ES2335380B1 - NEW QUATERNARY AMINO ACIDS DERIVED FROM AZEPANOS AND ITS APPLICATIONS. - Google Patents

Abstract

New quaternary amino acids derived from Azepanos and their applications.

Compounds (alpha amino acids, alpha-heterocyclic) in which the heterocycle has azepane, oxoazepane or thioazepane structure, capable of inducing secondary structure in peptides or serving as skeletons of utility in the preparation of chemical libraries of compounds of interest therapeutic. In addition, the invention relates to the process of obtaining said compounds.

Description

New quaternary amino acids derived from Azepanos and their applications.

This invention fits into the sectors chemical and pharmaceutical, and refers to compounds (amino acids α, α-heterocyclic) capable of inducing secondary structure in peptides or serving as skeletons of utility in the preparation of chemical libraries of compounds of interest therapeutic.

State of the art

Amino acids α, α-disubstituted have captured large interest in the field of biology and chemistry because, incorporated into peptides, they are able to mimic or induce concrete elements of the secondary peptide structure and help study molecular recognition processes.

Acid α, α-aminoisobutyric acid (Aib) is one of the most widely studied, and although it is not one of the 20 Proteogenic amino acids, found in nature in a series of peptides of microbial origin1. Has been shown experimentally that the Aib residue is able to stabilize 3_ {10} and α-helix conformations in a large number of synthetic peptides 2. They have also been described numerous amino acids of this type including Aib homologs chiral and different derivatives of Gly aquirales3. The interest of these amino acids has motivated the development of synthetic routes suitable for accessing them 4.

Within amino acids α, α-disubstituted has been provided special attention to derivatives in which the two substituents in position α form a cycloalkyl 3,5-7, mainly symmetric carbocyclic amino acids with different size of ring.

A second large group of amino acids cyclic quaternaries are those that incorporate into the cycle heteroatoms (heterocycles). Thus, atoms of O, N have been introduced and S in rings of 5 and 6 members. In some cases it has only been described its route of synthesis, without carrying out studies later conformational, as in the preparation of the four diastereoisomers of the derivative of 4-amino-2,4-carboxypropyrrolidine, designed as conformationally restricted acid analogs glutamic (A) 8. On the other hand, studies conformational performed on small peptides that incorporate derivatives of 4-amino-4-carboxylate-1,2-dithiolanes (B) 9 or of 3-amino-3-carboxylate tetrahydrofuran (C) 10 showed that they adopt turn conformations \beta. Regarding derivatives with a heterocyclic ring of six D members, it has been observed that their incorporation into peptides small force these to adopt structure of turns? or helical structures 11,12, although there are discrepancies between solid state and solution conformation13,14. Finally, heterocyclic derivatives of 7 have also been described links that have a nitrogen atom in the ring. Some of they, like the E compounds, are commercial [Tyger company Scientific Inc. (USA)], while for other derivatives, such as compounds (F) 15 and (G) 16, have been described effective methods for its synthesis.

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one

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There are two bibliographic compilations that collect different methods of enantio- and synthesis amino acid diastereoselectives α, α-heterocyclic conformationally Restricted 5.6.

Finally, it should be noted that some of these heterocyclic derivatives, suitably substituted, have been used as a central skeleton of active compounds biological Perhaps the most representative example is the lofentanil 17, which is a receptor agonist µ-opioids, with greater analgesic potency than the Morphine and useful as an anesthetic. On the other hand, the derivative from 4-amino-2,4-carboxylatopyrrolidine A is a potent and selective receptor agonist mGluRs 18. Finally, the replacement of some Ala residues by Aib, Ac6 c and / or compound D (X = NH) in peptides antimicrobial helicals (KAAKKAA) 2 led to a series of restricted analogues that have interesting properties antibacterials 19.

References

1. Nagaraj , G .; Uma , MV; Shivayogi , MS and Balaram , H. Antimicrob. Chemother Agents 2001 , 45 , 145-149.

2. Karle , IL and Balaram , P. Biochemistry 1990 , 29 , 6747-6756.

3. Toniolo , c .; Crisma , M .; Formaggio , F. and Peggion , C. Biopolymers 2001 , 60 , 396-419.

4. Cativiela , C. and Díaz-de-Villegas , MD Tetrahedron: Asymmetry 1998 , 9 , 3517-3599.

5. Cativiela , C. and Díaz-de-Villegas , MD Tetrahedron: Asymmetry 2000 , 11 , 645-732.

6. Maity , P. and König , B. Pept. Sci . 2007 , 90 , 8-27.

7. Avenoza , A .; Bust , JH; Cativiela , C .; Peregrina , JM and Rodríguez F. Tet. Lett . 2002 , 43 , 1429-1432.

8. Tanaka , Kl and Sawanishi , H. Tetrahedron: Assymetry 1995 , 6 , 1641-1656.

9. Morera , E .; Lucente , G .; Ortar , G .; Nalli , M .; Mazza , F .; Gavuzzo E. and Spisani , S. Bioorg. Med. Chem . 2002 , 10 , 147-157.

10. Maity , P .; Zabel , M. and König , B. J. Org. Chem 2007 , 72 , 8046-8053.

11. Yokum , TS; Gauthier , TJ; Hammer , RP and McLaughlin , ML J. Am. Chem. Soc . 1997 , 119 , 1167-1168.

12. Strässler , C .; Linden , A. and Heimgartner , H. Helv. Chim. Minutes 1997 , 80 , 1528-1554.

13. Torrini , I .; Pagani Zecchini , G .; Paglialunga Paradisi , M .; Lucente , G .; Gavuzzo , E .; Mazza , F .; Pochetti , G .; Calm down , S .; Spisani , S. and Cericheli , G. Biopolymers 1994 , 34 , 1291-1302.

14. Torrini , I .; Pagani Zecchini , G .; Paglialunga Paradisi , M .; Lucente , G. and Mastropietro , G. Gavuzzo , E .; Mazza , F .; Pochetti , G .; Traniello , S. and Spisani , S. Biopolymers 1996 , 39 , 327-337.

15. Sivaprakasam , M .; Couty , F .; David , O .; Marrot , J .; Sridhar , R .; Srinivas , B. and Rao , KR Eur. J. Org. Chem 2007 , 5734-5739.

16. Gelmi , ML; Cattaneo , C .; Pellegrino , S .; Clerici , F .; Montali , M. and Marini , C. J. Org. Chem 2007 , 72 , 9811-9814.

17. Filizola , M .; Villar , HO and Loew , GH Bioorg. Med. Chem . 2001 , 9 , 69-76.

18. Monn , JA; Valli , MJ; Jonson , BG; Salhoff , CR; Wright , RA; Howe , T .; Bond , A .; Lodge , D .; Spangle , LA; Pascual , JW; Campbell , JB; Griffey , K .; Tizzano , JP and Schoepp , DD J. Med. Chem . 1996 , 39 , 2990-3000.

19. Yokum , TS; Elzer , PH and McLaughlin , ML J. Med. Chem . 1996 , 39 , 3603-3605.

Description of the invention

The present invention is based on obtaining α, α-heterocyclic amino acids, which with respect to the existing ones they present two stereogenic centers defined and asymmetry in the location of the ring heteroatom heterocyclic, which allow selective addressing of substituents on said heteroatom in the propeller assembly. In addition, the heterocyclic system may contain carbonyl groups or thiocarbonyl, which contribute to stabilize certain structures secondary in the peptides that contain them.

