ES2372420T3 - DERIVATIVES OF N-HYDROXYAMIDE AND USE OF THE SAME. - Google Patents

Abstract

A derivative of N-hydroxyamide according to formula (I), in which: A is chosen from -C (B) - and N; B is H or B forms a bond with the carbon atom that supports either R 5 or R 7; R 1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C3-C8 cycloalkyl-C1-C6 alkyl, heterocyclylalkyl-C1-C6 alkyl, heteroaryl-C1-C6 alkyl, amino and alkoxy; R 2 is chosen from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, alkoxy, aryl and heteroaryl; R 3 is selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R 4, R 5, R 6 and R 7 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; or R 4 and R 7 together form a bond -CH2-; n is an integer chosen from 1, 2, 3, 4, 5 and 6; the carbon atoms (2) and (3) are two chiral centers, in which the chiral center (2) has a configuration chosen between "S" and "R" and where the chiral center (3) has a "S" configuration ", as well as its pharmaceutically acceptable salts.

Description

N-hydroxyamide derivatives and use thereof

Field of the Invention

The present invention relates to N-hydroxyamide derivatives of formula (I), their pharmaceutical compositions, methods for their preparation and their use for the treatment and / or prophylaxis of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, diseases neurodegenerative, cancer, respiratory diseases and fibrosis. Specifically, the present invention relates to Nhydroxyamide derivatives for modulation, mainly inhibition, of the activity or function of matrix metalloproteinases.

Background of the invention

Metalloproteinases are a superfamily of proteinases (enzymes) named for their dependence on a metal ion (zinc) at the active site.

Matrix metalloproteinases (usually abbreviated as MMPs by their initials in English: matrix metalloproteinases) form a subfamily of metalloproteinases that have as one of their main biological functions to catalyze the breakdown of connective tissue or extracellular matrix by their ability to hydrolyze various tissue components or of the matrix, such as collagens, jellies, proteoglycans, fibronectins and elastin.

The matrix metalloproteinase family is further divided according to its function and substrates (Visse et al., 2003, Circ. Res. 92: 827-839) and comprises collagenases (MMP-1, MMP-8, MMP-13 and MMP -18), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10 and MMP-11), membrane type MMPs (MT-MMP-1 to MT-MMP-6 and MMP14, MMP -15, MMP-16, MMP-17, MMP-24 and MMP-25), matrilysins (MMP-7 and MMP-26) and other unclassified MMPs, such as metalloelastase (MMP-12), enamelisin (MMP -20), epilysin (MMP-28), MMP-19, MMP-22 and MMP-23.

Apart from their role in the degradation of connective tissue, MMPs are involved in the biosynthesis of TNF-alpha and in the processing of post-translation proteolysis or shedding of biologically important membrane proteins (Hooper et al., 1997, Biochem. J. 321: 265-279). MMPs contribute for example to the local growth and expansion of malignant lesions and, therefore, have been a target for the development of antitumor drugs (Fingleton et al., 2003, Expert Opin. Ther. Targets, 7 (3): 385-397). It has been shown that disorders such as inflammatory disorders such as arthritis (Clark et al., 2003, Expert Opin. Ther. Targets 7 (1): 1934), respiratory disorders, such as emphysema, arteriosclerosis (Gallis et al., 2002, Circ Res., 90: 251-262), neurological disorders such as degenerative diseases of the nervous system, multiple sclerosis (Leppert et al., 2001, Brain Res. Rev. 36: 249-257), periodontitis (Ingman et al., 1996, J. Clin. Periodontal, 23: 1127-1132), premature delivery (Makrakis et al., 2003, J. Matern. Fetal & Neonatal Medicine, 14 (3): 170-6) and wound healing are associated with the expression and / or activity of the MMPs.

A wide variety of inhibitors of matrix metalloproteinases have been developed (generally abbreviated as MMPIs by their initials in English: matrix metalloproteinase inhibitors) (Skiles et al., 2001, Current Medicinal Chemistry, 8: 325-474; Henrotin et al. , 2002, Expert Opin. Ther. Patents, 12 (1): 29-43). However, many MMPIs have a musculoskeletal syndrome (tendinitis, fibroplasties, malaysia, arthritis) as a dose-limiting side effect. It has been proposed that the inhibition of MMP-1 or MMP-14 may be responsible for such effects.

Therefore, there is a growing need to develop matrix metalloproteinase inhibitors with a well defined specificity profile.

Specific inhibitors have been reported, especially against MMP-1, including MMP-13 inhibitors (Skotnicki et al., 2003, Current Opinion in Drug Discovery and Development, 6 (5): 742-759), inhibitors of MMP12 (Expert Opin. Ther. Patents, 2004, 14 (11): 1637-1640) and MMP-2 and MMP-8 inhibitors (Wada et al., 2002,

J. Med. Chem., 45: 219-232).

The great importance of the metalloproteinase pathway in some widely spread diseases, highlights the need to develop inhibitors, including selective inhibitors of MMPs, especially MMP2.

Summary of the Invention

An object of the invention is to provide substances that are suitable for the treatment and / or prevention of disorders related to autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer and malignancy, respiratory diseases, metabolic diseases, diseases Allergic and dermatological, premature delivery, endometriosis and fibrosis.

A further objective of the present invention is to provide substances that are suitable for the treatment and / or prevention of multiple sclerosis, arthritis such as osteoarthritis and rheumatoid arthritis, emphysema, psoriasis, obstructive pulmonary disease and fibrosis.

Particularly, an objective of the present invention is to provide chemical compounds that are capable of modulating, especially inhibiting, the activity or function of matrix metalloproteinases, especially gelatinases and elastase, in mammals, especially in humans.

An object of the present invention is also to provide a new category of pharmaceutical formulations for the treatment of mediated diseases chosen from autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer and malignancy, respiratory diseases, metabolic diseases, diseases. Allergic and dermatological, premature delivery, endometriosis and fibrosis.

An object of the present invention is also to provide processes for making the chemical compounds according to the invention.

In a first aspect, the invention provides N-hydroxyamide derivatives of formula (I):

wherein A, R1, R2, R3, R4, R5, R6, R7 and n are defined in the detailed description.

In a second aspect, the invention provides a compound according to formula (I) for use as a medicament.

In a third aspect, the invention provides a use of a compound according to formula (I) for the preparation of a pharmaceutical composition for the treatment of a disorder chosen from autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer and malignancy, respiratory diseases, metabolic diseases, allergic and dermatological diseases, premature delivery, endometriosis and fibrosis.

In a fourth aspect, the invention provides a pharmaceutical composition comprising at least one compound according to formula (I) and one of its pharmaceutically acceptable carriers, diluents or excipients.

In a fifth aspect, the invention provides methods of synthesis of a compound according to formula (I).

In a sixth aspect, the invention provides compounds according to formula (II):

wherein R1, R2, R3, R4, R5, R6, R7 and n are defined as above and PG1 is H or a protecting group such as benzyl, t-butyl, THP, TMS or TBS.

Detailed description of the invention

The following paragraphs provide definitions of various chemical moieties that make up the compounds according to the invention, and which are intended to be applied uniformly throughout the specification and the claims unless an expressly proposed definition provides a broader definition.

The term "MMPs" refers to "matrix metalloproteinases." For recent reviews of the MMPs see Visse et al., 2003, cited above; Fingleton et al., 2003, cited above; Clark et al., 2003, cited above; and Doherly et al., 2002, Expert Opinion Therapeutic Patents 12 (5): 665-707.

Illustrative but non-limiting examples of said MMPs are:

Collagenases:

Generally associated with diseases related to collagen-based tissue rupture, for example rheumatoid arthritis and osteoarthritis:

MMP-1 (also known as collagenase 1, or fibroblastic collagenase); substrates collagen I, collagen II, collagen III, gelatin and proteoglycans. It is believed that overexpression of this enzyme is associated with emphysema, with hyperkeratosis and atherosclerosis, overexpressed alone in papillary carcinoma.

MMP-8 (also known as collagenase 2 or neutrophilic collagenase); substrates Collagen I, Collagen II, Collagen III, Collagen V, Collagen VII, Collagen IX and Gelatin; Its overexpression can lead to non-healing of chronic ulcers.

MMP-13 (also known as collagenase 3); substrates Collagen I, Collagen II, Collagen III, Collagen IV, Collagen IX, Collagen X, Collagen XIV, Fibronectin and Gelatin; It has recently been identified that it is overexpressed alone in breast carcinoma and implicated in rheumatoid arthritis.

Stromelysins:

MMP-3 (also known as stromelysin 1); substrates Collagen III, Collagen IV, Collagen V, Collagen IX, Collagen X, Laminin and Nidogen; its overexpression is believed to be involved in atherosclerosis, aneurysm and restenosis.

Jellies:

Its inhibition is believed to have a favorable effect on cancer, particularly on invasion and metastasis.

MMP-2 (also known as gelatinase A, 72 kDa gelatinase, basement membrane collagenase or proteoglycanase); substrates Collagen I, Collagen II, Collagen IV, Collagen V, Collagen VII, Collagen X, Collagen XI, Collagen XIV, Elastin, Fibronectin, Gelatin and Nidogen; It is believed to be associated with tumor progression through its specificity for type IV collagen (high expression is seen in solid tumors and is believed to be associated with its ability to grow, invade, develop new blood vessels and metastases) and which is involved in acute pulmonary inflammation and respiratory distress syndrome (Krishna et al., 2004, Expert Opin. Invest. Drugs, 13 (3): 255-267).

