mmol) is added. The reaction mixture is stirred for 60 minutes. MeCN is evaporated and the residue is redissolved with ethyl acetate. The organic phase is washed with a saturated NaCl solution to give compound (XX) (110 mg, 87%).

In the case of the carbamic acid derivative (XVIIa) (acid derivative / -Laminated), the cyclic compound (XX) obtained after deprotection of the Boc group and intramolecular cyclization, comprises a 5-atom ring. This compound has been previously described in the literature.

This example has been given in order to demonstrate that the preparation process of the present invention makes it possible to obtain cyclic urea compounds already described in the literature.

Scheme 6

Preparation of the cyclic urea compound (IIIf-4)

<img file="ES2301554T3_D0061.tif" />

1) Compound (XIXa) (500 mg, 1.17 mmol) is dissolved in 10 ml of a TFA / CH mixture₂Cl₂ (50/50 v / v), and the solution is stirred at room temperature for 30 minutes. The solvent is then concentrated and the TFA salt (VIc-4) is precipitated by adding ether. The precipitate is filtered and dried with a paddle pump for 12 hours to give a white solid (VIc-4) (450 mg, 87%).

ES 2 301 554 T3

2) The compound (VIc-4) (430 mg, 0.97 mmol) is dissolved in 80 ml of MeCN, and the solution is added dropwise to a solution of diisopropylethylamine (421 // l, 2.4 mmol) in MeCN (500 ml) for 1 hour. The reaction mixture is stirred for 5 h. The MeCN is evaporated and the residue is taken up in CH2Cl2. The organic phase is washed with KHSO₄ 1N, dry over MgSO₄, and concentrates. The residue is purified by reverse phase chromatography on a C18 column to give compound (IIIf-4) (140 mg, 70%).

In the case of the carbamic acid derivative (XIXa), a dipeptide derivative for which the amide bond is not in the cis configuration, a cyclic dimer (IIIf-4) of 14 atoms is mainly obtained with a yield of 70% (scheme 6 ).

The compound (IIIf-4) is new.

Scheme 7

Preparation of compound (Ii)

<img file="ES2301554T3_D0062.tif" />

In the case of the carbamic acid derivative (XIXb), for which the amide bond can adopt a cis configuration, the corresponding 7-atom cyclic monomer (Ii) is obtained with a yield greater than 70% (scheme 7).

Compound (Ii) is new.

Scheme 8

Preparation of compound (Ij)

<img file="ES2301554T3_D0063.tif" />

1) Compound (XIXc) (3g, 6.91 mmol) is dissolved in 20 ml of a TFA / CH mixture₂Cl₂ (50/50 v / v), and the solution is stirred at room temperature for 30 minutes. The solvent is then concentrated and the TFA salt (VIc-6) is paddle pump dried for 12 hours to give a solid foam (VIc-6) (3.23 g, 100%).

2) Compound (VIc-6) (400 mg, 0.89 mmol) is dissolved in MeCN (30 ml), and the solution is added dropwise to a solution of diisopropylethylamine (353 Jul, 2.0 mmol) in MeCN (40 ml) at -20 ° C for 1 hour. The reaction mixture is stirred for 3 hours. MeCN is evaporated and the residue is recrystallized from a CH mixture₂Cl₂/ diisopropylether to give (Ij) (135mg, 70%).

ES 2 301 554 T3

Scheme 9

Compound preparation (Ik)

<img file="ES2301554T3_D0064.tif" />

<img file="ES2301554T3_D0065.tif" />

Vla-7

1) Compound (XlXd) (2.02 g, 4.49 mmol) is dissolved in trifluoroacetic acid (v = 10 ml) for 30 minutes. The precipitate formed by the addition of diethyl ether is collected on sinter, washed with ether and dried with a paddle pump for 12 hours to give a white solid (VIc-7): 1.98 g, 95%.

2) The compound (VIc-7) (1.94 g, 4.17 mmol) is dissolved in MeCN (90 ml), and the solution is added dropwise to a solution of diisopropylethylamine (1.78 ml, 10, 42 mmol) in MeCN (50 ml) at room temperature for 4 hours. MeCN is evaporated and the residue is recrystallized from a CH mixture₂Cl₂/ diisopropylether to give (Ik) (586 mg, 60%).