In addition, the compounds of the invention are more polar, increasing the solubility of the compounds that they contain, and can incorporate different substituents without increasing excessively synthetic difficulty. The capacity of these α, α-heterocyclic amino acids for induce secondary peptide structure, mainly propellers α, has been corroborated by theoretical studies of molecular modeling

Amino acids α, α-heterocyclic subject of the invention may contain carbonyl or thiocarbonyl groups in the heterocyclic ring that can contribute to fix structures Secondary peptides. They allow the incorporation of different substituents at positions 1 and 3 of the heterocyclic system, which they help modulate possible intermolecular interactions and / or the solubility of compounds containing these amino acids α, α-heterocyclic. They have two centers Stereogenic defined that, together with the non-symmetric arrangement of the ring nitrogen atom, can allow the spatial addressing of the substituents on said atom.

Amino acids α, α-heterocyclics of the invention e intermediates for their preparation, they are useful as skeletons Inductors of secondary peptide structure after incorporation in peptides, mainly α-helices, for application in the search for new biologically relevant peptide mimetics, protein-protein interaction modulators of therapeutic interest, of potential application as drugs and for the study of the bioactive conformation of peptides. Focused on it interest, these compounds could alternatively serve as central skeletons of combinatorial chemists, through the incorporation of molecular diversity in three of the positions Functional they own. These libraries could be used in the New drug development process.

Thus, one aspect of the invention is constituted α, α-heterocyclic amino acids, in forward amino acids α, α-heterocyclic or compounds of the invention, in which the heterocycle has an azepane structure, oxoazepane or thioazepane and constituted by the general formula I

2

in which R 1 represents a hydrogen atom, an alkyl group (linear or branched), alkyl substituted (the substitution with one or more selected groups of between halogen, hydroxyl, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), aralkyl, aryl, substituted aryl (the substitution with one or more alkyl, halogen, hydroxyl, alkoxide, thiol, nitro groups, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups), heteroaryl, substituted heteroaryl (with alkyl, halogen, hydroxyl, alkoxide, thiol, nitro groups, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups), acyl (with linear alkyl groups and branched, aralkyl, aryl, heteroaryl, aryls or heteroaryls substituted, with the above meanings), sulfonyl (with groups linear or branched alkyl, aralkyl, aryl, heteroaryl, substituted aryls or heteroaryls, with the above meanings), aminos protecting groups in peptide chemistry (Boc, Z, Fmoc, Alloc, etc.), aminoacyl derivatives of natural amino acids and non-proteinogenic, protected or unprotected, or fragments peptides, protected or unprotected

And it is selected from the list comprising a oxygen, sulfur or nitrogen atom, a CH2 group or a group substituted amino (represented by "NR", where R in turn represents an alkyl group, linear or branched, aralkyl, aryl, heteroaryl, or substituted aryl or heteroaryl).

R2 is selected from the list comprising a hydrogen atom, or an alkyl group (linear or branched), aralkyl, aryl, heteroaryl, or aryl or heteroaryl replaced.

The grouping R2 Y can represent natural and non-proteinogenic amino acids, protected or unprotected, or peptide fragments, protected or unprotected

R 3 represents a hydrogen atom, or a alkyl group (linear or branched), substituted alkyl (with groups halogen, hydroxyl, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), substituted aralkyl, aryl or aryls (with alkyl groups, halogen, hydroxide, alkoxide, thiol, nitro, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), heteroaryl or substituted heteroaryl (with alkyl groups, halogen, hydroxide, alkoxide, thiol, nitro, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), acyl (with linear and branched alkyl groups, aralkyl, aryl, heteroaryl, aryls and substituted heteroaryls, with the above meanings), sulfonyl group (with alkyl groups linear and branched, aralkyl, aryl aryl, heteroaryl, aryls and substituted heteroaryls, with the above meanings), group aminos protector in peptide chemistry (Boc, Z, Fmoc, Alloc, etc.), aminoacyl derived from natural amino acids and not Proteogenic, protected or unprotected, or fragments peptides, protected or unprotected.

X represents an oxygen or sulfur atom, or two hydrogen atoms

R 4 represents a linear alkyl group or branched or a substituted alkyl (with halogen, hydroxide groups, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups).

In preferred embodiments, the compounds of The invention has the following substitutions:

R1 is selected from the list comprising alkyl, acyl, alkyl- or aryloxycarbonyl, aminoacyl derived from protected and non-proteinogenic natural amino acids or unprotected or protected or unprotected peptide fragments. More preferably, R1 is an alkyl group (C_ {1} -C_ {3}), a protective group of aminos in peptide chemistry, such as, but not limited to t-butoxycarbonyl group (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc) or benzyloxycarbonyl.

And it is selected from the list comprising a oxygen atom, nitrogen or a substituted amino group. Plus preferably an oxygen atom.

R2 is selected from the list comprising a hydrogen atom, an alkyl group (C 1 -C 6) linear or branched, or next to Y form the R2 Y group representing natural amino acids and not Proteogenic, protected or unprotected, or fragments peptides, protected or unprotected.

R 3 is selected from the list comprising a hydrogen atom, an alkyl group (C 1 -C 6) substituted or unsubstituted, a aralkyl, or alkyl- or aryloxycarbonyl groups. More preferably R 3 is a hydrogen, an alkyl (C 1 -C 3) unsubstituted or an aralkyl as for example, but not limited to, a benzyl group.

X is an oxygen atom, sulfur or equivalent to two protons (the latter case indicates the non-replacement in that position). More preferably X is an oxygen atom.

R 4 is an alkyl group (C 1 -C 6) substituted or unsubstituted. More preferably R 4 is an alkyl (C 1 -C 3) unsubstituted.

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In an even more preferred embodiment, the compound described above is selected from the list that understands:

to.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane.

b.

(3 S , 4 S ) -4- tert -butoxycarbonyl-4- ( tert -butoxycarbonyl) amino-3-methyl-2-oxoazepane.

C.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-1,3-dimethyl-4-methoxycarbonyl-2-oxoazepane.

d.

(3 S , 4 S ) -1-benzyl-4- ( tert -butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane.

and.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-4-carboxy-3-methyl-2-oxoazepane.

F.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-4-carboxy-1,3-dimethyl-2-oxoazepane.

g.

(3 S , 4 S ) -4-amino-3-methyl-4-methoxycarbonyl-2-oxoazepane trifluoroacetate.

h.

(3 S , 4 S ) -4-amino-4-carboxy-3-methyl-2-oxoazepane trifluoroacetate.

i.

(3 S , 4 S ) -4-amino-1-benzyl-3-methyl-4-methoxycarbonyl-2-oxoazepane trifluoroacetate.

j.

(3 S , 4 S ) -1,3-dimethyl-4-methylamino-4-methoxycarbonyl-2-oxoazepane trifluoroacetate.

or their corresponding enantiomers.