MMP-9 (also known as gelatinase B or 92 kDa gelatinase); substrates Collagen I, Collagen III, Collagen IV, Collagen V, Collagen VII, Collagen X, Collagen XIV, Elastin, Fibronectin, Gelatin and Nidogen. It is believed that the previous enzyme is associated with tumor progression through specificity by type IV collagen, which is released by eosinophils in response to exogenous factors such as contaminants, allergens and viruses, which is involved in the inflammatory response. in multiple sclerosis (Opdenakker et al., 2003, The Lancet Neurology, 2, 747-756) and in asthma and which is involved in acute pulmonary inflammation, respiratory distress syndrome, chronic obstructive pulmonary disorder (COPD) and / or asthma (Krishna et al., 2004, cited above). It is also believed that MMP-9 is involved in stroke (Horstmann et al., 2003, Stroke 34 (9): 2165-70).

MMPs not classified:

MMP-12 (also known as metalloelastase, human macrophage elastase or HME); substrates: fibronectin and laminin; It is believed that it has a role in the inhibition of tumor growth and in the regulation of inflammation as in multiple sclerosis (Vos et al., 2003, Journal of Neuroimmunology, 138: 106-114) and that it has a pathological role in the emphysema, COPD (Belvisi et al., 2003, Inflamm. Res., 52: 95-100) and in atherosclerosis, aneurysm and restenosis.

The term "MMP-associated disorder" refers to a disorder that can be treated according to the invention and that includes all disorders in which the expression and / or activity of at least one MMP must be decreased, regardless of the cause of such disorders. Such disorders include, for example, those caused by degradation of the extracellular matrix (usually abbreviated as ECM by its initials in English: extracellular matrix) inappropriate.

Illustrative but not limiting examples of such disorders associated with MMP are:

Cancer, such as breast cancer and solid tumors; inflammatory disorders such as, for example, inflammatory bowel diseases and neuroinflammation such as multiple sclerosis; lung diseases such as chronic obstructive pulmonary disorder (COPD), emphysema, asthma, acute lung injury and acute respiratory failure syndrome; dental diseases such as periodontal disease and gingivitis; joint and bone diseases such as osteoarthritis and rheumatoid arthritis; liver diseases such as liver fibrosis, cirrhosis and chronic liver disease; fibrotic diseases such as pulmonary fibrosis, pancreatitis, lupus, glomerulosclerosis, systemic sclerosis skin fibrosis, post-radiation fibrosis and cystic fibrosis; vascular pathologies such as aortic aneurysm, atherosclerosis, hypertension, cardiomyopathy and myocardial infarction; restenosis; ophthalmological disorders such as diabetic retinopathy, dry eye syndrome, degeneration of the macula and corneal ulceration and degenerative diseases of the central nervous system such as amyotrophic lateral sclerosis.

The term "C1-C6 alkyl" refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like. By analogy, the term "C1-C12 alkyl" refers to monovalent alkyl groups having 1 to 12 carbon atoms, including "C1-C6 alkyl" groups and the heptyl, octyl, nonyl, decanoyl, undecanoyl and dodecanoyl groups. , and the term "C1-C10 alkyl" refers to monovalent alkyl groups having 1 to 10 carbon atoms, the term "C1-C8 alkyl" refers to monovalent alkyl groups having 1 to 8 carbon atoms and The term "C1-C5 alkyl" refers to monovalent alkyl groups having 1 to 5 carbon atoms.

The term "heteroalkyl" refers to C1-C12 alkyl groups, preferably C1-C6 alkyl, in which at least one carbon atom has been replaced by a hetero atom chosen from O, N or S, including 2-methoxyethyl.

The term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (for example, phenyl) or multiple condensed rings (for example, naphthyl). The term aryl includes phenyl, naphthyl, phenanthrenyl and the like.

The term "C1-C6-aryl alkyl" refers to aryl groups having a C1-C6 alkyl substituent, including methylphenyl, ethylphenyl and the like.

The term "aryl-C1-C6 alkyl" refers to C1-C6 alkyl groups having an aryl substituent, including benzyl and the like.

The term "heteroaryl" refers to a monocyclic heteroaromatic group, or a bicyclic or tricyclic fused heteroaromatic group. Particular examples of heteroaromatic groups include the optionally substituted groups pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxaxolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1, 2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3 -dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, quinazolinyl, quinazolinyl, quinazolinyl, quinozinyl, quinazolinyl, quinozolinyl [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3 , 4-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

The term "C1-C6 alkyl-heteroaryl" refers to heteroaryl groups having a C1-C6 alkyl substituent, including methylfuryl and the like.

The term "heteroaryl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a heteroaryl substituent, including furylmethyl and the like.

The term "C2-C6 alkenyl" refers to alkenyl groups that preferably have 2 to 6 carbon atoms and that have at least 1 or 2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH = CH2), n-2-propenyl (allyl, -CH2CH = CH2) and the like.

The term "C2-C6-aryl alkenyl" refers to aryl groups having a C2-C6 alkenyl substituent, including vinylphenyl and the like.

The term "C2-C6-alkenyl-heteroaryl" refers to heteroaryl groups having a C2-C6 alkenyl substituent, including vinyl pyridinyl and the like.

The term "C2-C6 heteroaryl-alkenyl" refers to C2-C6 alkenyl groups having a heteroaryl substituent, including pyridinylvinyl and the like.

The term "C2-C6 alkynyl" refers to alkynyl groups that preferably have from 2 to 6 carbon atoms and that have at least 1-2 alkynyl unsaturation sites. Preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH) and the like.

The term "C3-C8 cycloalkyl" refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (for example, cyclohexyl) or several condensed rings (for example, norbornyl). C3-C8 cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

The term "heterocycloalkyl" refers to a C3-C8 cycloalkyl group according to the above definition, in which up to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S or NR, where R is defined as hydrogen or methyl. The term "heterocycloalkyl" includes pyrrolidone, piperidine, piperazine, morpholine, tetrahydrofuran and the like.

The term "C1-C6 alkyl-cycloalkyl" refers to C3-C8 cycloalkyl groups having a C1-C6 alkyl substituent, including methylcyclopentyl and the like.

The term "cycloalkyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a C3-C8 cycloalkyl substituent, including 3-cyclopentylpropyl and the like.

The term "C1-C6 alkyl-heterocycloalkyl" refers to heterocycloalkyl groups having a C1-C6 alkyl substituent, including 1-methylpiperazine and the like.

The term "heterocycloalkyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a heterocycloalkyl substituent, including 4-methylpiperidyl and the like.

The term "carboxy" refers to the group -C (O) OH.

The term "carboxy-C1-C6 alkyl" refers to C1-C6 alkyl groups having a carboxy substituent, including 2carboxyethyl and the like.

The term "acyl" refers to the group -C (O) R, where R includes "C1-C12 alkyl", preferably "C1-C6 alkyl", "aryl", "heteroaryl", "C3-C8 cycloalkyl" , heterocycloalkyl "," aryl-C1-C6 alkyl "," heteroaryl-C1-C6 alkyl "," C3-C8 cycloalkyl-C1-C6 alkyl "or" heterocycloalkyl-C1-C6 alkyl ".

The term "acyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having an acyl substituent, including acetyl, 2acetylethyl and the like.

The term "acylaryl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

The term "acyloxy" refers to the group -OC (O) R in which R includes H, "C1-C6 alkyl", C2-C6 alkenyl "," C2-C6 alkynyl "," C3-C8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl-C1-C6 alkyl "or" heteroaryl-C1-C6 alkyl "," C2-C6 arylalkyl "," C2-C6 heteroaryl-alkenyl "," aryl-C2 alkynyl -C6 "," heteroaryl-C2-C6 alkynyl "," cycloalkyl-C1-C6 alkyl "and" heterocycloalkyl-C1-C6 alkyl ".

The term "acyloxy-C1-C6 alkyl" refers to C1-C6 alkyl groups having an acyloxy substituent, including the propionic acid ethyl ester and the like.

The term "alkoxy" refers to the group -O-R, wherein R includes "C1-C6 alkyl" or "aryl" or "heteroaryl" or "aryl-C1-C6 alkyl" or "heteroaryl-C1-C6 alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

The term "C1-C6 alkoxy-alkyl" refers to alkoxy groups having a C1-C6 alkyl substituent, including methoxy, methoxyethyl and the like.

The term "alkoxycarbonyl" refers to the group -C (O) OR in which R includes H, "C1-C6 alkyl" or "aryl" or "heteroaryl"

or "aryl-C1-C6 alkyl" or "heteroaryl-C1-C6 alkyl" or "heteroalkyl".

The term "C1-C6 alkoxycarbonyl-alkyl" refers to C1-C6 alkyl groups having an alkoxycarbonyl substituent, including 2- (benzyloxycarbonyl) ethyl and the like.

The term "aminocarbonyl" refers to the group -C (O) NRR 'in which each R and R' independently includes hydrogen or C1-C6 alkyl or aryl or heteroaryl or "aryl-C1-C6 alkyl" or "heteroaryl-alkyl" C1-C6, including N-phenylformamide.

The term "aminocarbonyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having an aminocarbonyl substituent, including 2- (dimethylaminocarbonyl) ethyl, N-ethylacetamide, N, N-diethylacetamide and the like.

The term "acylamino" refers to the group -NRC (O) R 'in which each R and R' is independently hydrogen, "C1-C6 alkyl", C2-C6 alkenyl "," C2-C6 alkynyl "," cycloalkyl C3-C8 "," heterocycloalkyl "," aryl "," heteroaryl, "C1-C6 arylalkyl" or "heteroaryl-C1-C6 alkyl", "C2-C6 aryl-alkenyl", "C2-C6 heteroaryl-alkenyl", "Aryl-C2-C6 alkynyl", "heteroaryl-C2-C6 alkynyl", "cycloalkyl-C1-C6 alkyl" and "heterocycloalkyl-C1-C6 alkyl".

