Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
  • C07D239/10—Oxygen or sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
  • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
  • C07D255/04—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a new process for preparing cyclic urea compounds and new cyclic urea compounds.
• cyclic ureas are present in a certain number of active principles currently under development in the pharmaceutical industry such as inhibitors of the protease of NLH, or indeed inhibitors of factor Xa (fXa). Cyclic ureas described in the literature (WO 93/07128, WO
• 96/29329, WO 97/08150, WO 98/20009) generally have rings with 5, 6, 7 or 8 atoms. These cycles can sometimes contain an additional hetero atom, 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 restricted conformation on which are arranged the pharmacophoric groups used for the recognition by the protease of the NLH.
• cyclic ureas described in the literature are generally prepared from the corresponding diamines by intramolecular cyclization of said diamines using a carbonylating agent such as carbonyldiimidazole.
• a carbonylating agent such as carbonyldiimidazole.
• the alkylation of ureas ⁇ , ⁇ '-disubstituted with alkyl bis-halide for the preparation of cyclic ureas ⁇ has also been described (WO96 / 00708 and WO 93/07128).
• the Applicant Company has previously developed a simple and effective method allowing the preparation of new stable activated derivatives of carbamic acid, starting from an amino acid derivative N -protected, comprising three stages: a) a stage of transformation of the -COOH group of the N- protected amino acid derivative (amino acids ⁇ , ⁇ , ⁇ and ⁇ ) into the group -CON 3 to obtain an acyl azide, b) a step of transformation of the group -CON 3 of the acyl azide into the group -NCO to obtain an isocyanate, c) a step for treating the isocyanate in order to obtain the above-mentioned stable derivative of carbamic acid.
• amino acid derivative must be interpreted in the broad sense, as understood by a person skilled in the art, and notably denotes a peptide, polypeptide, protein, pseudopeptide or oligourea derivative.
• Carbamic acid derivatives are stable, crystalline intermediates, which react with amines to form substituted ureas. Carbamic acid derivatives also make it possible to prepare peptides containing urea units
• One of the aspects of the invention is to propose a new process for the preparation of cyclic urea compounds.
• One of the other aspects of the invention is to propose a new process for the preparation of cyclic urea compounds, making it possible to obtain easily and in very few steps a great molecular diversity of cyclic urea compounds.
• One of the other aspects of the invention is to propose new cyclic urea compounds.
• the invention relates to a process for the preparation of cyclic urea compounds from at least one activated derivative of carbamic acid containing an unprotected primary or secondary amine function, comprising a step of cyclization by reaction between the primary or secondary amine function and the carbamic acid function of said one or more carbamic acid derivatives.
• Activated carbamic acid derivative denotes a carbamic acid derivative, in particular a carbamate, containing 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.
• 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 referred to in the following as “released”, “free” or “deprotected” primary or secondary amine function.
• activated carbamic acid derivative containing an unprotected primary or secondary amine function is also understood to mean: - an oligomeric carbamic acid derivative, also called in the following "activated derivative of homo-oligomeric carbamic acid", or “homo-oligomeric derivative” or “activated derivative of hetero-oligomeric carbamic acid” or “hetero derivative - oligomer "or, - a monomeric carbamic acid derivative, corresponding to an activated derivative of non-homo-oligomeric carbamic acid or to an activated derivative of non-hetero-oligomeric carbamic acid.
• 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 derivative of monomeric carbamic acid.
• Homo-oligomerization or hetero-oligomerization reactions can also be referred to in the following as "intermolecular reactions”.
• cyclization step is meant an intramolecular cyclization step or, an intermolecular cyclization step.
• Intramolecular cyclization takes place by reaction between the unprotected primary or secondary amine function of the activated derivative of carbamic acid and its carbamic acid function.
• the invention relates to a process for the preparation of cyclic urea compounds comprising:
• a step for 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 selective release of said protected amine function from said activated derivative (s) stable (s) of carbamic acid, by cleavage or transformation of said protective 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 (s).
• 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.
• protecting group means a group protecting the amine function of the activated derivative of carbamic acid, in particular in order to prevent it from reacting with other chemical functional groups, during the synthesis of said derivative.
• stable activated derivative of carbamic acid is meant an isolable, purifiable and storable carbamic acid derivative (preferably at 4 ° C.) for a period of at least 3 months without significant 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 (LR).