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The term "alkyl" refers, in the present invention, to aliphatic, linear or branched chains, having 1 to 6 carbon atoms, for example, methyl, ethyl, n- propyl, i- propyl, n -butyl, tert -butyl, sec -butyl, n -pentyl, etc. Preferably the alkyl group has between 1 and 3 carbon atoms. The alkyl radicals may be optionally substituted by one or more substituents such as halogen, hydroxyl, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, aryl or heteroaryl or combinations of these groups.

The term "aryl" refers, in the present invention, to aromatic rings having between 5 and 7 links in which a proton has been removed from the ring. Preferably the aryl group has between 5 and 6 carbon atoms. The aryl radicals may be optionally substituted by one or more substituents such as alkyl, halogen, hydroxyl groups, alkoxide, thiol, nitro, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups.

The term "heteroaryl" refers, in the present invention, to aromatic heterocyclic rings (mono- or bicyclics) that have between 5 and 10 links in which removed a proton from the ring. Preferably the heteroaryl group It has between 5 and 6 carbon atoms. Aryl radicals can be optionally substituted by one or more substituents such as alkyl, halogen, hydroxyl, alkoxide, thiol, nitro groups, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups.

The term "aralkyl" refers, in the present invention, to an aliphatic chain in which at least one of the hydrogens have been replaced by an aryl group, with the previous meanings As for example, but not limited to, a benzyl or phenethyl group.

The term "acyl" refers, in the present invention, to a carboxylic acid derivative by elimination of a hydroxyl group. Acid derivatives carboxylic have as general formula R 5 -CO-, where R 5 refers to linear or branched alkyl groups, substituted aralkyl, aryl, heteroaryl or aryl and heteroaryl, with the previous meanings.

The term "sulfonyl" refers, in the present invention, to a sulfonic acid derivative by elimination of a hydroxyl group. The sulphonic acid derivatives have as general formula R 6 -SO 2 -, where R 6 is refers to linear or branched alkyl, aralkyl, aryl groups, heteroaryl or aryl and heteroaryl substituted, with the meanings previous.

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Another aspect of the invention is the process for preparing the compound or compounds of the invention, which includes the following steps:

to.

reaction of a derivative of N-p-methoxybenzylornitine of formula general II

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3

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with chlorides of acid of general formula ClCOCH (R 4) Cl,

where R2 and R 4 are described above,

b.

basic medium cycling of compounds obtained in step (a),

C.

oxidation reaction for the elimination of the p -methoxybenzyl group of the 2-oxoazetidines obtained in step (b),

d.

reaction with di- tert-butyl dicarbonate for the incorporation of a tert- butyloxycarbonyl group in the NH of the ring of the 2-oxoazetidines obtained in step (c),

and.

group check out benzyloxycarbonyl and ring opening 2-oxoazetidine of the compounds obtained in the step (d).

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Finally, to obtain the different types of compounds with the different possible substituents could well perform hydrolysis or alkylation according to steps (f) or (g) and subsequent transformations according to step (h), which are described as continuation:

F.

acidic or basic hydrolysis of carboxylic esters and / or urethane groups of substituents in position 4 of the compounds obtained in step (e).

g.

reaction of the compounds obtained in the step (e.) with alkylating agents of the general formula R 3 X, in basic medium, where X is a halogen atom and R3 as Specify above. In addition to this step, you can deprotect the compounds obtained, as described in the step

h.

Incorporation of substituents R1 and / or YR2 in the compounds obtained in step (e) or (g), by suitable reactions (alkylation, acylation, sullfonación ...). In addition to this step, they can be checked out the compounds obtained, as described in the step (F).

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More concretely this procedure with the following reaction scheme (Scheme 1).

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Scheme one

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4

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Compounds of general formula I (among the which are those of type 1.1, 1.2, 1.3 or 1.4) can be Prepare in several stages (Scheme 1) from derivatives of orthogonally protected ornithine of general formula 2, where R2 maintains the significance already indicated.

The chloroalkyl derivatives 3, where R 2 and R 4 maintain the significance already indicated, can be obtained from the N- benzyl derivatives 2 by treatment with acid chlorides of the general formula ClCOCH (R 4 }) Cl, commercially available, or prepared in situ from the corresponding carboxylic acid, in the presence of a hydrocidic collecting agent.

The β-lactams 4, where R2 and R4 maintain the significance already indicated, they can be prepared from chloroalkyl derivatives 3 by treatment in strong basic medium.

Β-lactams 5 can be prepare by removing the Pmb group from analogs 4 through an oxidation process using K 2 S 2 O 8 / K 2 HPO 4.

Protected β-lactams N -Boc 6 are obtained from β-lactams 5 by reaction with di- tert-butyl dicarbonate.

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Therefore, another aspect of the invention is directed to the intermediate reaction compounds of the general formula III (which include β-lactams of type 4, 5 and 6):

5

where R2 and R4 are specified above and R 7 is selected from hydrogen, aryl, aralkyl, or Boc groups; and Z is a group benzyloxycarbonyl.

A preferred embodiment is one where the R 4 radical of the compound of general formula III is an atom of hydrogen or a (C 1 -C 3) alkyl group and / or where R2 is selected from the list comprising an atom of hydrogen, a linear (C 1 -C 4) alkyl group or branched or an aralkyl.

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More preferably, the compound of formula General III is selected from the list comprising:

to.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-3-methyl-1- p -methoxybenzyl-4-methoxycarbonyl-2-oxoazetidine.

b.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine.

C.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-1- tert -butoxycarbonyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine.

d.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-1- p -methoxybenzyl-2-oxoazetidine.

and.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-2-oxoazetidine.

F.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-1,4-di- tert -butoxycarbonyl-3-methyl-2-oxoazetidine.

or their corresponding enantiomers

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To obtain the compounds of formula general I from the β-lactams of general formula III described above, are made different synthetic steps that have been described in general and that detail in a more concrete way below.

Azepane 1.1 derivatives can be prepared by opening the Boc-imido derivatives 6 by nucleophilic attack of the amino group of the substituent 4- (3-aminobutyl), after deprotection of group Z by catalytic hydrogenation using Pd-C as catalyst.

Compounds 1.2 can be prepared by reaction of oxoazepane derivatives 1.1, with different agents alkylating agents of the general formula R 3 X (where X is an atom of halogen and R3 maintains the significance already indicated) in medium basic.

Compounds 1.3 and 1.4 can be prepared by suitable transformations on the amino groups, carboxylate and amide (see Scheme 1).

Molecular modeling studies, collected in Examples 11 and 12 demonstrate the structure inducing capacity peptide secondary of the compounds of general formula I. By all of this, another aspect of the present invention relates to the use of the compound (s) of general formula I, for the study of peptide conformation, as well as central skeleton for the elaboration of combinatorial chemists.

Another aspect of the present invention is refers to a pharmaceutical composition characterized because comprises a compound of general formula I, compounds of the invention, together with one or more pharmaceutically excipients acceptable and / or one or more active therapeutic agents.

The pharmaceutically acceptable excipients that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and used usually in the elaboration of therapeutic compositions.

In the sense used in this description, the expression "therapeutically effective amount" refers to the amount of agent or compound capable of carrying out the action therapeutic determined by its pharmacological properties, calculated to produce the desired effect and, in general, will come determined, among other causes, by the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and of the route and frequency of administration.