The term "acylamino-C1-C6 alkyl" refers to C1-C6 alkyl groups having an acylamino substituent, including 2- (propionylamino) ethyl and the like.

The term "ureido" refers to the group -NRC (O) NR'R '' in which each R, R 'and R' 'is independently hydrogen, "C1-C6 alkyl", C2-C6 alkenyl "," alkynyl C2-C6 "," C3-C8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6 arylalkyl "or" C1-C6 heteroaryl-alkyl "," C2-C6-aryl-alkenyl "," C2-C6 heteroaryl-alkenyl "," C2-C6-aryl-alkynyl "," C2-C6 heteroaryl-alkynyl "," C1-C6-cycloalkyl-alkyl "and" C1-C6-heterocycloalkyl-alkyl ", and wherein R ' and R '' together with the nitrogen atom to which they are attached can optionally form a 3- to 8-membered heterocycloalkyl ring.

The term "ureido-C1-C6 alkyl" refers to C1-C6 alkyl groups having a ureido substituent, including 2- (N'methylureido) ethyl and the like.

The term "carbamate" refers to the group -NRC (O) OR 'in which each R and R' is independently hydrogen, "C1-C6 alkyl", C2-C6 alkenyl "," C2-C6 alkynyl "," cycloalkyl C3-C8 "," heterocycloalkyl "," aryl "," heteroaryl, "C1-C6-aryl alkyl" or "heteroaryl-C1-C6 alkyl", "C2-C6 aryl-alkenyl", "C2-C6 heteroaryl-alkenyl "," Aryl-C2-C6 alkynyl "," heteroaryl-C2-C6 alkynyl "," cycloalkyl-C1-C6 alkyl "and" heterocycloalkyl-C1-C6 alkyl ".

The term "amino" refers to the group -NRR 'in which each R and R' is independently hydrogen or "C1-C6 alkyl" or "aryl" or "heteroaryl" or "C1-C6-alkyl-aryl" or "alkyl C1-C6-heteroaryl ”or“ cycloalkyl ”or“ heterocycloalkyl ”, and in which R and R 'together with the nitrogen atom to which they are attached can optionally form a 3- to 8-membered heterocycloalkyl ring.

The term "amino-C1-C6 alkyl" refers to C1-C6 alkyl groups having an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

The term "ammonium" refers to a positively charged group -N + RR'R '' in which each R, R 'and R' 'is independently "C1-C6 alkyl" or "C1-C6 alkyl-aryl" or "C1-C6 alkyl-heteroaryl" or "cycloalkyl" or "heterocycloalkyl" and wherein R and R 'together with the nitrogen atom to which they are attached can optionally form a 3- to 8-membered heterocycloalkyl ring.

The term "ammonium-C1-C6 alkyl" refers to C1-C6 alkyl groups having an ammonium substituent, including 1-ethylpyrrolidinium and the like.

The term "halogen" refers to the atoms of fluorine, chlorine, bromine and iodine.

The term "sulfonyloxy" refers to a group -OSO2-R in which R is selected from H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, for example a group -OSO2-CF3, " C2-C6 alkenyl "," C2-C6 alkynyl "," C3-C8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl, "aryl-C1-C6 alkyl" or "heteroaryl-C1-C6 alkyl", " C2-C6 aryl-alkenyl "," C2-C6 heteroaryl-alkenyl "," C2-C6-aryl-alkynyl "," C2-C6 heteroaryl-alkynyl "," C1-C6 cycloalkyl-alkyl "and" heterocycloalkyl-C1-alkyl C6 ".

The term "sulfonyloxy-C1-C6 alkyl" refers to C1-C6 alkyl groups having a sulfonyloxy substituent, including 2- (methylsulfonyloxy) ethyl and the like.

The term "sulfonyl" refers to the group -SO2-R in which R is selected from H, "aryl", "heteroaryl", "C1-C6 alkyl", "halogen-substituted C1-C6 alkyl", for example a group -SO2-CF3, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl," aryl-C1-C6 alkyl "or" heteroaryl- C1-C6 alkyl "," C2-C6 arylalkyl "," C2-C6 heteroaryl-alkenyl "," C2-C6-aryl-alkynyl "," C2-C6 heteroaryl-alkynyl "," "C-C6-alkyl-alkyl" and " heterocycloalkyl-C1-C6 alkyl ”.

The term "sulfonyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a sulfonyl substituent including 2 (methylsulfonyl) ethyl.

The term "sulfinyl" refers to a group -S (O) R in which R is selected from H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, for example a group -SO-CF3 , "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl," aryl-C1-C6 alkyl "or" heteroaryl-C1-C6 alkyl " , "C2-C6 aryl-alkenyl", "C2-C6 heteroaryl-alkenyl", "C2-C6-aryl-alkynyl", "C2-C6 heteroaryl-alkynyl", "cycloalkyl-C1-C6 alkyl" and "heterocycloalkyl-alkyl C1-C6 ”.

The term "sulfinyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a sulfinyl substituent, including 2 (methylsulfinyl) ethyl and the like.

The term "sulfanyl" refers to groups -SR in which R includes H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, for example a group -SO-CF3, "C2-C6 alkenyl" , "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl," aryl-C1-C6 alkyl "or" heteroaryl-C1-C6 alkyl "," C2-aryl-alkenyl C6 ”,

"C2-C6 heteroaryl-alkenyl", "C2-C6-aryl-alkynyl", "C2-C6-heteroaryl-alkynyl", "C 1-6 cycloalkyl-alkyl" and "C1-C6-heterocycloalkyl-alkyl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

The term "sulfanyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having a sulfanyl substituent, including 2 (ethylsulfanyl) ethyl and the like.

The term "sulfonylamino" refers to groups -NRSO2-R 'in which each R and R' includes hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3- cycloalkyl C8 "," heterocycloalkyl "," aryl "," heteroaryl, "aryl-C1-C6 alkyl" or "heteroaryl-C1-C6 alkyl", "C2-C6 aryl-alkenyl", "C2-C6 heteroaryl-alkenyl", "Aryl-C2-C6 alkynyl", "heteroaryl-C2-C6 alkynyl", "cycloalkyl-C1-C6 alkyl" and "heterocycloalkyl-C1-C6 alkyl".

The term "sulfonylamino-C1-C6 alkyl" refers to C1-C6 alkyl groups having a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl and the like.

The term "aminosulfonyl" refers to groups -SO2-NRR 'in which each R and R' includes hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3- cycloalkyl C8 "," heterocycloalkyl "," aryl "," heteroaryl, "aryl-C1-C6 alkyl" or "heteroaryl-C1-C6 alkyl", "C2-C6 aryl-alkenyl", "C2-C6 heteroaryl-alkenyl", "Aryl-C2-C6 alkynyl", "heteroaryl-C2-C6 alkynyl", "cycloalkyl-C1-C6 alkyl" and "heterocycloalkyl-C1-C6 alkyl".

The term "aminosulfonyl-C1-C6 alkyl" refers to C1-C6 alkyl groups having an aminosulfonyl substituent, including 2- (cyclohexylaminosulfonyl) ethyl and the like.

"Substituted or unsubstituted": unless otherwise indicated by the definition of the individual substituent, the groups mentioned above, such as the "alkenyl", "alkynyl", "aryl", "heteroaryl", "cycloalkyl" groups , "Heterocycloalkyl", etc. they may be optionally substituted with 1 to 5 substituents chosen from the group consisting of "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "cycloalkyl", "heterocycloalkyl", "C1-C6 arylalkyl "," Heteroaryl-C1-C6 alkyl "," cycloalkyl-C1-C6 alkyl "," heterocycloalkyl-C1-C6 alkyl "," amino "," ammonium "," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," aryl "," carbamate "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen "," carboxy ", trihalomethyl, cyano , hydroxy, mercapto, nitro and the like.

The term "pharmaceutically acceptable salts or complexes" refers to the salts or complexes of the compounds of formula (I) specified above. Examples of such salts include, but are not limited to, base addition salts formed by reacting the compounds of formula (I) with organic or inorganic bases such as hydroxide, carbonate or bicarbonate or a metal cation such as those chosen. between the group consisting of alkali metals (sodium, potassium or lithium), alkaline earth metals (for example, calcium or magnesium), or with a primary, secondary or tertiary organic alkylamine. It is contemplated that the amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-Me-D-glucamine, N, N'-bis (phenylmethyl) -1,2-ethanediamine, tromethamine, Ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine and the like are within the scope of the present invention.

Also included are salts that are formed from acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), as well as salts formed with organic acids , such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, naphthalendisulfonic acid and polygalacturonic acid, as well as salts formed with basic amino acids such as lysine or arginine.

The term "pharmaceutically active derivative" refers to any compound that, by administration to the recipient, is capable of directly or indirectly providing the activity described herein. The term "indirectly" also includes prodrugs that can be converted into the active form of the drug through endogenous enzymes or metabolism. Said prodrug comprises the active drug compound itself and a chemical masking group. For example, a chemical masking group for alcoholic derivatives could be chosen from an ester of the carboxylic acid (for example, acetate or lysine ester) or esters of phosphoric acid (for example, monoester of phosphoric acid).

The term "enantiomer excess" (ee) refers to products that are obtained by an asymmetric synthesis, that is, a synthesis that involves starting materials and / or non-racemic reagents or a synthesis that comprises at least one enantioselective stage, with which results in an excess of an enantiomer of the order of at least about 52% of ee.