• HPLC high performance liquid chromatography
• TLC thin layer chromatography
• NMR nuclear magnetic resonance
• LR infrared
• the stable activated derivative of carbamic acid containing an amine function protected by a protective group is obtained from an amino acid derivative in which the amino group is protected, by a process as described above and the three stages of which are as follows:
• the unprotected primary or secondary amine function of the activated derivative of carbamic acid occurs:
• the process for preparing cyclic urea compounds comprises, during or at the end of the selective release step, a homo-oligomerization step and / or hetero-oligomerization between:
• the process for preparing 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 of carbamic acid containing an unprotected primary or secondary amine function or,
• the bifunctional acyclic precursors obtained during or after the selective release of the protected amine function namely activated monomeric derivatives of carbamic acid containing a primary or secondary amine function in free or protonated form, can undergo, before the intramolecular cyclization step, intermolecular homo- and / or hetero-oligomerization reactions in order to form bifunctional acyclic homo-oligomeric and / or hetero-oligomeric precursors.
• the acyclic derivatives of homo-oligomeric and / or hetero-oligomeric carbamic acid thus obtained then undergo, like the non-homo- and / or non-hetero-oligomeric carbamic acid derivatives, an intramolecular cyclization (or macrocyclization) by reaction of their primary or secondary amine function unprotected with their carbamic acid function, in order to obtain cyclic homo-oligomeric and / or hetero-oligomeric ureas.
• 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 reaction of homo- or hetero-oligomerization, or by intramolecular cyclization.
• the activated carbamic acid derivative obtained at the end of the selective release stage contains an unprotected primary or secondary amine function in free form
• the homo- and / or hetero-oligomerization and intramolecular cyclization reactions can take place immediately after the formation of the activated carbamic acid derivative containing an unprotected primary or secondary amine function in free form, because said amine function in free form can react with the activated carbamic acid group.
• the activated carbamic acid derivative 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 neutralize said protonated form of the amine beforehand. free form so that the intermolecular homoligomerization and / or hetero-oligomerization reactions, and the intramolecular cyclization reactions can take place.
• the homo-oligomerization and / or hetero-oligomerization step is carried out by neutralizing the primary or secondary amine function in protonated form in 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 .
• the cyclization step is carried out by neutralizing the primary amine function or secondary in protonated form in primary or secondary amine function in free form.
• the neutralization of said protonated amine function in free form is in particular carried out using a base chosen 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.
• a solvent chosen from the group consisting of acetonitrile (MeCN), toluene, pyridine, N, N-di ethylformamide (DMF), tetrahydrofuran (THF), chloroform, dichloromethane, N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), ethyl acetate, methanol, ethanol or their mixtures.
• reaction solvent or cyclization solvent
• the step of intramolecular cyclization of the activated derivative of carbamic acid containing an unprotected primary or secondary amine function is carried out at a temperature of about -40 ° C. to about 40 ° C, especially from about -20 ° C to about 40 ° C, and preferably from about 0 ° C to about 20 ° C.
• 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 from approximately 10 " 6 M to approximately 10 M, in particular from approximately 10 " 5 M to approximately 1 M, and preferably from approximately 10 "4 M to approximately 1 M.
• the concentration of an activated arbamic acid derivative 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, especially from about 10 " 5 M to about 1 M, and preferably from about 10 '4 M to about 1 M.
• the concentration of the base in the reaction solvent for intramolecular cyclization is from approximately 10 "6 M to approximately 10 M, in particular from approximately 10 " 5 M to approximately 1 M, and preferably approximately 10 "4 M to about 1 M.
• the activated carbamic acid derivative containing a protected amine function is synthesized on a solid support, and is chemically linked to said solid support either (a) by its amine function, or (b) by its carbamic acid function, or (c) by any other functional group present in said activated carbamic acid derivative.
• solid support is meant the matrix on which the chemical reaction is carried out. It is generally an insoluble solid polymer which allows filtration or centrifugation, and therefore the separation of the reagents and the product formed on the resin.
• a solid support mention may be made of polystyrene resins, polyacrylamide, polyethylene glycol, cellulose, glass, silica.
• the selective release step leads to the cleavage of the amine function of said derivative with respect to the support
• the cyclization step results in the cleavage of the carbamic acid function of said derivative with respect to the support,
• 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 with respect to the support can take place during or at the end of the any of the selective release or cyclization steps.
• amm function of the activated derivative of carbamic acid is protected in the form of a group:
• R is a tert-butyl, 9-fluorenylmethyl, benzyl, allyl, tert-butyldimethylsilyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl group, - 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 protective group chosen from the group consisting by benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, diphenylmethyl, para-methoxyphenyl, 3,4-dimethoxybenzyl or 9-phenyl-9-fluorenyl,
• the liberation of the amine function can be carried out by reduction of the nitro or cyano groups to the amine, for example by catalytic hydrogenation in the presence of Pd / C and PtO 2 respectively.