Scheme 10

Preparation of compound (Il)

<img file="ES2301554T3_D0066.tif" />

Vla-8

1) Compound (XIXe) (1.21 g, 2.55 mmol) is dissolved in trifluoroacetic acid (v = 10 ml) for 30 minutes. The precipitate formed by the addition of diethyl ether is collected on sinter, washed with ether and dried with a paddle pump for 12 hours to give a white solid (VIc-8): (816 mg, 65%).

2) Compound (VIc-8) (200 mg, 0.41 mmol) is dissolved in MeCN (20 ml), and the solution is added dropwise to a solution of diisopropylethylamine (0.21 ml, 1.23 mmol ) in MeCN (100 ml) at room temperature for 4 hours. MeCN is evaporated, and the residue is purified by preparative HPLC to give (Il) after lyophilization (70 mg, 66%).

ES 2 301 554 T3

Scheme 11

Compound preparation (Im)

<img file="ES2301554T3_D0067.tif" />

1) Compound (XIXf) (1.05 g, 1.95 mmol) is dissolved in trifluoroacetic acid (v = 10 ml) for 30 minutes. The precipitate formed by the addition of diethyl ether is collected on sinter, washed with ether and dried with a paddle pump for 12 hours to give a white solid (VIc-9) (1.045 mg, 97%).

2) Compound (VIc-9) (200 mg, 0.36 mmol) is dissolved in MeCN (20 ml), and the solution is added dropwise to a solution of diisopropylethylamine (0.19 ml, 1.08 mmol ) in MeCN (100 ml) at room temperature for 4 hours. MeCN is evaporated and CH is added₂Cl₂ (1.5 ml). The cyclic urea derivative is then purified by treatment with a scavenger resin (polystyrene Tris- (2-aminoethyl) -amine) to give (Im): (116 mg, 99%).

TABLE 1

Cyclic ureas compounds (XX), (IIIf-4), (Ii), (Ij), (Ik), (Il) and (Im) obtained respectively from the stable activated derivatives of carbamic acid (XVIIa), ( XIXa), (XIXb), (XIXc), (XIXd), (XIXe) and (XIXf)

<td>Carbamates (XVII) 0 (XIX)</td><td>Cyclic ureas</td><td>Performance (%)^to</td><td>HPLC f_R (min.)⁶</td><td>MALDI-MS</td>

<td>(XVIIa)</td><td>(XX)</td><td> 90</td><td> 11,2^C</td><td>177.2 [M + H]⁺</td>

<td>(XIXa)</td><td>(lllf-4)</td><td> 70</td><td> 10,00^d</td><td>367.4 [M + Hf</td>

<td>(XIXb)</td><td>(I¡)</td><td> 70</td><td> 10,03^d ~</td><td>260.3 [M + H]⁺</td>

<td>(XIXc)</td><td>(ij)</td><td> 70</td><td> 9,39^d</td><td>234.5 [M + Hf</td>

<td>(XIXd)</td><td>(Ik)</td><td> 60</td><td> 9,22^d</td><td>234.3 [M + H]⁺</td>

<td>(XIXe)</td><td>(ll)</td><td> 66</td><td> 9,55°</td><td>260.4 [M + H]⁺</td>

<td>(XIXf)</td><td>(Im)</td><td> 99</td><td> 7,88^d</td><td>324.2 [M + H]⁺</td>

<td colspan="4">³ yields of the cyclic ureas compounds (XX), (lllf-4), (Ii), (Ij), (Ik), (II) and⁶ linear gradient of A (water solution containing 0.1% TFA) and B (solution containing 0.08% TFA),^c 5-65% B, 20 minutes (it goes from 5% to 65% of B in 20 minutes),^d 0-100% B, 20 minutes. HPLC: high performance liquid chromatography MALDI-MS: mass spectrometry</td><td>Im) acetonitrile tation</td>

The physicochemical data of the compounds (IIIf-4), (Ii), (Ij) and (Ik) are given below.