Throughout the description and the claims the word "comprises" and its variants not they intend to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.

Brief description of the figures

Fig. 1.- Representative examples of the conformers with α-pentapeptide twist structure singles that incorporate a 2-oxoazepane residue in position i + 1 (A) and i + 2 (B).

Fig. 2.- Global minimums of the models dodecapeptides incorporating heterocyclic amino acids I in position i + 2 (A), i + 9 (B), and in positions i + 2 and i + 6 (C)

Examples

The compounds of this invention, their synthesis chemistry, as well as the necessary intermediates, which are equally part of the invention, are illustrated by the following examples although these should not be considered as limiting it.

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Example one

Synthesis of the compound of the invention (3 S , 4 S ) -4- ( tert -Butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane (1.1a)

Stage one

Synthesis of intermediate compound N - [ (S) -2-Chloropropionyl] - N -Pmb-L-Orn (Z) -OMe (3a)

To a solution of (S) -2-chloropropionic acid ( 1.90 mL, 22.02 mmol) and Cl 3 CCN (2.90 mL, 28.98 mmol) in dry THF (50 mL), PPh_ is added at 0 ° C 3} (7.61 g, 29.03 mmol) and allowed to react for 30 minutes. Separately, the N - p -methoxybenzylornitin 2 derivative (5.80 g, 14.49 mmol) is dissolved in propylene oxide (15.2 mL, 217.32 mmol) and this solution is added slowly over the previous solution. After 2 h of reaction at room temperature the solvent is evaporated to dryness, the resulting residue is dissolved in ether, filtered over celite, and evaporated to dryness. Then, the resulting residue is purified by silica gel column chromatography using CH2Cl2 -acetone (30: 1) as eluent to give 5.27 g (74%) of the title product.

1 H-NMR (300 MHz, CDCl 3): δ 1.46 (m, 2H, γ-H), 1.62 (d, 3H, J = 6.4, 3'-H), 1.71 (m , 1H, β-H), 2.01 (m, 1H, β-H), 3.11 (m, 2H, δ-H), 3.51 (s, 3H, OCH 3), 3.77 (s, 3H , p -OCH3), 4.51 (m, 2H, 2'-H, N-CH2), 4.69 (m, 2H, α-H, N-CH2), 4.84 (sa , 1H, NH-Z), 5.07 (s, 2H, CH2, Z), 6.87 (d, 2H, J = 8.3, 3-H and 5-H, Pmb), 7.13 (d, 2H, J = 8.3, 2-H and 6-H, Pmb), 7.33 (s, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 25 H 31 ClN 2 O 6: C 61.16, H 6.36, N 5.71; Found: C 60.98, H 6.54, N 5.85.

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Stage 2

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-3-methyl-1- p -methoxybenzyl-4-methoxycarbonyl-2-oxoazetidine (4a)

To a solution of derivative 3a (2.97 g, 6.06 mmol) in dry CH 3 CN (20 mL), BTPP (2.8 mL, 9.09) is added mmol). After 48 h of stirring at room temperature, under atmosphere from Ar, the solvent is evaporated to dryness. The resulting residue is Dissolve in AcOEt and wash successively with H2O, and dissolve saturated with NaCl, then dried over Na2SO4. The solvent is evaporated to dryness and the reaction crude is purify by silica gel column chromatography, using a gradient of hexane-AcOEt as eluent from 4: 1 to 1: 1. 2.39 g (87%) of the indicated product are thus obtained in the epigraph in the form of sirupe.

[α] D 20 = -16.8 (c = 0.5, CHCl3).

1 H-NMR (300 MHz, CDCl 3): δ 1.14 (d, 3H, J = 7.5, 3-CH 3), 1.27 (m, 2H, 2'-H), 1.73 (m, 2H, 1'-H), 2.85 (m, 2H, 3'-H), 3.12 (c, 1H, J = 7.5, 3-H), 3.70 (s, 3H, p -OCH_ {3} ), 3.73 (s, 3H, OCH3), 4.07 (d, 1H, J = 15.4, 1-CH2), 4.31 (sa, 1H, NH-Z), 4.77 (d, 1H, J = 15.4, 1-CH2), 5.05 (s, 2H, CH2, Z), 6.82 (d, 2H, J = 8.6, 3-H and 5-H, Pmb), 7.19 (d, 2H, J = 8.6, 2-H and 6-H, Pmb), 7.34 (s, 5H, Ph, Z).

MS: 477.45 (M + Na) +.

Elemental Analysis.- Calculated for C 25 H 30 N 2 O 6: C 66.06, H 6.65, N 6.16. Found: C 65.87, H 6.72, N 6.15.

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Stage 3

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine (5a)

At a dissolution of the 1-Pmb-2-oxoazetidine 4a (3.48 g, 7.66 mmol) in CH3CN / H2O 1: 1 (260 mL), it is successively add K 2 HPO 4 (5.35 g, 30.69 mmol) and K 2 S 2 O 8 (10.37 g, 38.37 mmol), and 2 is allowed to react h at 75 ° C, under Ar. Then the solvent and the resulting aqueous phase is extracted with AcOEt. The phase Organic is washed with 10% NaHCO3 solution and solution saturated with NaCl, dried over Na2SO4, and evaporated to dryness. The resulting residue is purified by chromatography. on a silica gel column, using a gradient as eluent hexane-AcOEt from 3: 1 to 1: 1. They get like this 1.95 g of 5a (76%) in the form of a sirupe.

1 H-NMR (300 MHz, CDCl 3): δ 1.08 (d, 3H, J = 7.6, 3-CH 3), 1.62 (m, 2H, 2'-H), 2.12 (m, 2H, 1'-H), 3.03 (c, 1H, J = 7.6, 3-H), 3.12 (m, 2H, 3'-H), 3.69 (s, 3H, OCH_3), 4.95 (s, 1H, NH-Z), 5.01 (s, 2H, CH2, Z), 6.68 (s, 1H, 1-H), 7.27 (s, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 17 H 22 N 2 O 5: Calc: C 61.07, H 6.63, N 8.38. Found: C 61.36, H 6.51, N 8.13.

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Stage 4

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-1- tert -butoxycarbonyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine (6a)

To a solution of the derivative of 2-oxoazetidine 5a (1.51 g, 4.53 mmol) in Dry CH2Cl2 (65 mL), TEA (0.63 mL, 4.53) is added mmol), DMAP (0.06 g, 0.46 mmol) and Boc2O (0.97 g, 4.44 mmol). After 3 hours of stirring at room temperature it evaporates to dryness. The resulting crude is purified by chromatography on silica gel column, using as eluents AcOEt-hexane (1: 1), obtaining 1.51 g (77%) of product indicated above in the form of sirupe.

1 H-NMR (300 MHz, CDCl 3): δ 1.15 (d, 3H, J = 7.5, 3-CH 3), 1.48 (s, 9H, t Bu), 1.55 (m, 1H, 2'-H), 1.77 (m, 1H, 2'-H), 2.12 (m, 2H, 1'-H), 3.22 (m, 3H, 3-H, 3'-H ), 3.78 (s, 3H, OCH3), 4.90 (s, 1H, NH-Z), 5.08 (s, 2H, CH2, Z), 7.34 (s, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 22 H 30 N 2 O 7: C 60.82, H 6.96, N 6.45. Found: C 60.71, H 6.79, N 6.36.