• the transformation of an amide group into an amine group can be carried out by Hoff an rearrangement, for example by treatment of the amide with iodobenzyl bis-trifluoroacetate in a water / acetonitrile mixture.
• a subject of the invention is also cyclic urea compounds comprising a ring having at least 7 atoms, in particular from 7 to 50 atoms, and preferably from 7 to 20 atoms, which ring comprising at least one amide function and at least one urea function. , each amide or urea function being separated from the nearest adjacent amide or urea function by at least one carbon atom, and in particular by 1 to 4 carbon atoms.
• the invention particularly relates to cyclic urea compounds comprising a ring having at least 7 atoms, in particular from 7 to 50 atoms, and preferably from 7 to 10 atoms, which ring comprising an amide function and a urea function separated one on the other by at least one carbon atom, and in particular by 1 to 4 carbon atoms:
• the invention relates to cyclic urea compounds of formula (la):
• each and independently of each other a) - hydrogen, b) - halogen, c) - the side chain, protected or not, of an amino acid chosen from natural or non-natural amino acids, d) - an alkyl group (C1-C20), linear or branched, unsubstituted or substituted by one or more substituents among which: -COOR a , -CONHR a , -OR a , -NHR a , -NH (CO) R a , -NHCOOR a , an aryl or heteroaryl group!
• R a and R independently of one another representing hydrogen, an allyl, benzyl, t-butyl, fluorenylmethyl, benzyloxymethyl, tert-butyldimethylsilyl group,
• cyclic urea compounds possibly being, when one or more asymmetric carbons are present in formula (la), independently, either of configuration R (recruits) or of configuration S (sinister ).
• An advantageous group of cyclic urea compounds corresponding to the general formula (la) consists of cyclic urea compounds corresponding more particularly to the formulas (Ib), (le), (Id), (le), (If), (Ig) , (Ih):
• the R and R groups also being able to form an intramolecular cyclization, the said cyclic urea compounds possibly being, when one or more asymmetric carbons are present in the formulas (Ib) to (Ih), independently, either of configuration R ( recruit) or of configuration S (sinister).
• the invention also relates to the cyclic urea compounds of formulas (Ha),
• groups d 1 , d 2 , d 3 and d 4 may each represent, independently of each other, a group: nitro, alkyl comprising from 1 to 4 carbon atoms, and in particular methyl, alkoxy comprising from 1 to 7 carbon atoms, and in particular a methoxy, aryloxy comprising from 5 to 10 carbon atoms, and in particular a benzyloxy, halogen such as a fluoro, bromo, chloro or iodo, CN, guanidino, NHR a , NHCOOR a , COOR a , OR a ,
• the invention also relates to the cyclic urea compounds comprising a ring having at least 14 atoms, in particular from 14 to 30, preferably 14 to 20, which ring comprising two amide functions and two urea functions, each amide or urea function being separated from the closest adjacent function amide or urea by at least one carbon atom, and in particular by 1 to 4 carbon atoms.
• the invention relates to the cyclic urea compounds of formula (IIIa):
• the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings mentioned above with regard to the groups R 1 to R 5
• the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 can also form the following intramolecular cyclizations: 1 / cyclization between R 1 and R 2 and / or,
• cyclic urea compounds possibly being, when one or more asymmetric carbons are present in the formula (nie), independently, either of configuration R (rectus) or of configuration S (sinister ).
• cyclic urea compounds corresponding to the general formula (Illa) consists of cyclic urea compounds corresponding more particularly to the formulas (Illb), (I ⁇ c), ( ⁇ Id), (Ille), (I ⁇ if) and (JJIg) :
• the groups R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and R 10 have the meanings mentioned above with respect to the groups R 1 to R 5
• the groups R, R, R, R 8 and R 9 can also form intramolecular cyclizations as defined above with respect to the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 of compounds of general formula (Illa), said cyclic urea compounds possibly being, when one or more asymmetric carbons are present in formulas (111b) to (HIg), independently, either of configuration R (rectus) or of configuration S (sinister).
• a subject of the invention is also cyclic urea compounds comprising a ring having 7 atoms and comprising a urea function, of formula (INa):
• cyclic urea compounds possibly being, when one or more asymmetric carbons are present in the formula (INa), independently, either of configuration R (rectus), or of configuration S (sinister).