By "interferon" or "IFN", as used herein, it is intended to include any molecule defined as such in the literature, for example comprising any type of IFN mentioned in the previous section "Background of the invention". In particular, IFN- !, IFN-∀ and IFN- # are included in the previous definition. IFN-∀ is the preferred IFN according to the present invention. Suitable IFN-según according to the present invention is commercially available, for example as Rebif® (Serono), Avonex® (Biogen) or Betaferon® (Schering).

The term "beta interferon (IFN-beta or IFN-∀)", as used herein, is intended to include fibroblastic interferon in particular of human origin, as obtained by isolation from biological fluids or as obtained by Recombinant DNA techniques from prokaryotic or eukaryotic host cells, as well as their salts, functional derivatives, variants, analogs and active fragments. Preferably, it is intended that IFNbeta means recombinant Interferon beta-1a.

Suitable IFN-según according to the present invention is commercially available, for example as Rebif® (Serono), Avonex® (Biogen) or Betaferón® (Schering). The use of interferons of human origin is also preferred according to the present invention. The term interferon as used herein is intended to include its salts, functional derivatives, variants, analogs and active fragments.

Rebif® (recombinant interferon ∀) is the latest development in interferon therapy for multiple sclerosis (abbreviated as MS herein by its initials in English: multiple sclerosis) and represents a significant advance in treatment. Rebif® is interferon (IFN) -beta 1a, produced from mammalian cell lines. It has been established that interferon beta 1a given subcutaneously three times per week is effective in the treatment of multiple sclerosis with relapses and remissions (RRMS). Interferon beta 1a can have a positive effect on the long-term course of MS by reducing the number and severity of relapses and reducing the severity of the disease and disease activity measured by MRI.

The dosage of IFN-∀ in the treatment of MS with relapses and remissions according to the invention depends on the type of IFN-∀ used.

According to the present invention, when the IFN is recombinant IFN-b 1b produced in E. Coli, commercially available under the trademark Betaserón®, it can preferably be administered subcutaneously every two days with a dose of about 250 to 300 mg or 8 MIU to 9.6 MIU per person.

According to the present invention, when the IFN is recombinant IFN-∀ 1a produced in Chinese hamster ovary cells (CHO cells), commercially available under the registered trademark Avonex®, it can preferably be administered intramuscularly once a week with a dose from about 30 ∃ to 33 ∃ or 6 MIU to 6.6 MIU per person.

According to the present invention, when the IFN is recombinant IFN-∀ 1a produced in Chinese hamster ovary cells (CHO cells), commercially available under the trademark Rebif®, it can preferably be administered subcutaneously three times per week with one dose. from 22 to 4 or 6 MIU to 12 MIU per person.

The compounds according to the present invention also comprise their pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of formula (I) are acid addition salts formed with pharmaceutically acceptable acids such as the salts of hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, becenosulfonate or p-toluenesulfonate.

It has been found that the compounds of the present invention are modulators of matrix metalloproteinases, including MMP-12. When the matrix metalloproteinase enzyme is inhibited by the compounds of the present invention, the inhibited MMP (s) is (are) unable to exert its enzymatic, biological and / or pharmacological effects.

The compounds of the present invention are therefore useful in the treatment of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer and malignancy, respiratory diseases, metabolic diseases, allergic and dermatological diseases, premature delivery. , endometriosis and fibrosis.

In one embodiment, the invention provides derivatives of formula (I):

A is chosen between –C (B) - and N;

B is H or B forms a bond with the carbon atom that supports either R5 or R7:

R1 is chosen from H; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted C3-C8 cycloalkyl, including cyclohexyl; optionally substituted heterocycloalkyl; optionally substituted aryl, including optionally substituted phenyl such as phenyl, halophenyl such as fluorophenyl (for example, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl), chlorophenyl (for example, 2-chlorophenyl, 4-chlorophenyl), chloro- 2-fluorophenyl and 2-fluoro-5-methoxyphenyl, cycloalkylphenyl (for example, 4-cyclohexylphenyl), alkylphenyl (for example, 4-propylphenyl, 4-tert-butylphenyl, 4-methylphenyl), alkoxyphenyl such as methoxyphenyl (for example, 4- methoxyphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4 (trifluoromethoxy) phenyl), butoxyphenyl (for example, 4-tert-butoxyphenyl), propoxyphenyl (for example, 4- isopropoxyphenyl, 3-fluoro-4-isopropoxyphenyl) and ethoxyphenyl (for example, 4-ethoxyphenyl, 4-propoxyphenyl (for example, 4-ethoxyphenyl, 4-propoxyphenyl 2,2,2-trifluoroethoxyphenyl), cyanophenyl-phenyl-phenyl, for example (for example, 4trifluoromethylphenyl), trifluoromethoxyphenyl (4-trifluoromethoxy) phenyl), sulf onylphenyl (for example, 4- (methylsulfonyl) phenyl, 4 (trifluoromethylsulfonyl)), aminophenyl (for example, 4- (dimethylamino) phenyl), biphenyl (for example 4-biphenyl, methoxyphenyl, 4-fluorobiphenyl-4-yl, 4 -methoxybiphenyl-4-yl, 4-bromobiphenyl-4-yl), oxazolylphenyl (for example, 1,3-oxazol5-yl) phenyl and benzofuranylphenyl (for example 1-benzofuran-3-yl) phenyl; optionally substituted heteroaryl, including optionally substituted pyridinyl, such as pyridinyl, methylpyridinyl (e.g., 4-methylpyridin-2-yl, 6-methylpyridin-2yl), halopyridinyl such as chloropyridinyl (e.g., 6-chloropyridin-2-yl, 5 -chloropyridin-2-yl, 3,5-dichloropyridin-4-yl) and bromopyridinyl (5-bromopyridin-2-yl), trifluoromethylpyridinyl (for example, 3- (trifluoromethyl) pyridin-2-yl, 4 (trifluoromethyl) pyridin -2-yl, 5- (trifluoromethyl) pyridin-2-yl), cyanopyridinyl (for example, 5-cyanpyridin-2-yl), phenylpyridinyl (for example 5-phenylpyridin-2-yl) and optionally substituted condensed pyridinyl (for example, 4- [6-methyl-2 (trifluoromethyl) quinoli-4-yl], 4-quinolin-3-yl, 4-quinolin-5-yl); including optionally substituted pyrazinyl (eg, 4-pyrazinyl-2-yl); including optionally substituted thiadiazoyl, such as 3-phenyl-thiadiazolyl (for example, 3-phenyl-1,2,4-thiadiazoyl-5-yl); including optionally substituted pyrimidinyl (eg, 4-pyrimidinyl-2-yl, 5fluoropyrimidin-2-yl); including optionally substituted oxadiazolyl, such as 5-phenyl-1,2,4-oxadiazol-3-yl, 4-pyridin-4-yl-1,2,4-oxadiazol-3-yl, 5- (2-thienyl) -1 , 2,4-oxadiazol-3-yl and 5- (4-fluorophenyl) -1,3,4-oxadiazol-3-yl; including optionally substituted benzofuranyl (for example 1-benzofuran-5-yl); including optionally substituted thienyl (for example, 5-chloro-2-thienyl) and including optionally substituted benzodioxolyl (for example, 1,3-benzodioxol-5yl, 2,2-difluoro-1,3-benzodioxol-5-yl); C3-C8 cycloalkyl-optionally substituted C1-C6 alkyl; optionally substituted C1-C6 heterocycloalkylalkyl, including 2-morpholin-4-ylethyl; optionally substituted heteroaryl-C1-C6 alkyl, including 2-thienylethyl; optionally substituted amino, including optionally substituted phenylamino (for example, phenylamino, 3-methoxyphenylamino, 3- (dimethylamino) phenylamino, 4-ethoxyphenylamino), heteroarylamino (for example, 4-trifluoromethyl) pyrimidin-3-yl, 3-aminopyridine-2 -yl) and optionally substituted alkoxy, including 4- (pyridin-2-yloxy), 4- (trifluoromethyl) phenoxy and 2-chlorophenoxy;

R2 is selected from H, optionally substituted C1-C6 alkyl including isopropyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; optionally substituted C3-C8 cycloalkyl including cyclopentyl; optionally substituted heterocycloalkyl; optionally substituted alkoxy such as phenylmethyloxy; optionally substituted aryl including optionally substituted phenyl such as phenyl, ethoxyphenyl or trifluoromethoxyphenyl; and optionally substituted heteroaryl;

R3 is selected from H, optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl; and optionally substituted C2-C6 alkynyl;

R4, R5, R6 and R7 are independently selected from H, optionally substituted C1-C6 alkyl including methyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl; or R4 and R7 can together form a bond -CH2- for example to form with the piperazine ring a 2,5-diazabicyclo [2.2.1] hept-2-yl ring;

n is an integer chosen from 1, 2, 3, 4, 5 and 6;

the carbon atoms (2) and (3) are two chiral centers, in which the chiral center (2) has a configuration chosen between "S" and "R" and where the chiral center (3) has a "S" configuration "

The "S" configuration of the chiral center (3) is such that the carbon atom that supports R2 is assumed to have lower priority among the carbon atoms in the chirality rule of Cahn-Ingold-Prelog (see Eliel et al., 1994, in "Stereochemistry of Organic Compounds", Wiley Interscience).

Other chiral centers may be present in the compounds according to formula (I) and the invention also aims to include optically active forms such as enantiomers, diastereomers and their racemate forms, as well as pharmaceutically acceptable salts of the compounds according to formula (I) , "S" being the configuration of the chiral center (3).

In a preferred embodiment, the invention provides derivatives of formula (I) having the following formula (Ia):

in which A is chosen between –CH and N; and R1, R2, R3, R4, R5, R6, R7 and n have been defined in the detailed description.