(IIIf-4): Yield 70%, white solid; HPLC t_r 10.0 min. (linear gradient, 0-100% B, 20 min.) - NMR¹H ([D6] DMSO, 200 MHz): δ = 0.86 (d, J = 6.8 Hz, 6H, Me), 0.86 (d, J = 6.7 Hz, 6H, Me), 1 , 59-1.70 (m, 2H, CH (Me)₂), 1.76-2.11 (m, 1H, CHCH₂CH₂), 3.14-3.26 (m, 1H, CH₂N), 3.49-3.60 (m, 1H, CH₂N), 4.80 (m, 1H, NHCHNH), 5.58 (d, J = 8.9 Hz, NCONH), 6.48 (d, J = 6.5 Hz, CH2CONH).

(Ii): Yield 70%, white solid; HPLC t_r 10.0 min. (linear gradient, 0-100% B, 20 min.) - NMR¹H ([D₆] DMSO, 200 MHz): δ = 1.89-2.29 (m, 4H, CHCH₁CH₁), 2.78 (dd, J = 8.7, 14.5 Hz, 1H, CH2Ph), 3.37 (dd, J = 5.4, 14.4 Hz, 1H, CH2Ph), 3.45- 3.55 (m, 1H, CH2N), 3.75-3.86 (m, 1H, CH2N), 4.59 (hept., J = 2.7, 5.6, 8.5), 4, 84 (s, 1H, NH), 5.46 (brq, J =, 3.3 Hz, 1H, NCHNH), 6.4 (s, 1H, NH), 7.20-7.35 (m, 5 arom., H).

ES 2 301 554 T3 (lj): Yield 80%, white solid; HPLC t_r 9.39 min. (linear gradient, 0-100% B, 20 min.) - NMR¹H ([D₆] DMSO, 400 MHz): δ = 6.18 (s, H, NHPhe, 1H), 5.17 (d, ^αCH-gem-Sar, 1H), 4.77 (m, "CHPhe, 1H), 4.10 (dd," CHgem-Sar, 1H).

(lk): Yield 90%, white solid; HPLC t_r 9.22 min. (linear gradient, 0-100% B, 20 min.) - NMR¹H ([D₆] DMSO, 400 MHz): δ = 6.18 (s, H, NHPhe, 1H), 5.17 (d, "CH-gem-Sar, 1H), 4.77 (m," CH Phe, 1H) , 4.10 (dd, "CHgem-Sar, 1H).

Example 5

Preparation of cyclic ureas compounds by mono- or di-alkylation of cyclic ureas compounds (Ij)

1) Preparation of compounds (In), (Io), (Ip) and (Iq) by dialkylation of (Ij)

General procedure: to a solution of (Ij) (1 equivalent) in distilled THF is added NaH (5 equivalents) and then the electrophile (RX, 3 equivalents). The reaction mixture is left under stirring for 3 to 48 hours. The reaction is monitored by RP-HPLC on a C18 column. At the end of the reaction, ethyl acetate is added, and the organic phase is washed with NH4Cl. In order to remove excess electrophile if it is not volatile, and if purification on silica is not desired, a scavenger resin can be used, such as (mercaptoethyl) aminoethylpolystyrene resin for example. In this case, the scavenger resin (approximately 10 equivalents) is added to the reaction medium, and the mixture is left under stirring for 48 hours. At the end of this treatment, the resin is removed by filtration, and the organic phase is washed with NH₄Cl, dry and concentrate to give the desired purified product as shown in Scheme 12.

Scheme 12

<img file="ES2301554T3_D0068.tif" />

For the compounds (In), (Io), (Ip) and (Iq), the group R represents respectively; a methyl group (Me), a -CH group₂COOtBu, a group Bn (-CH₂-O) and a BnOBn group.

TABLE 2

<td>Product</td><td>RX</td><td>Scavenger resin</td><td>Purity (%)</td><td>Performance (%)</td><td>HPLC t_R(min) *</td>

<td>In</td><td>Mel</td><td>do not</td><td> 95</td><td> 99</td><td> 10,66^b</td>

<td>it</td><td>BrCH₂COOtBu</td><td>Yes</td><td> 94</td><td> 95</td><td> 15,82^b</td>

<td>Ip</td><td>BnBr</td><td>Yes</td><td> 94</td><td> 90</td><td> 16,30^b</td>

<td>lq</td><td>BnOBnBr + Nal</td><td>Yes</td><td> 86</td><td> 96</td><td> 16,44^c</td>