• the activated derivative of carbamic acid containing an unprotected primary or secondary amine function involved in the process for the preparation of the invention corresponds respectively: - either to one of the formulas (Nia), (VIb ), (Nie) or (Nid) following (to obtain the compounds of formulas (la) to (Ih) as defined above):
• the group X represents a group conferring on the derivative an activated derivative structure of carbamic acid, which group X being derived from a compound chosen in particular from phenols, optionally substituted by at least one nitro group or at least one halogen, or hydroxylamine derivatives, or benzylic alcohol derivatives grafted onto a solid support and more particularly chosen from the following compounds: N-hydroxysuccinimide, phenol, pentafluorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitrophenol, 2 , 4,5 -trichlorophenol, 2 5 4-dichloro-6-nitrophenol, hydroxy- 1,2,3 - benzotriazole, l-oxo-2-hydroxydihydrobenzotriazine (HODhbt), 7-aza-l-hydroxy-benzotriazole (HOAt) , 4-aza-1-hydroxybenzotriazole (4-HOAt), imidazole, t
• the groups R, R, R 3 , R 4 , R 5 and R 6 have the meanings mentioned above with respect to the groups R to R 5 , - either to one of the following formulas (Villa), (Vi ⁇ b), (Ville) or (VlIId) (to obtain the compounds of formulas (Ilb) as defined above):
• X is as defined above, the groups R, R, R and R have the meanings mentioned above with respect to the groups R to R 5 , the groups d, d, d 3 and d 4 have " the meanings mentioned above, - either to one of the formulas (Xa), (Xb), (Xc) or (Xd) below (to obtain the compounds of formulas (Ild) as defined above):
• X is as defined above, the groups R, ⁇ , R, R and R have the meanings mentioned above with respect to the groups R 1 to R 5 , the groups d, d, d and d have the meanings mentioned above,
• Examples of protective groups and deprotection solvents used to respectively obtain the compounds (Vlla), (Vllb), (VIIc), (VHd), (Villa), (VlIIb), (VIIIc), (VHId), (IXa ), (LXb), (LXc), (IXd), (Xa), (Xb), (Xc), (Xd), (XIa), (Xlb), (XIc), (Xld), (XTIa), (Xllb) are given below.
• the amine function of the activated activated carbamic acid derivatives will advantageously be protected by oxycarbonyl groups (such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z) groups) or benzyl groups, or will be masked in the form of nitro groups, cyano or azide.
• oxycarbonyl groups such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z) groups
• benzyl groups or will be masked in the form of nitro groups, cyano or azide.
• Two deprotection modes will be used advantageously according to the method of the invention.
• the Boc group will be deprotected by acid hydrolysis (for example using trifuoroacetic acid (TFA), or a TFA / dichloromethane mixture, or a solution of hydrochloric acid (HCl) in an organic solvent (dioxane , ether ...)), at a temperature of about 0 ° C to about 40 ° C, in order to obtain the acid derivatives carbamic containing a protonated primary or secondary amine function, in the form of trifiuoroacetate or hydrochloride.
• acid hydrolysis for example using trifuoroacetic acid (TFA), or a TFA / dichloromethane mixture, or a solution of hydrochloric acid (HCl) in an organic solvent (dioxane , ether 7)
• the hydrogenation will be used for the cleavage of the Z and benzyl groups, and for the reduction of the nitro, cyano or azide groups.
• the hydrogenation can be carried out with PtO 2 , Pd / C type catalysts in solvents such as efhanol, methanol, dimethylformamide (DMF), ethyl acetate, tetrahydrofuran (THF), chloroform or a mixture of said solvents, at a temperature from about 0 ° C to about 40 ° C, and at a pressure from about 1 bar to about 100 bar.
• the carbamic acid derivative containing a primary or secondary amine function in protonated form namely the derivative of formula (Vie), (VId), (VIIc), (Vlld), (VIIIc), (V ⁇ Id), (IXc) , (IXd), (Xc), (Xd), (XIc), (Xld) or (Xllb) is:
• cyclization solvent especially chosen from the group consisting of acetonitrile (MeCN), toluene, pyridine, N, N-dimethylformamide
• a solution containing a base in particular that chosen from the group consisting of diisopropylethylamine, triethylamine, lutidine, pyridine, 2,4,6-collidine, N-methylmorpholine, 2, 6-di-tert-butyl-4-methylpyridine or mixtures thereof, and the reaction solvent as defined above, at a temperature of from about -20 ° C to about 20 ° C, and in particular from about 0 ° C at 20 ° C.
• the concentration of the carbamic acid derivative containing a primary or secondary amine function in protonated form in the cyclization solvent is from approximately 10 "4 M to approximately 1 M, and in particular from approximately 10 " 3M to approximately 1 M.