In another preferred embodiment, the invention provides derivatives of formula (I) having the following formula (Ib):

wherein A is a carbon atom and R1, R2, R3, R4, R6, R7 and n have been defined in the detailed description.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R 1 is selected from an optionally substituted aryl and an optionally substituted heteroaryl.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R2 is selected from 10 H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R2 is selected from optionally substituted C3-C8 cycloalkyl, including cyclopentyl, and optionally substituted heterocycloalkyl.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R2 is an alkoxy

Optionally substituted, such as phenylmethyloxy. In another preferred embodiment, the invention provides derivatives of formula (I) in which R2 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R2 is an aryl such as an optionally substituted phenyl. In another preferred embodiment, the invention provides derivatives of formula (I) in which R3 is H.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R4, R5 and R7 are H. In another preferred embodiment, the invention provides derivatives of formula (I) in which R6 is selected from H and an optionally substituted C1-C6 alkyl including methyl.

In a further embodiment, the invention provides derivatives of formula (I) in which R6 is H. In a further embodiment, the invention provides derivatives of formula (I) in which R6 is methyl. In another preferred embodiment, the invention provides derivatives of formula (I) in which R4 and R7 can

together form a bond -CH2- for example to form a 2,5-diazabicyclo [2.2.1] hept-2yl ring with the piperazine ring. In another preferred embodiment, the invention provides derivatives of formula (I) in which A is N.

In another preferred embodiment, the invention provides derivatives of formula (I) in which A is -CH.

In another preferred embodiment, the invention provides derivatives of formula (I) in which R 1 is selected from optionally substituted aryl, including optionally substituted phenyl such as phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, biphenyl , 4-chloro-2-fluorophenyl, 2-fluoro5-methoxyphenyl, alkylphenyl, methoxyphenyl, butoxyphenyl, propoxyphenyl, ethoxyphenyl, sulfonylphenyl, aminophenyl, oxazolylphenyl and benzofuraphenyl; an optionally substituted heteroaryl, including optionally substituted pyridinyl such as pyridinyl, methylpyridinyl, chloropyridinyl, trifluoromethylpyridinyl, cyanopyridinyl, phenylpyridinyl and optionally substituted condensed pyridinyl; including optionally substituted pyrazinyl; including optionally substituted thiadiazolyl such as 3-phenylthiadiazolyl; including optionally substituted pyrimidinyl; including optionally substituted oxadiazolyl; including optionally substituted quinolinolyl; including optionally substituted thienyl; including optionally substituted benzofuranyl; including optionally substituted benzodioxolyl;

 R2 is selected from H, optionally substituted C1-C6 alkyl including isopropyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl and optionally substituted alkoxy including phenylmethyloxy;

R3, R4, R5 and R7 are H; R6 is chosen from H and methyl; A is N; and n is an integer chosen from 1, 2, 3, 4, 5 and 6, preferably chosen from 1, 2 and 3.

In another embodiment, the invention provides derivatives of formula (I) in which R 1 is selected from optionally substituted aryl including optionally substituted phenyl such as phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, biphenyl and 4 -chloro-2-fluorophenyl, 2-fluoro5-methoxyphenyl, alkylphenyl, methoxyphenyl, butoxyphenyl, propoxyphenyl, ethoxyphenyl, sulfonylphenyl, aminophenyl, oxazolylphenyl and benzofuraphenyl; optionally substituted heteroaryl, including optionally substituted pyridinyl such as such as pyridinyl, methylpyridinyl, chloropyridinyl, trifluoromethylpyridinyl, cyanopyridinyl, phenylpyridinyl and optionally substituted condensed pyridinyl; including optionally substituted pyrazinyl; including optionally substituted thiadiazolyl such as 3-phenylthiadiazolyl; including optionally substituted pyrimidinyl; including optionally substituted oxadiazolyl; including optionally substituted quinolinolyl; including optionally substituted thienyl; including optionally substituted benzofuranyl; including optionally substituted benzodioxolyl;

R2 is selected from H, optionally substituted C1-C6 alkyl including isopropyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl and optionally substituted alkoxy including phenylmethyloxy;

R3, R4, R5 and R7 are H; R6 is chosen from H and methyl; A is -CH; and n is an integer chosen from 1, 2, 3, 4, 5 and 6, preferably chosen from 1, 2 and 3.

In another embodiment, the invention provides derivatives of formula (I) in which R 1 is selected from optionally substituted aryl including optionally substituted phenyl such as phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, biphenyl and 4 -chloro-2-fluorophenyl, 2-fluoro5-methoxyphenyl, alkylphenyl, methoxyphenyl, butoxyphenyl, propoxyphenyl, ethoxyphenyl, sulfonylphenyl, aminophenyl, oxazolylphenyl and benzofuraphenyl; optionally substituted heteroaryl, including optionally substituted pyridinyl such as such as pyridinyl, methylpyridinyl, chloropyridinyl, trifluoromethylpyridinyl, cyanopyridinyl, phenylpyridinyl and optionally substituted condensed pyridinyl; including optionally substituted pyrazinyl; including optionally substituted thiadiazolyl such as 3-phenylthiadiazolyl; including optionally substituted pyrimidinyl; including optionally substituted oxadiazolyl; including optionally substituted quinolinolyl; including optionally substituted thienyl; including optionally substituted benzofuranyl; including optionally substituted benzodioxolyl;

R2 is selected from H, optionally substituted C1-C6 alkyl including isopropyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl and optionally substituted alkoxy including phenylmethyloxy;

R3, R4, R5 and R7 are H; R6 is chosen from H and methyl; R4 and R7 can form a –CH2- link together; A is N; and n is an integer chosen from 1, 2, 3, 4, 5 and 6, preferably chosen from 1, 2 and 3.

In another embodiment, the invention provides derivatives of formula (Ib) wherein R1 is selected from optionally substituted aryl including optionally substituted phenyl such as phenyl, fluorophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, biphenyl and 4 -chloro-2-fluorophenyl, 2-fluoro5-methoxyphenyl, alkylphenyl, methoxyphenyl, butoxyphenyl, propoxyphenyl, ethoxyphenyl, sulfonylphenyl, aminophenyl, oxazolylphenyl and benzofuraphenyl; optionally substituted heteroaryl, including optionally substituted pyridinyl such as such as pyridinyl, methylpyridinyl, chloropyridinyl, trifluoromethylpyridinyl, cyanopyridinyl, phenylpyridinyl and optionally substituted condensed pyridinyl; including optionally substituted pyrazinyl; including optionally substituted thiadiazolyl such as 3-phenylthiadiazolyl; including optionally substituted pyrimidinyl; including optionally substituted oxadiazolyl; including optionally substituted quinolinolyl; including thienyl

optionally substituted; including optionally substituted benzofuranyl; including optionally substituted benzodioxolyl;

 R2 is selected from H and optionally substituted C1-C6 alkyl including isopropyl; optionally substituted C2-C6 alkenyl; optionally substituted C2-C6 alkynyl and optionally substituted alkoxy including phenylmethyloxy;

R3, R4 and R6 are H;

n is an integer chosen from 1, 2, 3, 4, 5 and 6, preferably chosen from 1, 2 and 3.

The compounds of the present invention include in particular those chosen from the following group:

-

hydroxy ((2S) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide;

-

{(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl) hydroxyformamide.

In another embodiment of the invention, N-hydroxyamide derivatives according to formula (I) are provided for use as a medicament.

In another embodiment of the invention, there is provided a pharmaceutical composition comprising at least one N-hydroxyamide derivative according to the invention and one of its pharmaceutically acceptable carriers, diluents or excipients.

In another embodiment of the invention, the use of N-hydroxyamide derivatives according to formula (I) is provided for the preparation of a medicament for prophylaxis and / or the treatment of a disorder chosen from autoimmune disorders, inflammatory diseases. , stroke, cardiovascular diseases, neurodegenerative diseases, cancer and malignancy, metabolic diseases, allergic and dermatological diseases, respiratory diseases and fibrosis, including multiple sclerosis, inflammatory bowel disease, arthritis, psoriasis, asthma, emphysema, premature delivery, endometriosis, lung disease chronic obstructive, liver and lung fibrosis, pancreas fibrosis, skin fibrosis and liver fibrosis.

In a further embodiment of the invention, the use of N-hydroxyamide derivatives according to formula (I) is provided for the preparation of a medicament for prophylaxis and / or the treatment of a disorder chosen from the inflammatory disease of intestine, multiple sclerosis, osteoarthritis and rheumatoid arthritis.

In a further embodiment of the invention, the use of N-hydroxyamide derivatives according to formula (I) is provided for the preparation of a medicament for prophylaxis and / or the treatment of a disorder chosen from asthma, emphysema and chronic obstructive pulmonary disease.

In a further embodiment of the invention, the use of N-hydroxyamide derivatives according to formula (I) is provided for the preparation of a medicament for prophylaxis and / or the treatment of a disorder chosen from pulmonary, pancreatic fibrosis. , of skin and liver.

In another embodiment, the compounds according to the invention are selective inhibitors of the metalloproteinases chosen from MMP-2, MMP-9 and / or MMP-12 over MMP-1.

In another embodiment, the invention provides a method for the treatment and / or prophylaxis of a disease comprising the administration of a compound according to formula (I) to a patient in need and in which the disease is chosen from autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, allergic and dermatological diseases, metabolic disorders, cancer and malignancy, respiratory diseases and fibrosis, including multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, asthma, emphysema, premature delivery, endometriosis , chronic obstructive pulmonary disease (COPD), liver fibrosis, psoriasis, skin and lung fibrosis.