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Stage 5

Synthesis of compound (3 S , 4 S ) -4- ( tert -Butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane (1.1a)

To a solution of the N -Bac-2-oxoazetidine 6a (1.65 g, 3.79 mmol) in MeOH (288 mL), 10% Pd / C (0.16 g) is added. The suspension is hydrogenated at room temperature and 15 psi for 4 hours. After filtration of the catalyst, the solvent is evaporated to dryness and the resulting residue is purified by silica gel column chromatography, using CH2Cl2 -MeOH (60: 1) as eluents. 0.98 g of the title product (86%) are thus obtained in the form of a white solid (mp: 138-140 ° C).

[α] D 20 = -40.2 (c = 0.7, CHCl3)

1 H-NMR (300 MHz, CDCl 3): δ 1.04 (d, 3H, J = 7.0, 3-CH 3), 1.41 (s, 9H, t Bu), 1.73 (m, 2H, 6-H), 2.18 (m, 1H, 5-H), 3.05 (m, 1H, 5-H), 3.11 (c, 1H, J = 7.0, 3-H), 3.22 ( m, 1H, 7-H), 3.32 (m, 1H, 7-H), 3.73 (s, 3H, OCH3), 4.86 (s, 1H, 4-NH), 6.29 (s, 1H, 1 -H).

MS: 323.3 (M + Na) +.

Elemental Analysis.- Calculated for C 14 H 24 N 2 O 5: C 55.98, H 8.05, N 9.33. Found: C 55.73, H 8.18, N 9.11.

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Example 2

Synthesis of the compound of the invention (3 S , 4 S ) -4- tert -butoxycarbonyl-4- ( tert -Butoxycarbonyl) amino-3-methyl-2-oxoazepane (1.1b)

Stage one

Synthesis of intermediate compound N - [ (S) -2-Chloropropionyl] - N -Pmb-L-Orn (Z) -O t Bu (3b)

From N- Pmb-Orn (Z) -O t Bu (2b) and following the procedure described in Step 1 of Example 1, and after purifying on a silica gel column using AcOEt-hexane (1: 6) as eluent the product indicated above is obtained in the form of sirupe (67%).

1 H-NMR (400 MHz, CDCl 3): δ 1.38 (s, 9H, (t Bu), 1.45 (m, 2H, γ-H), 1.64 (d, 3H , J = 6.0, 3'-H), 1.66 (m, 1H, β-H), 2.04 (m, 1H, β-H), 3.10 (m, 2H, δ-H), 3.79 (s , 3H, p -OCH3), 4.28 (t, 1H, J = 7.2, α-H), 4.56 (m, 2H, 2'-H, N-CH2), 4.64 (m, 1H, N-CH2), 4.78 (sa, 1H, NH-Z), 5.08 (s, 2H, CH2, Z), 6.88 (d, 2H, J = 7.8, 3-H and 5 -H, Pmb), 7.20 (d, 2H, J = 7.8, 2-H and 6-H, Pmb), 7.34 (s, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 28 H 37 ClN 2 O 6: C 63.09, H 7.00, N 5.26. Found: C 62.85, H 7.08, N 5.46.

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Stage 2

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-1- p -methoxybenzyl-2-oxoazetidine (4b)

From the compound of the previous stage and Following the procedure of Step 2 of Example 1, the title product (94%) as sirupe, after purification in silica gel column using as eluent a gradient of hexane-AcOEt from 6: 1 to 1: 1.

[α] D 20 = -10.7 (c = 0.70, CHCl3).

1 H-NMR (300 MHz, CDCl 3): δ 1.19 (d, 3H, J = 7.5, 3-CH 3), 1.47 (s, 9H, t Bu), 1.53 (m, 2H, 2'-H), 1.67 (m, 2H, 1'-H), 2.81 (m, 2H, 3'-H), 3.07 (c, 1H, J = 7.5, 3-H) , 3.69 (s, 3H, p -OCH3), 4.04 (d, 1H, J = 16.2, 1-CH2), 4.21 (sa, 1H, NH-Z), 4.79 (d, 1H, J = 16.2, 1-CH2), 5.03 (s, 2H, CH2, Z), 6.81 (d, 2H, J = 8.6, 3- H and 5-H, Pmb), 7.19 (d , 2H, J = 8.6, 2-H and 6-H, Pmb), 7.32 (s, 5H, Ph, Z).

MS: 497.47 (M + H) +.

Elemental Analysis.- Calculated for C 28 H 36 N 2 O 6: C, 67.72, H 7.31, N 5.64. Found: C, 67.43, H 7.50, N 5.39.

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Stage 3

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-2-oxoazetidine (5b)

The compound obtained in the previous stage is subject to the sequence of reactions indicated in Step 3 of Example 1 to give rise to compound 5b, in the form of a sirupe, with a 53% yield, after silica gel column purification using as eluent a gradient of hexane-AcOEt from 6: 1 to 1: 1.

1 H-NMR (300 MHz, CDCl 3): δ 1.22 (d, 3H, J = 8.0, 3-CH 3), 1.48 (s, 9H, t Bu), 1.52 (m, 2H, 2'-H), 2.01 (m, 2H, 1'-H), 3.15 (c, 1H, J = 8.0, 3-H), 3.20 (m, 2H, 3'-H) , 4.83 (s, 1H, NH-Z), 5.16 (s, 2H, CH2, Z), 6.24 (s, 1H, 1-H), 7.35 (s, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 20 H 28 N 2 O 5: C 63.81, H 7.50, N 7.44. Found: C 63.50, H 7.38, N 7.22.

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Stage 4

Synthesis of intermediate (3 S , 4 S ) -4- [3- (Benzyloxycarbonyl) amino] propyl-1,4-di- tert -butoxycarbonyl-3-methyl-2-oxoazetidine (6b)

From the compound of the previous stage following the methodology indicated in Step 4 of Example 1, obtains the title compound with a yield of 91% in white solid forms, after gel column purification of silica using as eluent a gradient of hexane-AcOEt from 7: 1 to 3: 1. (pf: 69-72 ° C).

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1 H-NMR (300 MHz, CDCl 3): δ 1.15 (d, 3H, J = 7.5, 3-CH 3), 1.42 (s, 9H, t Bu), 1.43 (s, 9H, t Bu), 1.64 (m, 2H, 2'-H), 2.03 (m, 2H, 1'-H), 3.15 (m, 3H, 3-H, 3'- H), 4.79 (s, 1H, NH-Z), 5.02 (s, 2H, CH2, Z), 7.28 (m, 5H, Ph, Z).

Elemental Analysis.- Calculated for C 25 H 36 N 2 O 7: C 63.01, H 7.61, N 5.88. Found: 62.78, H 7.91, N 5.89.

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Stage 5

Synthesis of the compound of the invention (3 S , 4 S ) -4- tert -butoxycarbonyl-4- ( tert -Butoxycarbonyl) amino-3-methyl-2- oxoazepane (1.1b)

In the manner indicated in Step 5 of Example 1 and using the 2-oxoazetidine from the previous stage the compound indicated above (75%) is obtained as a solid white (mp: 132-135 ° C), after purification by silica gel column using as eluent a gradient of CH 2 Cl 2 -MeOH from 80: 1 to 60: 1.