<td colspan="2">^to gradient of A (0.1% TFA in⁶ 0-100% B, 20 minutes.^c 30-100% 8, 20 minutes.</td><td colspan="4">H₂O) and B (MeCN containing 0.08% TFA).</td>

2) Preparation of compounds (Ir), (Is) and (It) by monoalkylation of (Ij)

General procedure: to a solution of (Ij) (1 equivalent) in an anhydrous solvent (THF, MeCN or CH₂Cl₂) distillate, potassium fluoride on alumina (40 w / w) (10 equivalents) is added followed by the electrophile (RX, between 1 and 20 equivalents). The reaction mixture is left under stirring for 20-72 hours. The reaction is monitored by RP-HPLC on a C18 column. At the end of the reaction, potassium fluoride on alumina is removed by filtration. In order to remove excess electrophile if it is not volatile, and if purification on silica is not desired, a scavenger resin can be used, such as (mercaptoethyl) aminoethylpolystyrene resin for example. In this case, the scavenger resin (approximately 10 equivalents) is added to the reaction medium and the mixture is left under stirring for 48 hours. At the end of this treatment, the resin is removed by filtration, and the organic phase is concentrated to give the desired purified product as shown in Scheme 13 and Table 3. It is possible under the best conditions (approximately 1 equivalent of RX, reaction time 48 hours, see table 3) obtain a selectivity of the mono-alkylated product relative to the di-alkylated product of the order of 93: 7.

ES 2 301 554 T3

Scheme 13

<img file="ES2301554T3_D0069.tif" />

TABLE 3

<td>RX</td><td>Eq.</td><td>Solvent</td><td>Time (hours)</td><td>Mono-: Dialkylated</td><td>Global purity (mono + di)</td><td>HPLC t_R(mono / di) (min.)^d</td>

<td>Mel</td><td> 1,05</td><td>THF</td><td>48 hours</td><td> 93:7</td><td>70c</td><td> 10,08/10,65</td>

<td>Mel</td><td> 20</td><td>MeCN</td><td>72 hours</td><td> 10:90</td><td> 92</td><td></td>

<td>BrCH₂COOtBu</td><td> 1,0</td><td>THF</td><td> 48</td><td> 93:7</td><td>87a, d</td><td> 12,73/15,79</td>

<td>BrCH₂COOtBu</td><td> 1,5</td><td>THF</td><td> 48</td><td> 93:7</td><td>93a</td><td></td>

<td>BrCH₂COOtBu</td><td> 10</td><td>MeCN</td><td> 20</td><td> 89:11</td><td>67a</td><td></td>

<td>BnBr</td><td> 2</td><td>DMF</td><td> 20</td><td>Difficult reaction</td><td> -</td><td> 13,18/16,17</td>

<td>BnBr</td><td> 2</td><td>THF</td><td> 72</td><td> 72,28</td><td>96a</td><td></td>

<td>BnBr</td><td> 1,05</td><td>THF</td><td> 48</td><td> 87,13</td><td>87a</td><td></td>

<td>BnBr</td><td> 1,05</td><td>MeCN</td><td> 72</td><td> 83,17</td><td>87a</td><td></td>

<td>BnBr</td><td> 1</td><td>CH₂CI₂</td><td> 48</td><td> 94,6</td><td>74a, b</td><td></td>

^to after treatment with the resin N- (2-mercaptoethyl) aminomethylpolystyrene ^b 6% starting material Ij is present.

^c 20% starting material Ij is present.

^d 10% starting material Ij is present.

^and gradient from A (0.1% TFA in H₂O and B (MeCN containing 0.08% TFA). 0-100% B, 20 minutes.

Example 6

Structural properties of cyclic urea compounds (I)

The cyclic urea compounds (I) have an extremely strong structure, well defined on the basis of X-ray diffraction or NMR. Knowledge of this structure is extremely useful for the use of the compound (I) -based heterocyclic platform for the conception and discovery of new compounds of pharmacological interest. The structure of (Ij) (see Figures 1A and 1B) has been obtained by X-ray diffraction and is representative of the structure of compounds (I). This structure is consistent with that obtained for the same compound by two-dimensional NMR and by modeling. The 1,3,5-triazepine-2,6-dione ring has a highly folded conformation. The planes of the two groups amide and urea lie along a line joining the alpha carbon of the gem-Sarcosine residue (-N (CH₃)-^toCH₂-NH-) and the alpha carbon of phenylalanine with a dihedral angle of 120 °. By way of comparison, in the case of the more folded diketopiperazines, the dihedral angle defined by the amide planes is of the order of 140-160 °. On the other hand, the hydrogen atoms in axial positions on the alpha carbon of the gem-Sarcosine residue and the alpha carbon of phenylalanine are extremely close in space: they are separated by only 2.03 angstroms. By way of comparison, the distance between the protons on the alpha carbons in the folded diketopiperazines is on the order of 2.7-2.8 angstroms.