In another embodiment, the invention provides a process for the preparation of a Nhydroxyamide derivative according to formula (I), which comprises the step of reacting a compound of formula (II) with a formulating agent (FA) ):

wherein R1, R2, R3, R4, R5, R6, R7 and n have been defined above, PG1 is H or a protecting group such as benzyl, t-butyl, THP, TMS or TBS, and LG1 is such a leaving group as –OH, -OAc, -OPiv, -OCH2CN, -OCH2CF3, -OPh and –OPfp.

In a further embodiment, the invention provides a compound according to formula (II) chosen from the following group:

-

(2S) -N- (benzyloxy) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentan-1-amine;

-

(2S) -N- (benzyloxy) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentan-1-amine.

The compounds of the invention have been named according to the standards used in the "ACD / Name" program of Advanced Chemistry Development Inc., ACD / Labs (version 7.00).

The compounds of the formula (I) are useful in the treatment and / or prophylaxis of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, stroke, cancer and malignancy, allergic and dermatological diseases, metabolic disorders, respiratory diseases, premature delivery , endometriosis and fibrosis, including multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, emphysema, chronic obstructive pulmonary disease, psoriasis and liver and lung fibrosis.

In another embodiment, the compounds of the invention can be used in the treatment of autoimmune diseases, especially demyelinating diseases such as multiple sclerosis, alone or in combination with a co-agent useful in the treatment of autoimmune diseases, where the co -agent is chosen, for example, from the following compounds:

a) interferons, for example pegylated or non-pegylated interferons, for example administered subcutaneously, intramuscularly or orally, preferably beta interferon;

b) glatiramer, for example in the form of acetate;

c) immunosuppressants with antiproliferative / antineoplastic activity, for example mitoxantrone, methotrexate, azathioprine, cyclophosphamide or steroids, for example methylprednisolone, prednisone or dexamethasone, or steroid secreting agents, for example ACTH;

d) adenosine deaminase inhibitors, for example Cladribine;

e) VCAM-1 expression inhibitors or ligand antagonists, for example antagonists of! 4 / integr1 integrin VLA-4 and / or alpha-4-beta-7 integrins, for example natalizumab (ANTEGREN).

Additional co-agents such as anti-inflammatory agents (in particular for demyelinating diseases such as multiple sclerosis) are described below:

An additional anti-inflammatory agent is Teriflunomide which is described in WO 02/080897.

Still another additional anti-inflammatory agent is Fingolimod which is described in EP-0627406 and WO 2004/028521.

Still another additional anti-inflammatory agent is Laquinimod which is described in WO 99/55678.

Still another additional anti-inflammatory agent is Tensirolimus which is described in WO 02/28866.

Still another additional anti-inflammatory agent is Xaliprodene which is described in WO 99/48802.

Still another additional anti-inflammatory agent is Deskar Pirfenidone which is described in WO 03/068230.

Still another additional anti-inflammatory agent is the following benzothiazole derivative which is described in WO 01/47920.

Still another additional anti-inflammatory agent is the following hydroxamic acid derivative which is described in WO 03/070711.

Still another additional anti-inflammatory agent is MLN3897 which is described in WO 2004/043965.

Still another additional anti-inflammatory agent is CDP323 which is described in WO 99/67230.

Still another additional anti-inflammatory agent is Simvastatin which is described in WO 01/45698.

Still another additional anti-inflammatory agent is Fampridine which is described in US 5,540,938.

The compounds according to the present invention also comprise their tautomers, their geometric isomers, their optically active forms such as enantiomers, diastereomers and their racemic forms, as well as their pharmaceutically acceptable salts.

The derivative examples of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that when experimental conditions (ie, temperatures and reaction times, moles of reagents, solvents, etc.) are typical or preferred, other experimental conditions can also be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures.

When employed as pharmaceutical compounds, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising a compound of the invention and a vehicle, diluent or excipient are, therefore, also within the scope of the present invention. Those skilled in the art know a complete variety of said carrier compounds, diluents or excipients suitable for formulating a pharmaceutical composition.

The compounds of the invention, together with a co-adjuvant, vehicle, diluent or excipient used can be arranged in the form of pharmaceutical compositions and their dosage units, and in such form they can be used as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs or capsules filled with them, all for oral use, or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Said pharmaceutical compositions and their dosage unit forms may comprise ingredients in conventional proportions, with or without conventional active compounds or principles, and said dosage unit forms may contain any suitable effective amount of the active ingredient in accordance with the expected daily dosage range. It must be used.

Pharmaceutical compositions containing a compound of this invention can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound administered in particular will generally be determined by the physician in the light of important circumstances, including the condition to be treated, the route of administration chosen, the particular compound administered, the age, weight and response of the individual patient. , the severity of the patient's symptoms and the like.

The pharmaceutical compositions of the present invention can be administered by several routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Compositions for oral administration may have the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "dosage unit forms" refers to physically discrete units suitable for unit doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, associated with a suitable pharmaceutical excipient. . Dosage unit forms include ampoules or syringes measured and prefilled with liquid compositions or tablets, tablets, capsules or the like in the case of solid compositions. In said compositions, the derivative of the invention is generally a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) the remainder being several vehicles or carriers and useful processing aids to form the desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffer solutions, suspending and dispensing agents, colorants, flavorings and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a sliding agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

Injectable compositions are generally based on a sterile injectable saline solution or a phosphate buffered saline solution or other injectable vehicles known in the art. As mentioned above, the N-hydroxyamide derivatives of formula (I) in said compositions are generally a minor component, frequently varying between 0.05 to 10% by weight, the rest being the injectable vehicle and the like.

The components described above for injectable or orally administered compositions are simply representative. Additional materials as well as processing techniques and the like are

described in Part 5 of Remington’s Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of this invention can also be administered in prolonged release forms or from prolonged drug distribution systems. A description of representative extended release materials can also be found in the materials incorporated in Remington’s Pharmaceutical Sciences.

Synthesis of the compounds of the invention:

The new derivatives according to formula (I) can be prepared from readily available starting materials by various synthetic approaches, using chemical protocols both in solution and in solid phase. Examples of synthetic pathways for these derivatives will be described.

The following abbreviations refer respectively to the following definitions:

Aq (aqueous), atm (atmosphere), Boc (tert-butoxycarbonyl), Bn (benzyl), h (hour), g (gram), L (liter), mg (milligram), MHz (megahertz), min (minute ), mm (mm), mmol (millimol), mM (millimolar), mp (melting point), eq. (equivalent), mL (milliliter), L (microliter), Ac (acetyl), ACN (acetonitrile), Bu (butyl), c-Hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), ESI (electrospray ionization), HATU (dimethylamino hexafluorophosphate - ([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) -methylene] dimethylammonium), HPLC (high performance liquid chromatography), iPr (isopropyl), LC (liquid chromatography), Me (methyl), MS (mass spectrometry), NMM (N-methyl morpholine), NMR (nuclear magnetic resonance), Pfp (pentafluorophenyl ), PyBOP® (benzotriazol-1-yloxy-tris-pyrrolidine-phosphonium hexafluorophosphate), ta (room temperature), Rt (retention time), TBS (tert-butyl dimethylsilyl), TBTU (2- (1 H -benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate), TEA (triethylamine ), THF (tetrahydrofuran), THP (tetrahydropyranyl), TMS (trimethylsilyl), TLC (thin layer chromatography), UV (ultraviolet), Z (benzyloxycarbonyl).

Synthesis Approaches:

Generally, the compounds of formula (I) can be obtained by formulating a compound of formula (II) in which R1, R2, R3, R4, R5, R6, R7 and n are as defined above, PG1 is H or a protecting group such as benzyl, t-butyl, THP, TMS or TBS with a formylating agent of formula (FA) (scheme 1 below). If PG1 is not H, the formulation stage should be followed or preceded by a known deprotection stage.

The general protocols for such formylation are given below in the examples. The use of formylating agents (FA) is well known to those skilled in the art, where LG1 is a leaving group such as -OH, -OAc, -OPiv, -OCH2CN, -OCH2CF3, -OPh and -Opfp. For example, a formylating agent can be obtained by reaction between formic acid and acetic anhydride.

Scheme 1

A preferred synthesis approach for the preparation of a compound of formula (II) is the coupling of a carboxylic acid of formula (IV) with an amine of formula (V) in which R2, R3, PG1 and n are as has been defined above and PG2 is H or a protecting group such as Boc, Z or Bn (scheme 2 below), in the following examples several protocols are given for said coupling, using conditions and methods well known to those skilled in the art to prepare a Amide bonding from an amine and a carboxylic acid or carboxylic acid derivative (for example, acid chloride), with or without standard coupling agents such as, for example, DIC, EDC, TBTU, DCC, HATU, PyBOP® , isobutyl chloroformate, 1-methyl-2-chloropyridinium iodide (Mukaiyama reagent) or others in the presence or absence of bases such as TEA, DIEA or NMM, in a suitable solvent such

such as DCM, THF or DMF. When PG2 is not H, the coupling stage should be followed or preceded by a known deprotection stage (scheme 2 below).

Scheme 2

The compounds of formula (IV) in which R2, R3, PG1, PG2 and n are as defined above can be prepared by hydrolysis of a compound of formula (VI) in which G is a chiral auxiliary such as chiral oxazolidinones from Evans. Preferred conditions involve the use of lithium hydroxide in the presence of hydrogen peroxide in a solvent such as THF (scheme 3 below).

Scheme 3

The compounds of formula (VI) can be prepared by diastereoselective addition of hydroxylamine or a hydroxylamino derivative (VIII) in which PG1 is H or a protecting group such as benzyl, t-butyl, THP, TMS or TBS and PG2 is H or a protecting group such as Boc, Z or Bn.