[α] D 20 = -46.6 (c = 1.4, CHCl3).

1 H-NMR (300 MHz, CDCl 3): δ 1.09 (d, 3H, J = 7.0, 3-CH 3), 1.38 (s, 9H, t Bu), 1.44 (s, 9H, t Bu), 1.65 (m, 2H, 6-H), 2.11 (m, 1H, 5-H), 2.98 (m, 1H, 5-H), 3.08 (c, 1H, J = 7.0, 3-H), 3.19 (m, 1H, 7-H), 3.31 (m, 1H, 7-H), 4.84 (s, 1H, 4-NH), 6.60 (s, 1H, 1 HOUR).

MS: 365.42 (M + Na) +.

Elemental Analysis.- Calculated for C 17 H 30 N 2 O 5: C 59.63, H 8.83, N 8.18. Found: C 59.48, H 9.12, N 8.10.

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Example 3

Synthesis of the compound of the invention (3 S , 4 S ) -4- ( tert -Butoxycarbonyl) amino-1,3-dimethyl-4-methoxycarbonyl-2-oxoazepane (1.2a)

To a solution of the derivative of 2-oxoazepane 1.1a of Example 1 (0.19 g, 0.64 mmol) in CH 3 CN (9 mL), BTPP (0.59 mL, 1.93 mmol) is added. After 1 h stirring at room temperature, MeI (0.32 mL, 5.14 mmol). After 48 h the solvent is evaporated to dryness, the The resulting residue is dissolved in AcOEt and washed with H2O. The Organic phase is dried over Na2SO4. After evaporating the solvent to dryness, the reaction crude is purified by silica gel column chromatography, using as eluent a hexane-AcOEt gradient from 3: 1 to 1: 1. Thus obtain the product of the heading with a 21% yield (0.04 g) in the form of white solid (mp: 76-79 ° C).

1 H-NMR (300 MHz, CDCl 3): δ 1.04 (d, 3H, J = 6.9, 3-CH 3), 1.41 (s, 9H, t Bu), 1.70 (m, 2H, 6-H), 2.21 (m, 1H, 5-H), 2.97 (m, 1H, 5-H), 3.01 (s, 3H, 1- CH 3), 3.15 (m , 1H, 7-H), 3.19 (c, 1H, J = 6.9, 3-H), 3.72 (m, 1H, 7-H), 3.72 (s, 3H, OCH3), 4.92 (s, 1H, 4-NH).

Elemental Analysis.- Calculated for C 15 H 26 N 2 O 5: C 57.31, H 8.34, N 8.91. Found: C 57.18, H 8.07, N 9.04.

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Example 4

Synthesis of the compound of the invention (3 S , 4 S ) -1-Benzyl-4- ( tert -butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane (1.2b)

To a derivative solution of 2-oxoazepane 1.1a of Example 1 (0.02 g, 0.07 mmol) in CH 3 CN (0.75 mL), BTPP (0.06 mL, 0.20 mmol) is added and BnBr (0.02 mL, 0.20 mmol). After microwave heating at 120 ° C for 30 min, evaporate to dryness and AcOEt is added. The solution obtained is washed successively with H2O and solution saturated NaCl. The organic phase is dried over Na2SO4 and It evaporates to dryness. The resulting residue is purified by silica gel column chromatography, using as eluent a hexane-AcOEt gradient from 10: 1 to 2: 1. Be thus obtain 0.02 g (59%) of product 1.2a in the form of a sirupe.

1 H-NMR (400 MHz, CDCl 3): δ 1.09 (d, 3H, J = 6.9, 3-CH 3), 1.42 (s, 9H, t Bu), 1.57 (m, 2H, 6-H), 2.14 (m, 1H, 5-H), 2.92 (m, 1H, 5-H), 3.21 (m, 1H, 7-H), 3.23 (c, 1H, J = 6.9, 3-H), 3.57 (m, 1H, 7-H), 3.72 (s, 3H, OCH 3), 4.44 (d, 1H, J = 14.7, I-CH 2), 4.80 (d, 1H, J = 14.7, 1-CH2), 4.98 (s, 1H, 4-NH), 7.25-7.31 (m, 5H, Ph).

Elemental Analysis.- Calculated for C 21 H 30 N 2 O 5: C 64.59, H 7.74, N 7.17. Found: C 64.36, H 7.53, N 6.89.

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Example 5

Synthesis of the compound of the invention (3 S , 4 S ) -4- ( tert -Butoxycarbonyl) amino-4-carboxy-3-methyl-2-oxoazepane (1.3a)

To a solution of the derivative of 2-oxoazepane 1.1a of Example 1 (0.05 g, 0.17 mmol) in MeOH (2 mL) 2N NaOH (0.33 mL, 0.66 mmol) is added. After 4 days stirring at room temperature, the solvent is removed and add H2O (5 mL), acidify with 1N HCl until pH = 3 and mix Extract the product with AcOEt. The organic phase is washed with saturated NaCl solution, dried over Na2SO4 and dried evaporates to dryness. This gives 0.04 g (90%) of the product of the heading in the form of a yellow solid (mp: 83-86 ° C).

1 H-NMR (300 MHz, CDCl 3): δ 1.26 (d, 3H, J = 7.2, 3-CH 3), 1.38 (s, 9H, t Bu), 1.89 (m, 3H, 6-H, 5-H), 2.46 (m, 1H, 5-H), 3.11 (c, 1H, J = 7.2, 3-H), 3.26 (m, 1H, 7-H ), 3.38 (m, 1H, 7-H), 5.26 (s, 1H, 4-NH), 6.90 (s, 1H, 1-H).

Elemental Analysis.- Calculated for C 13 H 22 N 2 O 5: C 54.53, H 7.74, N 9.78. Found: C 54.28, H 7.61, N 9.55.

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Example 6

Synthesis of the compound of the invention (3 S , 4 S ) -4- ( tert -Butoxycarbonyl) amino-4-carboxy-1,3-dimethyl-2-oxoazepane (1.3b)

From the derivative of 2-oxoazepane 1.2a of Example 3 and following the methodology of Example 5 the compound indicated above is obtained with a 93% yield in the form of sirupe.

1 H-NMR (400 MHz, CDCl 3): δ 1.25 (d, 3H, J = 7.4, 3-CH 3), 1.40 (s, 9H, t Bu), 1.86 (m, 1H, 5-H), 1.94 (m, 1H, 6-H), 2.03 (m, 1H, 6-H), 2.45 (m, 1H, 5-H), 3.02 (s, 3H, 1-CH 3), 3.19 (c, 1H, J = 7.4, 3-H), 3.38 (m, 2H, 7-H), 5.42 (s, 1H, 4-NH).