Example 7

Preparation of compounds (XV) and (XVIa) according to schemes 14 to 20

The reaction sequence leading to obtaining compound (XVIa-2) is represented in scheme 14 and the detailed procedure is given below.

ES 2 301 554 T3

Scheme 14

<img file="ES2301554T3_D0070.tif" />

To a solution of compound 2 (see formula above, in scheme 14) (930 mg; 3.74.10^-3 moles) in acetonitrile (5 ml), the DIEA (1.27 ml: 7.48.10^-3 moles) and then compound (XVII-b) (1.18 g, 3.74.10^-3moles). The reaction is monitored by TLC. After 30 minutes, the acetonitrile is evaporated and the residue is taken up in ethyl acetate, then washed with 1N KHSO4 solutions, saturated NaHCO3, and finally saturated NaCl. The organic phase thus obtained is dried (Na2SO4) and evaporated. The residue is chromatographed on silica with a 50/50 AcOEt / Hexane system, in order to obtain compound 3. Yield 74% (1.26 g). Translucent oil. HPLC t_R 14.89 min. (linear gradient, 20-80 B, 20 min.).

Compound 3 (650mg, 1.45.10^-3 moles) is deprotected by adding trifluoroacetic acid (3 ml) with stirring. This is eliminated by successive coevaporations with the help of hexane until obtaining a residue that dries. The product thus obtained is solubilized in acetonitrile (5 ml). DIEA (246 μl; 1.45.10^-3 moles), and then compound (XVII-b) (457 mg; 1.45.10^-3 moles). The reaction is monitored by TLC. After 30 minutes, the acetonitrile is evaporated and the residue is taken up in ethyl acetate, then washed by means of

ES 2 301 554 T3 1N KHSO solutions₄, NaHCO₃ saturated, and finally saturated NaCl. The organic phase thus obtained is dried (Na₂SW₄) and evaporate, in order to obtain compound 4. Yield 87% (700 mg). HPLC t_R 13.72 min. (linear gradient, 20-80 B, 20 min.); MS (MALDI-TOF) m / z 548.46 [M + H]⁺, 571.31 [M + Na]⁺, 587.81 [M + K]⁺.

Compound 4 (640mg; 1.17.10^-3 moles) is deprotected by adding trifluoroacetic acid (3 ml) with stirring. This is eliminated by successive coevaporations with the help of hexane until a residue is obtained that dries. The product thus obtained is solubilized in acetonitrile (5 ml). DIEA (199 μl; 1.17.10^-3 moles) and then compound (XVII-b) (368 mg; 1.17.10^-3 moles). The reaction is monitored by TLC. After 30 minutes, the acetonitrile is evaporated and the residue is taken up in ethyl acetate, then washed with 1N KHSO4 solutions, saturated NaHCO3, and finally saturated NaCl. The organic phase thus obtained is dried (Na₂SO4) and evaporate, in order to obtain compound 5. Yield 70% (530 mg). HPLC t_R 13.62 min (linear gradient, 20-80 B, 20 min); MS (MALDI-TOF) m / z 671.17 [M + Na]⁺, 687.68 [M + K]⁺.

To a solution of compound 5 (460 mg; 7.09.10^-4 moles) in dichloromethane (5 ml), 1 mol% Pd (PPh3) 4 (8.2 mg; 7.09.10^-6 moles) followed by NHEt2 (600 Jul; 4.25.10^-3 moles). The reaction is monitored by TLC. After 30 minutes, the dichloromethane is evaporated. The residue is taken up in water (50 ml) with 1% acetic acid, and washed with AcOEt twice, and then lyophilized, in order to obtain compound 6. Quantitative yield (446 mg). HPLC t_R 7.40 min. (linear gradient, 20-100 B, 20 min.); MS (MALDI-TOF) m / z 565.68 [M + H]⁺, 587.38 [M + Na]⁺.