• the concentration of the base in the cyclization solvent is from approximately 10 " 6 M to approximately 10 M, in particular from approximately 10 " 5 M to approximately 1 M, ⁇ t preferably from approximately 10 "4 M to approximately 1 Mr.
• the invention relates to a process for the preparation as defined above, of cyclic urea compounds of formula (IIIa) to (III) as defined above, characterized in that said compounds ( Illa) to (III) 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, corresponding at least one of the formulas (Via), (VIb), (Vie) or (VId) as defined above.
• the homo-oligomerization or hetero-oligomerization reaction of activated carbamic acid derivatives containing a primary or secondary amine function of formula (Via), (VIb), (Vie) or (VId), as well as the cyclization of homo- or hetero-oligomers thus obtained in cyclic urea compounds of formula (III) to (III), is favored for derivatives of carbamic acid of formula (Via), (VIb), (Life) or (VId) in which the -CO-NR bond mainly adopts a trans conformation.
• the homo-oligomerization or hetero-oligomerization reaction is advantageously carried out for low concentrations of the activated derivatives of carbamic acid of formula (Via), (VIb), (Vie) or (VId) in the cyclization solvent, i.e. concentrations from about 10 " 3M to about 10 " 5 M, at temperatures from about 0 ° C to about 20 ° C.
• the process for preparing the invention is characterized in that it comprises:
• the stage of alkylation of the hydrogen of the group (s) -NH- included in the urea function of the cyclic urea compound obtained at the end of the cyclization stage consists in reacting an alkylating agent on the NH function (s) cyclic urea in the presence of a suitable base.
• an alkylating agent mention may in particular be made of a halogen derivative, the halogen group generally being chlorine, bromine or iodine.
• a metal hydride such as a sodium hydride (NaH), - a metal alcoholate such as sodium methanolate or potassium t-butanolate,
• the process for preparing the cyclic urea compounds of formula (la), (Ib), (le), (Id), (le), (If), (Ig) and (Ih) such that described above is more particularly characterized in that it comprises: a cyclization step:
• the process for preparing the cyclic urea compounds of formula (IIa) is more particularly characterized in that it comprises:
• the process for the preparation of the cyclic urea compounds of formula (Ilb) is more particularly characterized in that it comprises: a cyclization step:
• the process for preparing the cyclic urea compounds of formula (Ile) is more particularly characterized in that it comprises:
• step 4 a step of alkylation respectively: - of the hydrogen of the urea function of formula -NH-CO-NR 1 - obtained at the end of the step of cyclization using an alkylating agent comprising the group R 6 or,
• the process for preparing the cyclic urea compounds of formula (Ild) is more particularly characterized in that it comprises:
• the process for the preparation of the cyclic urea compounds of formula (IIIa), (IIIc), (IIIc), (III), (III), (III) and (III) is more particularly characterized in that that it includes:
• the process for preparing the cyclic urea compounds of formula (IVa) is more particularly characterized in that it comprises:
• the alkylation stage of the process for the preparation of the cyclic urea compounds as described above, may in particular be carried out under the specific 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 one NH to alkylate, 2-2.4 equivalents if two NH to alkylate) in THF (under Argon and at 0 ° C).
• the reaction medium is stirred at 0 ° C for 60 minutes then the alkylating agent (1-1.5 equivalents if one NH to alkylate, 2-3 equivalents if two NH to alkylate) dissolved in THF is added at 0 ° C.
• the reaction is left for 12 h then the reaction medium is diluted with ethyl acetate and with a saturated NH 4 C1 solution.