Elemental Analysis.- Calculated for C 14 H 24 N 2 O 5: C 55.98, H 8.05, N 9.33. Found: C 55.79, H 8.27, N 9.09

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Example 7

Synthesis of the compound of the invention Trifluoroacetate (3 S , 4 S ) -4-amino-3-methyl-4-methoxycarbonyl-2-oxoazepane (1.3c)

To a solution of the derivative of 2-oxoazepane 1.1a of Example 1 (0.04 g, 0.13 mmol) in CH 2 Cl 2 (4 mL), TFA (2 mL, 26.92 mmol) is added. After 4 hours of reaction at room temperature, it is evaporated at dryness, coevaporating several times with CH 2 Cl 2. The residue resulting is dissolved in H2O and lyophilized. They get the compound 1.3c in the form of sirupe, with a 96% yield.

1 H-NMR (300 MHz, D 2 O): δ 1.00 (d, 3H, J = 7.1, 3-CH 3), 1.62 (m, 1H, 6-H), 1.83 (m, 1H, 6-H), 2.08 (m, 1H, 5-H), 2.34 (m, 1H, 5-H), 3.22 (m, 1H, 7-H), 3.35 (m, 1H, 7 -H), 3.49 (c, 1H, J = 7.1, 3-H), 3.77 (s, 3H, OCH_3).

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Example 8

Synthesis of the compound of the invention Trifluoroacetate (3 S , 4 S ) -4-amino-4-carboxy-3-methyl-2-oxoazepane (1.3d)

As indicated in Example 7 and from of the 2-oxoazepane derivative 1.1b of Example 2, obtains the compound indicated above with a yield of 99% in hygroscopic sirupe form.

1 H-NMR (300 MHz, D 2 O): δ 1.00 (d, 3H, J = 7.0, 3-CH 3), 1.54 (m, 1H, 6-H), 1.78 (m, 1H, 6-H), 1.89 (m, 2H, 5-H), 3.19 (m, 2H, 7-H), 3.39 (c, 1H, J = 7.0, 3-H).

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Example 9

Synthesis of the compound of the invention Trifluoroacetate (3 S , 4 S ) -4-amino-1-benzyl-3-methyl-4-methoxycarbonyl-2-oxoazepane (1.4a)

From derivative of 2-oxoazepane 1.2b of Example 3 and following the methodology of Example 7, the compound indicated above is obtained with a 97% yield in the form of sirupe.

1 H-NMR (300 MHz, CDCl 3): δ 1.11 (d, 3H, J = 7.0, 3-CH 3), 1.65 (m, 2H, 6-H), 2.16 ( m, 1H, 5-H), 3.20 (m, 1H, 5-H), 3.25 (m, 1H, 7-H), 3.32 (c, 1H, J = 7.0, 3-H), 3.56 (m, 1H, 7-H), 3.75 (s, 3H, OCH_3), 4.48 (d, 1H, J = 14.6, 1-CH2), 4.81 (d, 1H, J = 14.6, 1-CH_ {2}), 7.27-7.30 (m, 5H, Ph).

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Example 10

Synthesis of the compound of the invention Trifluoroacetate of (3 S , 4 S ) -1,3-Dimethyl-4-methylamino-4-methoxycarbonyl-2-oxoazepane (1.4b).

To a solution of the derivative of 2-oxoazepane 1.1a of Example 1 (0.12 g, 0.39 mmol) in CH 2 Cl 2 (6 mL), NaH 60% dispersion is added in mineral oil (0.03 g, 1.18 mmol). After 1 h of stirring at room temperature, MeI (0.17 mL, 2.75 mmol) is added. After 2 days of stirring at room temperature, the solvent evaporates at dryness, the resulting residue is dissolved in AcOEt, washed with Saturated NaCl solution and dried over Na2SO4. After evaporate the solvent to dryness, the crude is purified by silica gel column chromatography, using as eluent a hexane-AcOEt gradient from 3: 1 to 1: 1. Thus you get a Boc-protected product that is about the form indicated in Example 7 to give rise to the compound of epigraph in the form of sirupe, with a 20% overall yield of two stages.

1 H-NMR (300 MHz, DMSO): δ 1.20 (d, 3H, J = 7.0, 3-CH 3), 1.77 (m, 2H, 6-H), 2.22 (m, 2H , 5-H), 2.57 (s, 3H, 4-NCH 3), 2.92 (s, 3H, 1-CH 3), 3.27 (m, 1H, 7-H), 3.59 (c, 1H , J = 7.0, 3-H), 3.80 (m, 1H, 7-H), 3.82 (s, 3H, OCH3), 9.36 (sa, 1H, 4-NH).

Elemental Analysis.- Calculated for C 13 H 21 N 2 O 5 F 3: C 45.61, H 6.18, N 8.18. Found: C 45.47, H 5.81, N 7.91.

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Example eleven

Study of the inductive capacity of secondary structure peptide of the compounds of general formula I when incorporated in pentapeptide models

Inductive capacity of secondary structure peptide of the compounds of general formula I, object of this invention, has been evaluated by molecular dynamics studies, using the AMBER force field implemented in Insightll (version 2000.1, Byosym Tech, San Diego, USA). For this they have incorporated these amino acids α, α-heterocyclic systems simple peptides based on alanine-rich sequences. The calculations were performed using a dielectric constant \ varepsilon = 4r. After molecular dynamics studies, conformers grouped in families in a + 3 Kcal window mol -1 of the global minimum as a function of the torsion angles of the peptide skeleton (\ phi and \ psi). Then it was studied the presence of hydrogen bonds between carbonyl oxygens and the amide protons of the peptide skeleton, in order to compare this hydrogen bond pattern with the one in the different elements of secondary peptide structure. So, the sequential replacement of the residues present in the model pentapeptide Ac-Ala-Ala-Ala-NHMe by the heterocyclic amino acids claimed herein patent has shown the ability of these quaternary amino acids to induce reverse turns when incorporated into any of the positions i + 1, i + 2 and i + 3. Figure 1 collects examples illustrative of α (CO i -NH + 4) turns \ leq 2.5 \ ring {A}).

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Example 12

Study of the inductive capacity of secondary structure peptide of the compounds of general formula I when incorporated into dodecapeptide models

For the conformational analysis the methodology described in Example 11, using a constant dielectric ε = 1, and selecting the families of conformer in a window of + 5 Kcal mol -1 of the global minimum. Thus, studies on model dodecapeptide derivatives have been performed. rich in Alanites in which both substitutions have been made sequential of each residue by the different amino acids heterocyclics object of this patent, as substitutions Simultaneous two waste. Molecular dynamics studies have shown that conformationally restricted amino acids revindicated in this general formula patent I are capable of induce helical conformations when incorporated into the dodecapeptide sequence, positions 1, 2 being more favorable, 3, 4 or 9. On the other hand, when two residues of heterocyclic amino acid high percentages of helical conformations. The minimums are shown in Figure 2 global peptide derivatives incorporating amino acids α, α-heterocyclics revindicated in the present patent.