A solution of compound 6 (75.5 mg; 1.34.10^-3 moles) in acetonitrile (400 µl). In parallel, a succinimidyl carbonate solution (69 mg; 2.68.10^-3 moles) in 2.69 ml of acetonitrile. 50 ml of the succinimidyl carbonate solution is added 8 times in the solution of 6, followed by the addition of about 6 µ DIEA. After the last addition, the mixture is left under stirring for one hour, and then evaporated. Compound 7 is then obtained. HPLC t_R 11.32 min. (linear gradient, 20-80 B, 20 min.); mS (MALDI-TOF) m / z 729.03 [M + Na]⁺, 745.31 [M + K]⁺.

In a first stage, compound 7 is deprotected with the help of HCl in dioxane to give (XXV-a). The mixture is coevaporated several times and the residue is dried. Then, to a DIEA solution (442 μl; 2.68.10^-3 moles) in 100 ml of acetonitrile a solution of the product (XXV-a) previously obtained in 10 ml of acetonitrile is added dropwise over one hour. The mixture is evaporated and purified by preparative HPLC (linear gradient 0-80) to give (XVIa-1). HPLC t_R 7.56 min. (linear gradient, 20-80 B, 20 min.); MS (MALDI-TOF) m / z 491.02 [M + H]⁺, 513.46 [M + Na]⁺, 529.66 [M + K]⁺.

To a solution of (XVIa-1) (42 mg, 8.57.10^-3 moles) in ethanol (10 ml), palladium on carbon is added. After two hours of reaction under an atmosphere of H2, filter over Celite^® and evaporates. The aggregate is taken up in 1 ml of TFA until partial solubilization, and then approximately 20 ml of water are added. The whole is centrifuged and the supernatant is lyophilized. The compound (XVIa-2) is then obtained. Yield 73% (25mg). White powder. HPLC t_R 9.34 min. (linear gradient, 0-100 B, 20 min.); MS (MALDI-TOF) m / z 401.19 [M + H]⁺; NMR¹H (500 MHz, CDCl3 + TFA, 333 K) δ 1.22 (d, 12H), 3.07 (br s, 4H), 3.39 (br d, 4H), 3.91 (br s, 4H ).

In the same way, the compounds (XV-1) and (XV-2), (XVIa-3) and (XVIa-4), (XVIa-5) and (XVIa-6), (XV-3) are synthesized. and (XV-4), (XV-5), (XV-6) and (XV-7), (XV-8) and (XV-9) as indicated respectively in schemes 15 to 20.

(Scheme goes to next page)

ES 2 301 554 T3

Scheme 15

<img file="ES2301554T3_D0071.tif" />

ES 2 301 554 T3

Scheme 16

<img file="ES2301554T3_D0072.tif" />

ES 2 301 554 T3

Scheme 17

<img file="ES2301554T3_D0073.tif" />

DMF pipermine, DMF

2JXVIM.DIEA

AOocHN

NHAJoc i; pipertdlna / DMF

-----&gt;.

2) XVII-d. DIEA

1) trimethylphostine, dloxane / H₂OR

2) CO (OSuh, DIEA

XVI ¡H

Alloc = allloxicartxxVIo TEOC »trimefilsillletoxicartwnito

ES 2 301 554 T3

Scheme 18

<img file="ES2301554T3_D0074.tif" />

ES 2 301 554 T3

Scheme 19

<img file="ES2301554T3_D0075.tif" />

ES 2 301 554 T3

<img file="ES2301554T3_D0076.tif" />

Example 8

Intramolecular cyclization reactions

1. Importance of peptide amide bond geometry in carbamic acid derivatives of formula (VIc)

Cyclization experiments carried out within the scope of the present invention from carbamic acid derivatives of type (VIc) (with X = succinimide) indicate that the geometry of the amide bond -CO-NR³- (peptide bond) plays an important role in the nature of the products obtained, and more precisely in the size of the cycles obtained. The peptide bond is characterized by its geometry that has been established from crystallographic and NMR data. The peptide bond -CO-NR³- it can be either in the trans configuration, or in the cis configuration (see scheme 21). Generally, the balance is highly displaced towards the trans form. In the presence of proline or in case of N-substitution, the cis form can become as important as the trans form.