• the organic phase is washed with a saturated solution of KHSO IN, H 2 O, a solution of
• the invention also relates to a process for the preparation as defined above of cyclic urea compounds comprising a 6-atom ring and comprising a urea function, of formula (Va):
• R 1 , R 2 , R 3 , R 4 and R 5 may each represent, independently of each other: a) - hydrogen, b) - a halogen, c) - the side chain, protected or not, of an amino acid chosen from natural or non-natural amino acids, d) - an alkyl group (C1-C20), linear or branched, unsubstituted or substituted by one or more substituents among which: -COOR a , -CONHR a , -OR a , -NHR a ,
• -NH (CO) R a , -NHCOOR a an aryl or heteroaryl group, the cyclic structure of which 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, guanidino or nitro group, e) - an aryl group the ring structure of which 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 c SO2) h) - an acyl group (RcCO) i) - an ORb group j) - a NH 2 group k) -COORb 1) -CONHRb m) -CH 2 CONH 2 R a and
• Rc representing an alkyl group having from 1 to 20 carbon atoms, or an aryl group whose ring structure contains from 5 to 20 carbon atoms, or a heteroaryl, arylalkyl or heteroarylalkyl group
• the groups R 1 , R 2 , R 3 and R 4 can form the following intramolecular cyclizations:
• group X represents a group conferring on the derivative an activated derivative structure of carbamic acid, which group X being derived from a compound chosen in particular from phenols, optionally substituted by at least one nitro group or at least one halogen, or hydroxylamine derivatives, or benzylic alcohol derivatives grafted onto a solid support and more particularly chosen from the following compounds: N-hydroxysuccinimide, phenol, pentafluorophenol, pentachlorophenol, p-nitrophenol, 2,4-dinitro ⁇ henol, 2 , 4,5-trichlorophenol, 2,4-dichloro-6-nitrophenol, hydroxy-1,2,3 - benzotriazole, l-oxo-2-hydroxydihydrobenzotriazine (HODhbt), 7-aza-l-hydroxy-benzotriazole (HOAt) , 4-aza-1-hydroxybenzotriazole (4-HOAt), imidazole
• a subject of the invention is also a process for the preparation, as defined above, of cyclic urea compounds comprising a ring having at least 8 atoms, which cycle comprising at least two urea functions spaced from each other by at least a carbon atom and in particular by 1 to 4 carbon atoms.
• the subject of the invention is more particularly a process for the preparation as defined above, of cyclic urea compounds comprising a ring having at least 8 atoms and comprising at least two urea functions spaced apart from each other by 2 carbon atoms, corresponding to the formulas (XTV), (XV) and (XVIa):
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 s R 9 , R 10 , R " R ⁇ R 14 , R 15 and R 16 have the meanings mentioned above with respect to the groups R 1 to R 5 , the groups R 1 , R 2 , R 5 , R 6 , R 9 , R 10 , R 13 and R 14 can also form the following intramolecular cyclizations:
• the subject of the invention is also a process for the preparation as defined above, of cyclic urea compounds comprising at least four urea functions, of formulas (XVIb), (XVIc), (XVId) and (XVIe):
• R 2 , R 6 , R 10 and R 14 are chosen from:
• the substituents R 3 , R 7 , R 11 and R 15 represent a hydrogen atom, from activated derivatives of carbamic acid of formula (XXV), as mentioned above, in which: i) - the substituents R 2 , R 6 , R 10 and R 14 have the same definition as above and the substituents R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 11 , R 12 , R 15 and R 16 represent a hydrogen atom, or
• R 3 , R 7 , R 11 and R 15 have the meanings mentioned above for R 2 , R 6 , R 10 and R 14 and the substituents R 1 , R 2 , R 4 , R 5 , R 6 ,
• R 8 , R 9 , R 10 , R 12 , R 14 and R 16 represent a hydrogen atom
• the group R 13 is an arylalkyl or heteroarylalkyl group, which can be linked to a solid support, and allowing the formation, before the final deprotection step, of a synthetic intermediate having the formula (XVIa), as mentioned above, in which the different substituents R 1 to R 16 have the same meanings as mentioned above for the compound of formula (XXV).
• the subject of the invention is also a process for the preparation as defined above, of compounds of formula (XV), in which: the substituents R 2 , R 6 and R 10 are chosen from:
• R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 11 and R 12 represent a hydrogen atom, from activated derivatives of carbamic acid of formula (XXIV) , as mentioned above, in which: i) - the substituents R, R and R have the meanings mentioned above and the substituents R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 11 and R 12 represent a hydrogen atom, or - the substituents R 3 , R 7 and R 11 have the meanings mentioned above for R 2 , R 6 and R 10 , and the substituents R 1 , R 2 , R 4 , R 5 , R 6 , R 8 ,
• R 10 and R 12 represent a hydrogen atom, ii) the group R 9 is an arylalkyl or heteroarylalkyl group, which can be linked to a solid support, and allowing the formation, before the final deprotection step, of a synthetic intermediate having the formula (XV), as mentioned above, in which the different substituents R 1 to R 12 have the same meanings as mentioned above for the compound of formula (XXIN).
• the invention also relates to compounds of formulas (XV) or (XVIa) as mentioned above, in which the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 represent:
• the invention also relates to compounds as defined above, corresponding to the following formulas:
• Alloc represents an allyloxycarbonyl group
• the preparation process of the present invention makes it possible in particular to obtain new cyclic urea compounds which would have been difficult to obtain by the preparation processes of the prior art which generally require the preparation of diamines.