Claims (22)

1. Compound of general formula I 6 where R 1 and R 3 are equal or different and are independently selected from the list that it comprises a hydrogen atom, an alkyl group (linear and branched), substituted alkyl (with one or more halogen groups, hydroxyl, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations of these groups), aralkyl, aryl, substituted aryl (with alkyl, halogen groups, hydroxyl, alkoxide, thiol, nitro, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), heteroaryl or substituted heteroaryl (with alkyl groups, halogen, hydroxyl, alkoxide, thiol, nitro, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups), acyl (with linear and branched alkyl groups, aralkyl, aryl, heteroaryl, aryls and substituted heteroaryls, with the above meanings), sulfonyl (with alkyl groups linear and branched, aralkyl, aryl, heteroaryl, aryls and substituted heteroaryls, with the above meanings), groups aminos protectors in peptide chemistry, aminoacyl derivatives of natural and non-proteinogenic amino acids, protected or unprotected, or peptide fragments, protected or unprotected And it is selected from the list comprising a oxygen, sulfur or nitrogen atom, a CH2 group or a group substituted amino (NR, where R represents alkyl groups, linear or branched, aralkyl, aryl, heteroaryl or aryl or heteroaryl replaced). R2 is selected from the list comprising a hydrogen atom, alkyl groups (linear and branched), aralkyl, aryl, heteroaryl, aryl or heteroaryl replaced. The R 2 Y cluster is selected from the list comprising natural and non-proteinogenic amino acids, protected or unprotected, or peptide fragments, protected or unprotected X is selected from the list comprising a oxygen or sulfur atom, or equivalent to two hydrogen atoms. R 4 is selected from the list comprising a linear or branched alkyl group or a substituted alkyl (with halogen groups, hydroxide, alkoxide, thiol, amino, acylamino, cyano, carboxylate, carboxamide, carboxy ester, or combinations thereof groups).

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2. Compound according to claim 1 wherein R1 is an alkyl, acyl, alkyl- or aryloxycarbonyl group, aminoacyl derived from natural and non-proteinogenic amino acids protected or unprotected or protected peptide fragments or unprotected 3. Compound according to any of the claims 1 to 2 wherein Y is an oxygen, nitrogen or a substituted amino group. 4. Compound according to any of the claims 1 to 3 wherein R2 is selected from the list that comprises a hydrogen atom or an alkyl group (C 1 -C 3) linear or branched. 5. Compound according to any of the claims 1 to 4 wherein the YR2 cluster is an amino natural or non-proteinogenic acid, protected or unprotected, or peptide fragment, protected or unprotected. 6. Compound according to any of the claims 1 to 5 wherein R 3 is selected from the list that comprises a hydrogen atom, an alkyl group (C 1 -C 3) substituted or unsubstituted, a aralkyl, or an alkyl- or aryloxycarbonyl. 7. Compound according to any of the claims 1 to 6 wherein X is an oxygen or sulfur atom. 8. Compound according to any of the claims 1 to 7 wherein R 4 is an alkyl group (C_ {1} -C_ {3}). 9. Compound according to any of the claims 1 to 8 selected from the list comprising:

to.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane,

b.

(3 S , 4 S ) -4- tert -butoxycarbonyl-4- ( tert -butoxycarbonyl) amino-3-methyl-2-oxoazepane,

C.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-1,3-dimethyl-4-methoxycarbonyl-2-oxoazepane,

d.

(3 S , 4 S ) -1-benzyl-4- ( tert -butoxycarbonyl) amino-3-methyl-4-methoxycarbonyl-2-oxoazepane

and.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-4-carboxy-3-methyl-2-oxoazepane,

F.

(3 S , 4 S ) -4- ( tert -butoxycarbonyl) amino-4-carboxy-1,3-dimethyl-2-oxoazepane,

g.

(3 S , 4 S ) -4-amino-3-methyl-4-methoxycarbonyl-2-oxoazepane trifluoroacetate,

h.

(3 S , 4 S ) -4-amino-4-carboxy-3-methyl-2-oxoazepane trifluoroacetate,

i.

(3 S , 4 S ) -4-amino-1-benzyl-3-methyl-4-methoxycarbonyl-2-oxoazepane trifluoroacetate, or

j.

(3 S , 4 S ) -1,3-dimethyl-4-methylamino-4-methoxycarbonyl-2-oxoazepane trifluoroacetate,

or their corresponding enantiomers.

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10. Procedure for obtaining compounds of general formula I according to any one of claims 1 to 9, which includes the following steps:

to.

reaction of an N- p-methoxybenzylornitine derivative of general formula II

7

with chlorides of acid of general formula ClCOCH (R 4) Cl,

where R2 and R 4 are described in claim 1

b.

basic medium cycling of compounds obtained in step (a.),

C.

oxidation reaction for the elimination of the p -methoxybenzyl group of the 2-oxoazetidines obtained in step (b.),

d.

reaction with di- tert-butyl dicarbonate for the incorporation of a tert- butyloxycarbonyl group in the NH of the ring of the 2-oxoazetidines obtained in step (c.),

and.

group check out benzyloxycarbonyl and ring opening 2-oxoazetidine of the compounds obtained in the step (d.).

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11. Method according to claim 10 that It also includes the step of:

F.

acidic or basic hydrolysis of carboxylic esters and / or urethane groups of substituents in position 4 of the compounds obtained in step (e.).

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12. Method according to claim 10 that It also includes the step of:

g.

reaction of the compounds obtained in the step (e.) with alkylating agents of the general formula R 3 X, in basic medium, where X is a halogen atom and R3 as Specify above.

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13. Procedure according to any of the claims 10 or 12 further comprising the step of:

h.

Incorporation of substituents R1 and / or YR2 in the compounds obtained in step (e.) Or (g.), by suitable reactions (alkylation, acylation, sullfonación ...).

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14. Procedure according to any of the claims 12 or 13 further comprising the step of:

i.

acidic or basic hydrolysis of carboxylic esters and / or urethane groups of substituents in position 4 of the compounds obtained in step (g) or (h).

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15. Compound of general formula III:

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8

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where R2 and R4 are specify in the claim one, R 7 is selected from hydrogen, groups aryl, aralkyl, or Boc and Z is a benzyloxycarbonyl group.

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16. Compound according to claim 15 wherein R 4 is a hydrogen atom or an alkyl group (C_ {1} -C_ {3}). 17. Compound according to any of the claims 15 to 16 wherein R2 is selected from the list that comprises a hydrogen atom, an alkyl group (C 1 -C 4) linear or branched or a aralkyl

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18. Compound according to any of the claims 15 to 17 selected from the list comprising:

to.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-3-methyl-1- p -methoxybenzyl-4-methoxycarbonyl-2-oxoazetidine.

b.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine.

C.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-1- tert -butoxycarbonyl-3-methyl-4-methoxycarbonyl-2-oxoazetidine.

d.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-1- p -methoxybenzyl-2-oxoazetidine.

and.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-4- tert -butoxycarbonyl-3-methyl-2-oxoazetidine.

F.

(3 S , 4 S ) -4- [3- (benzyloxycarbonyl) amino] propyl-1,4-di- tert -butoxycarbonyl-3-methyl-2-oxoazetidine.

or their corresponding enantiomers.

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19. Use of the compound (s) of the formula general I according to any one of claims 1 to 9 for the study of peptide conformation. 20. Use of the compound (s) of the formula general I according to any one of claims 1 to 9 for the elaboration, as a central skeleton, of chemotheques combinatorics

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21. Pharmaceutical composition characterized in that it comprises a compound according to any one of claims 1 to 9, together with one or more pharmaceutically acceptable excipients. 22. Composition according to claim 21 characterized in that it further comprises one or more active therapeutic agents.