ES 2 301 554 T3

<img file="ES2301554T3_D0077.tif" />

Compounds (VIc) for which R³ is not a hydrogen, for example those for which R³ is a methyl (see compound (VIc-6) of scheme 8) or those for which R³ shape with R⁴ a 5-atom proline cycle (see compound (VIc-5) of scheme 7), preferably cyclize without any intermolecular reaction before cyclization, to give only the corresponding 7-atom cycle (cyclic monomer) of type (Ia) . This is surely due to the cis preference of the amide bond in this type of compound. Indeed, in these very restrictive cycles, the amide bond is of cis geometry, and this geometry must be the majority in order to allow the formation of the 7-atom cycle.

The cyclization of the compounds (VIc) for which R³ it is a hydrogen, it does not lead to obtaining the cyclic monomer. This is explained by the trans preference of the amide bond -CO-NR³- in this type of precursors. Cyclization occurs after one or more intermolecular bonding reactions, which leads to the production of cyclic oligomers of variable size. Thus the cyclization of compound (XIXa) (scheme 6) preferably leads to obtaining the cyclic dimer (IIIf-4) (70%). However, the mass spectrometry study of the crude reaction product makes it possible to identify the largest macrocycles (trimer, tetramer, pentamer) according to a Gaussian distribution.

2. Preferred conditions of cyclization in the case of succinimidyl carbamate derivatives of type (VIc)

The importance of a certain number of parameters (order of addition of reagents, dilution, temperature) has been evaluated during the cyclization of derivatives (XIXa), (XIXb) and (XIXc) (see schemes 6, 7 and 8).

• Order of addition of reactive agents

In general, the carbamic acid derivative containing an unprotected amine function ((VIc-4), (VIc-5) or (VIc6)) solubilized in the reaction solvent (solvent used to effect cyclization) (MeCN for example ) is added dropwise to a solution containing a base and the reaction solvent (MeCN for example).

Likewise, it is possible to reverse this order by adding dropwise the solution containing a base and the reaction solvent to the solution containing the derivative to be cyclized ((VIc-4), (VIc-5) or (VIc-6)) and the reaction solvent.

A reaction mixture is thus obtained which contains respectively the cyclic urea compounds (IIIf-4), (Ii) and (Ij).

• Dilution conditions

Regarding dilution, the concentration of the carbamic acid derivative containing an unprotected amine function ((VIc4), (VIc5) or (VIc-6)) in the reaction solvent (solvent used for cyclization) has no no influence on the cyclization of the derivatives (XIXb) and (XIXc). In these examples, the concentrations used range from about 1 M to about 10^-3 M.

On the contrary, in the case of the cyclization of the compound (XIXa), the dilution has an effect on the nature of the cyclic compounds obtained. When the reaction is carried out in a dilute solution (containing a carbamic acid derivative containing an unprotected amine function (VIc4), (VIc5) or (VIc-6) in the reaction solvent) whose concentration varies approximately from 10^-5 M to 10^-3 M, the major product obtained is the cyclic dimer (IIIf-4) (70%). The cyclic trimer represents less than 15%, and the cyclic tetramer less than 5%. On the contrary, when the reaction is carried out at a higher concentration (greater than 10^-3 M), intermolecular reactions are clearly favored, and larger size cycles are obtained (up to the cyclic pentamer) in higher proportions, to the detriment of the cyclic dimer.

ES 2 301 554 T3 • Temperature conditions

The temperature only has a low incidence on the cyclization of the products (XIXb) and (XIXc). Thus, the cyclization reaction of derivatives (XIXb) and (XIXc) leads respectively to derivatives (Ii) and (Ij) to similar yields, regardless of whether the reaction takes place at 20 ° C, 0 ° C or - 10 ° C.

On the contrary, the cyclization yield of compound (XIXa), which leads to compound (IIIf-4), seems more sensitive to temperature, the best yield being obtained when the reaction is carried out between 0 ° C and 20 ° C. For temperatures above 40 ° C, the reaction leads to a marked increase in the formation of the larger size rings (increased oligomerization reaction) while at a temperature of -20 ° C, the reactivity of (XIXa) it is very weak and does not lead to obtaining the compound (IIIf-4)