The compounds of formula (VII) can be obtained by coupling the carboxylic acid of formula (IX) in which

R2, R3 and n are as defined above with the chiral auxiliary (GH) according to conditions well known to those skilled in the art (scheme 4 below). The compound of formula (IX) can be obtained following the protocols described in the literature (for example, WO 02/102790).

Scheme 4

The compounds of formula (I) and their precursors of formulas (II), (III), (IV), (V) and (VI) contain at least one chiral center (3S), and all individual forms and optically combinations active agents of these are described in the invention, as well as their corresponding racemates.

The procedures outlined in the above schemes, in particular in schemes 1, 2 and 3, provide the compounds of formula (I) and their precursors of formula (II), (III), (IV) and (VI) as pure stereoisomers , or in racemic form or as mixtures of diastereoisomers. In the latter case, pure stereoisomers can be obtained from mixtures of stereoisomers using procedures well known to those skilled in the art.

technique, including, for example, the separation of enantiomers by chiral HPLC or recrystallization and / or chromatography of the mixture of diastereoisomers.

For example, an alternative preparation for the compound of formula (IV) in which R2, R3 and PG1, PG2 and n are as defined above, may be the enantiomeric or diastereomeric separation of a mixture of compounds of formula (IVa), obtained by Michael's addition of hydroxylamine derivatives (VIII) to the unsaturated ester of formula (VIIa) in which R2, R3, PG1, PG2 and n are as defined above and R8 is H or a C1-C6 alkyl group such as methyl or ethyl (scheme 5 below).

Scheme 5

According to a further general procedure, the compounds of the formula (I) can be converted into alternative compounds of the formula (I) using suitable interconversion techniques well known to those skilled in the art.

If the above series of general synthesis methods is not applicable to obtain compounds according to formula (I) and / or the intermediates necessary for the synthesis of the compounds of formula (I), suitable preparation methods known to those skilled in the art should be used in the technique

In general, the synthetic pathways for any individual compound of formula (I) will depend on the specific substituents of each molecule and the easy availability of the necessary intermediates; again, said factors will be appreciated by those skilled in the art. For all protection and deprotection methods, see Philip

J. Kocienski in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York 1994 and Theodora W. Greene and Peter GM Wits in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition, 1999. Those skilled in the art will recognize that Some reactions are best performed when the reactive functional group of the molecule is masked or protected, thus avoiding side reactions and / or increasing the yield of the reaction. Examples of protecting groups can be found in Philip J. Kocienski 1994, cited above, and in Greene et al. 1999, cited above. The need and choice of the protecting groups for a particular reaction are known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy, amino, carboxy, etc.), the structure and stability of the molecule of which the substituent or reaction conditions are part.

The compounds of this invention can be isolated associated with solvent molecules by crystallization by evaporation of an appropriate solvent. Pharmaceutically acceptable acid addition salts of the compounds of formula (I), which contain a basic center, can be prepared in a conventional manner. For example, a solution of the free base can be treated with a suitable acid, either pure or in a suitable solution, and the resulting salt can be isolated either by filtration or by evaporation under vacuum of the reaction solvent. The pharmaceutically acceptable base addition salts can be obtained analogously by treating a solution of the compound of formula (I) with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.

In the following part the present invention is illustrated by means of some examples, which are not intended to be considered as limiting the scope of the invention.

The following commercially available reagents were used:

Isobutylmalonic acid (prepared as described in Kortylewicz et al., 1990, J. Med. Chem. 33, 263-273), diterc-butyl bicarbonate (from Aldrich), 1-biphenyl-4-ylpiperazine (from Apollo), 1- (4-methoxyphenyl) -piperazine (from Chess), HATU (from Aldrich).

Intermediate A: (2S) -2 - {[(benzyloxy) (tert-butoxycarbonyl) amino] methyl} -4-methyl-pentanoic acid

Stage a) Formation of the ((2S) -2 - {[(4R) -4-benzyl-2-oxo-1,3-oxazolidin-3-yl] carbonyl} -4-methylpentyl) (benzyloxy) tert-carbamate butyl

10 To a solution of 4-benzyl-3- [2- (benzyloxyamino-methyl) -4-methyl-pentanoyl] -oxazolidin-2-one (1.0 g; 2.44 mmol; 1.0 eq. Prepared according to WO 02/102790 but starting from isobutylmalonic acid) and diterc-butyl bicarbonate (585 mg; 2.7 mmol; 1.1 eq.) in DCM (10 mL), triethylamine (416 ∃L; 2, 9 mmol; 1.2 eq.) And the reaction mixture was stirred overnight at room temperature. DMAP (0.1 eq.) And then di-tert-butyl bicarbonate (200 mg) were added and the mixture was stirred at room temperature overnight. Added one

Aqueous HCl solution (1N) and the reaction mixture was extracted with EtOAc (3x). The combined organic phases were dried over MgSO4, filtered and evaporated to give a colorless oil. Purification by column chromatography (Silicagel, 13% EtOAc in c-Hex) gave the title product as a colorless oil (920 mg, 74%). HPLC, Rt: 5.33 min (purity: 88.9%).

Stage b) Formation of ((2S) -2 - {[(benzyloxy) (tert-butoxycarbonyl) amino] methyl} -4-methylpentanoic acid

A solution of ((2S) -2 - {[(4R) -4-benzyl-2-oxo-1,3-oxazolidin-3-yl] carbonyl} -4-methylpentyl) (benzyloxy) carbamate of was stirred overnight tert-butyl (1.66 g; 3.25 mmol), LiOH (156 mg, 6.5 mmol, 2 eq.) and an aqueous solution of H2O2 (30%, 1.33 mL, 4 eq.). A saturated solution of Na2SO3 was added at 0 ° C. The mixture was extracted with a saturated NaHCO3 solution, washed with DCM (3x). The aqueous phase was saturated with NaCl, acidified to pH 2 with an aqueous solution of HCl (5N), then extracted with DCM (2x), EtOAc (2x) and

25 Et2O (2x). The combined organic phases were dried over MgSO4, filtered and evaporated in vacuo to give 300 mg of the title product as a colorless oil used as such in the next step. M- (LC-MS (ESI)): 350.3.

Example 1: hydroxy (2S) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide (1)

Step a) Formation of (benzyloxy) ((2S) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) tert-butyl carbamate

To a cold solution (0 ° C) of (2S) -2 - {[(benzyloxy) (tert-butoxycarbonyl) amino] methyl} -4-methylpentanoic acid (Intermediate A, 120 mg; 0.34 mmol; 1.0 eq. ) and DIEA (115 mg, 0.9 mmol, 2.1 eq.) in DMF (3 mL) was added once HATU (124 mg, 0.47 mmol, 1.1 eq.). The resulting solution was stirred for 2 minutes at 0 ° C and then 1- (4-methoxyphenyl) -piperazine (72 mg; 0.38 mmol; 1.1 eq.) Was added. The resulting mixture was stirred overnight at room temperature. Et2O was added and the mixture was washed with water (3x), dried over MgSO4, filtered and evaporated to give the title compound as an oil. Purification by column chromatography (Silicagel, gradient of 25% EtOAc to 33% EtOAc in c-Hex) gave the title product as a

10 colorless oil (110 mg, 61%). HPLC, Rt: 4.04 min (purity: 100%). M + (LC-MS (ESI)): 526.3.

Stage b) Formation of (2S) -N- (benzyloxy) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentan-1-amine

A solution of (benzyloxy) ((2S) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) tert-butyl carbamate (134 mg; 0.25) was stirred at room temperature mmol; 1.0 eq.) and 4M HCl in dioxane (0.938 mL, 15 15 eq.) in DCM (1 mL). The solvents were evaporated to give the title product as a yellow oil (130 mg, 100%). M + (LC-MS (ESI): 426.4.

Stage c) Formation of the N- (benzyloxy) -N - ((2S) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide

To a solution of (2S) -N- (benzyloxy) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentan-1-amine (122 mg; 0.29

20 mmol; 1.0 eq.) And triethylamine (123 ∃L; 0.86 mmol; 3.0 eq.) In THF (2 mL) was added formic acetic anhydride (63 mg; 0.72 mmol; 2.5 eq. ; prepared as described in Krimen et al. in Organic Syntheses Coll. Vol. 6. p. 8). The solution was stirred for 4.5 h at room temperature. The solvents were evaporated and the residue was purified by column chromatography (Silicagel, 1/1 EtOAc / c-Hex) to give the title product as a colorless oil (105 mg, 81%). HPLC, Rt: 3.17 min (purity: 100%). M + (LC-MS (ESI)): 454.4.

Step d) Formation of N-hydroxy-N - ((2S) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide

A solution of N- (benzyloxy) -N - ((2S) -2 - {[4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide (100 mg; 0.22 mmol) was hydrogenated to a pressure of 1 atm of hydrogen in the presence of Pd / C (10%; 23 mg; 0.02 mmol; 0.1 eq.) for 2 h at room temperature. The mixture was filtered on a bed of celite, evaporated to give the title product as an orange foam (60 mg; 75%). HPLC, Rt: 1.95 min (purity: 100%). M + (LC-MS (ESI)):

30 364.4.

Example 2: {(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} hydroxyformamide (2)

Stage a) Formation of (benzyloxy) {(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} tert-butyl carbamate

The title product was obtained following the protocol of Example 1 (step a), but initially using Intermediate I (300 mg; 0.85 mmol) and 1-biphenyl-4-ylpiperazine (357 mg; 0.94 mmol; 1 , 1 eq.). Purification by column chromatography (Silicagel, 33% gradient of EtOAc to 50% EtOAc in c-Hex) gave the title product as a colorless oil (240 mg, 49%). HPLC, Rt: 5.33 min (purity: 100%). M + (LC-MS (ESI)): 527.1.