• the preparation process of the present invention allows the cyclization of carbamic acid derivatives obtained from derivatives of ⁇ -protected amino acids (amino acids ⁇ , ⁇ , ⁇ and ⁇ ), 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 also applies 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 (amino acids ⁇ , ⁇ , ⁇ and ⁇ ) in group -CON 3 to obtain an acyl azide, b) a stage of transformation of the group -CON 3 of acyl azide into group -NCO to obtain an isocyanate, c) a stage of treatment isocyanate to obtain the above-mentioned stable derivative of carbamic acid, and this from very simple molecules, such as N-protected dipeptides, to give cyclic urea molecules which are extremely functionalized and asymmetrical.
• amino acid derivative must be interpreted in the broad sense, as understood by a person skilled in the art, and notably denotes a derivative of peptide, polypeptide, protein, pseudopeptide or oligourea.
• Figures 1A and IB show the two-dimensional structure of the compound of formula (Ij).
• Figure 1A corresponds to the view above the urea cycle.
• Figure IB corresponds to the view along the axis formed by the carbons C ⁇ , denoted C (l) and C (4).
• the macrocyclization process from bifunctional acyclic precursors activated carbamic acid derivatives containing a primary or secondary amine function
• acyclic precursors activated carbamic acid derivatives containing a primary or secondary amine function
• homo-oligomeric cyclic urea compounds and / or hetero-oligomers the size distribution of which depends on the dilution of the reaction medium and on the effective molarity of the various linear precursors. It is the competition which exists between the processes of intermolecular and intramolecular which leads to obtaining a reaction mixture which can be more or less complex.
• Diagram 1 represents the homoligomeric cyclic urea compounds obtained after intermolecular and intramolecular reactions.
• 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 stage, the intermolecular reaction of homo- oligomerization can take place directly after said release step, without the addition of a base.
• VIa-1 activated derivative of carbamic acid containing a secondary amine function in free form
• 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 in secondary amine function in free form (VIa-1).
• a bifunctional homo-oligomeric acyclic precursor containing a secondary amine function in free form XXI
• XXII homo-oligomeric acyclic precursor containing a secondary amine function in free form
• the secondary amino functions of the bifunctional acyclic precursors are represented in protonated form (NIc-1) and (NIc-2) and in free form (NIa-1) and. (VIa-2).
• the two bifunctional acyclic precursors (NIc-1) and (VIc-2) (activated carbamic acid derivatives containing a secondary amine function in protonated form) each undergo, in the presence of a base, homo-dimerization to respectively form two homodimeric bifunctional acyclic precursors (XIa-1) and (XIa-3) containing a secondary amine function in free form, as well as a heterodimerization to form a bifunctional dimeric precursor (XIa-2) containing a secondary amine function in free form .
• X represents a group conferring on said derivative an activated carbamic acid function
• A represents the part of the molecule separating the activated carbamic acid function and the protected amine function
• 111 represents the solid support (resin).
• the activated carbamic acid derivative is chemically linked to the resin either (1) by its amine function (the resin and the arm of the resin serving as a protective group) [case # l], or (2) by its acid function activated carbamic [case # 2], or (3) by another functional group present in said activated carbamic acid derivative [case # 3].
• the cleavage can be carried out either before the intramolecular cyclization step.
• O-succinimidyl carbamate is not degraded in the presence of trifluoroacetic acid or hydrochloric acid as an organic solvent: the step of liberation of the amine function (via deprotection of the Boc group) is therefore completely selective .
• • • This example is in no way limiting.
• One can imagine other types of orthogonality such as the use of the benzyloxycarbonyl group with O-succinimidyl carbamate.
• Diagram 4 below represents the selective deprotection by trifluoroacetic acid (TFA) of the Boc group of carbamic acid derivatives (XVII) and (XIX) of succ-protected succinimidyl.
• the protected amique-Boc carbamic acid derivatives (XNII) and (XIX) are each dissolved in a solution of trifluoroacetic acid (CF 3 COOH or TFA) (deprotection solvent) containing methylene chloride (CH 2 C1) ( 50/50 v / v for example) or, in a solution of pure TFA. After 30 min, the TFA is evaporated or coevaporated in the presence of ether (Et 2 O) or hexane. In a certain 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.
• TFA (XNIIIa) and (NIc-3) salts previously isolated are each dissolved or suspended in a volume of solvent (for example acetonitrile (MeC ⁇ )) (cyclization solvent) to reach a dilution ranging from approximately 0.0001 M to about 0.1 M.
• solvent for example acetonitrile (MeC ⁇ )
• a tertiary base at least one equivalent to neutralize the salt of the amine formed during the deprotection step
• diisopropylethylamine, ⁇ -methylmorpholine, triethylamine (Et 3 ⁇ ), lutidine or collidine pure or diluted in an organic solvent such as MeCN
• MeCN organic solvent
• Diagram 5 Preparation of the cyclic urea compound (XX).
• 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.
• Table 1 cyclic urea compounds (XX), (IIIf-4), (Ii), (Ij), (Ik), (II) and (Im) • obtained respectively from stable activated derivatives of carbamic acid (XNIIa ), (XIXa), (XlXb), (XIXe), (XlXd), (XIXe) and (XlXf).
• the group R represents respectively: a methyl group (Me), a group -CH 2 COOtBu, a group Bn (-CH 2 - ⁇ ) and a BnOBn group.
• a resin "scavenger” such as (mercaptoethyl) aminoethylpolystyrene resin for example.
• the "scavenger” resin (approximately 10 equivalents) is added to the reaction medium and the mixture is allowed to stir 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 product purified as shown in diagram 13 and in table 3. It is possible under the best conditions (about 1 equivalent of RX, reaction time of 48 h, see table 3) to obtain a selectivity of mono-alkylated product with respect to the di-alkylated product of the order of 93: 7.
• the cyclic urea compounds (I) have an extremely constrained structure, well defined on the basis of X-ray diffraction or else NMR. Knowledge of this structure is extremely useful for the use of the heterocyclic platform based on the compounds (I) for the design and discovery of new compounds of pharmacological interest.
• the structure of (Ij) (see Figures 1 A and IB) was obtained by X-ray diffraction and is representative of the structure of the compounds (I). This structure is in agreement with that obtained for the same compound by two-dimensional NMR and by modeling.
• the 1,3,5-triazepin-2,6-dione ring has a strongly folded conformation.
• the planes of the two amide and urea groups meet along a line joining the alpha carbon of the gem-Sarcosine residue (-N (CH 3 ) - ⁇ CH 2 -NH-) and the alpha carbon of phenylalanine with a 120 ° dihedral angle.
• the dihedral angle defined by the amide planes is of the order of 140-160 °.
• 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 only separated by 2.03 angstroms.
• the distance between the protons located on the alpha carbons in the folded diketopiperazines is of the order of 2.7-
• the compounds (Vie) for which R 3 is not hydrogen, for example those for which R 3 is methyl (cf. compound (VIc-6) of scheme 8) or those for which R 3 forms a ring with R 4 of proline with 5 atoms (cf. compound (VTc-5) of scheme 7) preferably cyclize without intermolecular reaction before cyclization, to give only the corresponding 7 atom ring (cyclic monomer) of type (la). This is most certainly due to the cis preference of the amide bond in this type of compound. In fact, in these very constrained cycles, the amide bond is of cis geometry, and this geometry must be in the majority in order to allow the formation of the 7-atom ring.
• the carbamic acid derivative containing an unprotected amine function ((NIc-4), (NIc-S) or (NIc-6)) dissolved in the reaction solvent (solvent used to carry out the cyclization) (MeC ⁇ by example) is added dropwise to a solution containing a base and the reaction solvent (MeC ⁇ for example). It is also 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), (NIc-5) or (NIc-6 )) and the reaction solvent.
• the reaction solvent solvent used to carry out the cyclization
• the concentration of the carbamic acid derivative containing an unprotected amine function ((VTc4), (NIc5) or (NIc-6)) in the reaction solvent (solvent used for cyclization) is not has no influence on the cyclization of derivatives (XlXb) and (XIXth).
• the concentrations used vary from approximately 1 M to approximately 10 ⁇ 3 M.
• the dilution has an effect on the nature of the cyclic compounds obtained.
• a dilute solution containing a carbamic acid derivative containing an unprotected amine function (NIc4), (NIc5) or (NIc-6) in the reaction solvent) whose concentration varies from approximately 10 "5 M to 10 " 3M
• the majority product obtained is the cyclic dimer (IHf-4) (70%).
• the cyclic trimer represents less than 15%, and the cyclic tetramer less than 5%.
• the temperature has only a small impact on the cyclization of the products (XlXb) and (XIXth).
• the cyclization reaction of the derivatives (XlXb) and (XIXe) leads respectively to the derivatives (Ii) and (Ij) in similar yields, whether the reaction takes place at 20 ° C, 0 ° C or -10 ° C.

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