Stage b) Formation of (2S) -N- (benzyloxy) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentan-1-amine

The title product was obtained following the protocol of example 1 (step b) but using (benzyloxy) {(2S) -2 - [(4biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} carbamate tert-butyl (232 mg; 0.41 mmol; 1.0 eq.) as a brown solid (219 mg; 99%). HPLC, Rt: 4.19 min (purity: 93.6%). M + (LC-MS (ESI)): 472.4.

Stage c) Formation of N- (benzyloxy) -N - {(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl) formamide

The title product was obtained following the protocol of example 1 (step c) but from (benzyloxy) {(2S) -2 - [(4biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} carbamate of tert-butyl (219 mg; 0.46 mmol) and a preformed mixture of formic acid (875 ;L; 23.2 mmol; 50 eq.) and acetic anhydride (220 ∃L; 2.32 mmol; 5.0 eq.) (mixture formed at 0 ° C for 30 min). By purification by column chromatography (Silicagel, 33% gradient

20 EtOAc up to 50% EtOAc in c-Hex) the title product was obtained as a white solid (120 mg; 52%). %). HPLC, Rt: 4.60 min (purity: 99.7%). M + (LC-MS (ESI)): 500.4.

Stage d) Formation of N - {(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} -N-hydroxyformamide

The title product was obtained following the protocol of example 1 (step d) but from N- (benzyloxy) -N - {(2S) 2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl) formamide (110 mg; 0.22; 1.0 eq.) As a white powder (62 mg; 78%). HPLC, Rt: 3.57 min (purity: 88.2%). M + (LC-MS (ESI)): 408.3.

Biological analysis

The compounds of the present invention can be subjected to the following analyzes:

Example 3: Enzyme Inhibition Analysis

The activity of the compounds of the invention as inhibitors of MMP-1, MMP-2, MMP-9, MMP-14 and MMP-12 was analyzed.

MMP-9 analysis protocol

The inhibitory activity of the compounds of the invention against 92 kDa gelatinase (MMP-9) was analyzed in an analysis using a coumarin-labeled peptide substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly -Leu- (3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (McaPLGLDpaAR) (Knight et al., FEBS Lett. 1992, 263-266).

Stock solutions were made as follows: Test medium: 100mM Tris-HCl, pH 7.6, containing 100mM NaCl, 10mM CaCl2 and 0.05% Brij 35.

Substrate: McaPLGLDpaAR 0.4mM (from Bachem) (0.437mg / mL) stock solution in 100% DMSO (stored at -20ºC). Diluted up to 8∃M in the test medium.

Enzyme: 92 kDa recombinant human gelatinase (MMP-9; APMA (4-aminophenyl-mercuric acetate) activated if necessary) properly diluted in the test medium.

The test compounds were initially prepared as a 10mM solution of the compound in 100% DMSO, diluted to 1mM in 100% DMSO and then serially diluted 3 times in 100% DMSO on columns 1-10 of a plate of 96-well microtiter with concentration range of 100∃M (column 1) to 5.1nM (column 10).

The assay was performed in a total volume of 100 µL per well in 96-well microtiter plates. Activated enzyme (20 µL) was added to the wells followed by 20 µL of the assay medium. The appropriate concentrations of the test compounds dissolved in 10 ∃L of DMSO were then added, followed by 50 ∃L of McaPLGLDpaAR (8∃M, prepared by dilution of the mother DMSO in the test medium). For each analysis, ten concentrations were examined in duplicate. In the control wells there was neither enzyme nor test compound. The reaction media were incubated at 37 ° C for 2 hours. Fluorescence was measured at 405 nm immediately with an SLT Fluostar fluorometer (SL T Labinstruments GMBH, Grödig, Austria) using an excitation at 320 nm without stopping the reaction.

The effect of the test compound was determined from the dose-response curve generated from the 10 concentrations in duplicate of the inhibitor. The IC50 (concentration of the compound necessary to obtain a 50% decrease in enzyme activity) was obtained by adjusting the data to the equation:

Y = a + ((b-a) / (1 + (c / X) d))

(Y = inhibition obtained for a particular dose; X = dose in nM; a = and minimum or 0% inhibition; c = IC50; d = pending).

MMP-12 analysis protocol

The inhibitory activity of the compounds of the invention against metalloelastase (MMP-12) was analyzed in an analysis using a coumarin-labeled peptide substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (McaPLGLDpaAR) (Knight et al. 1992, cited above). The protocol of this analysis was as described for the previous MMP-9 analysis.

MMP-1 analysis protocol

The inhibitory activity of the compounds of the invention against collagenase (MMP-1) was analyzed in an analysis using a coumarin-labeled peptide substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2,4-dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (Mca PLGLDpaAR) (Knight et al. 1992, cited above). The protocol of this analysis was as described for the previous MMP-9 analysis.

MMP-14 analysis protocol

The inhibitory activity of the compounds of the invention against MMP-14 was analyzed in an analysis using a coumarin-labeled peptide substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu- (3- [2,4-Dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (Mca PLGLD paAR) (Knight et al. 1992, cited above). The protocol of this analysis was as described for the previous MMP-9 analysis.

MMP-2 analysis protocol

The inhibitory activity of the compounds of the invention against gelatinase A (MMP-2) was analyzed in an analysis using a coumarin-labeled peptide substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu - (3- [2,4-Dinitrophenyl] -L-2,3-diaminopropionyl) -Ala-Arg-NH2 (Mca PLGLDpaAR) (Knight et al. 1992, cited above). The protocol of this analysis was as described for the previous MMP-9 analysis.

The results are expressed as IC50 (the concentration of the compound necessary to obtain a 50% decrease in enzyme activity) and are shown in Table 1 below.

Table 1: IC50 for different MMPs

Example

MMP-1 MMP-2 MMP-12

IC50 (nM)

IC50 (nM)

IC50 (nM)

Example 1

> 5000 13 68

Example 2

> 5000 9 8

Example 4: IL-2 induced peritoneal lymphocyte incorporation

The administration of IL-2 intraperitoneally causes the migration of lymphocytes into the intraperitoneal cavity. This is a model for cell migration that occurs during inflammation.

Protocol

CH3 / HEN mice (Elevage Janvier, France) were injected intraperitoneally with IL-2 (20 µg / kg, in saline solution).

The compounds of the invention were suspended in 0.5% carboxymethyl cellulose (CMC) / 0.25% Tween-20 and administered s.c. or p.o. (10 mL / kg) 15 minutes before the administration of IL-2.

Twenty-four hours after the administration of IL-2, the peritoneal white blood cells were collected by 3 successive washes of the peritoneal cavity with 5 mL of phosphate buffered saline (PBS) - 1mM EDTA (+ 4 ° C). The suspension was centrifuged (1700 g x 10 min at + 4 ° C). The resulting precipitate was suspended in 1 mL of 1mM PBS-EDTA.

Experimental design

The animals were divided into 6 groups (6 mice in each group): -Group 1: (baseline) received 0.5% CMC / 0.25% Tween-20 (vehicle for the compound of the

invention) and saline solution (vehicle for IL-2). -Group 2: (IL-2 control) received 0.5% CMC / 0.25% Tween-20 and IL-2 injection. -Group 3: Experimental group (dose 1 of the compound of the invention) received a compound of the invention

and the injection of IL-2. -Group 4: Experimental group (dose 2 of the compound of the invention) received a compound of the invention and the injection of IL-2. -Group 5: Experimental group (dose 3 of the compound of the invention) received a compound of the invention and the injection of IL-2. -Group 6: Reference group, received the dexamethasone reference compound and the injection of IL-2.

Calculations

Inhibition of lymphocyte incorporation was calculated as follows:

1% (Linf X% Linf1)

% inhibition & x 100%

(Linf 2% Linf1)

where Linf 1 = number of lymphocytes in group 1 (E3 / ∃L), Linf 2 = number of lymphocytes in group 2 (E3 / ∃L), Linf X = number of lymphocytes in group X (E3 / ∃L ).

The results for the compounds according to formula (I) are shown in the following table 2:

Table 2: Percent inhibition of peritoneal lymphocyte incorporation induced by IL-2 by the compounds of the invention.

Example

Dose (mg / kg) Via % inhibition

Example 1

3 p.o. 35 ± 10

Example 5: CCl4-induced liver fibrosis model

Carbon tetrachloride (CCl4) induces fibrosis in the liver when administered intraperitoneally (Bulbena O., Culat J., Bravo M. L., Inflammation 1997 Oct .; 21 (5): 475-488). The ability of the compounds of the invention to prevent the formation of fibrotic tissue induced by CCl4 can be evaluated.

Animals

Male Sprague-Dawley rats, 7 weeks old and weighing approximately 300 g, from Charles River / Iffa-Crédo. St. Germain / l’Arbresle, France.

The rats were acclimatized for 5 days before starting the experiments in air-conditioned rooms, 2 animals in each cage, temperature: 22ºC ± 2, relative humidity: 55% ± 10, light: 12-hour cycle (7 am - 7 pm ), cage: Makrolon®, cage 42.5 x 26.6 x 15 each provided with a food distributor coated with stainless steel.

The study included the following groups of 8 animals each, as indicated below:

-

Group 1: “white” animals received the CCl4 vehicle (i.p.) and once a day the vehicle of the test substance (s.c.).

-

Group 2: the positive control group received CCl4 (i.p.) and once a day the vehicle of the test substance (s.c.).

-

Group 3: experimental group that received CCl4 (i.p.) and once daily 2 mg / kg s.c. of the compound according to the invention.

-

Group 4: experimental group that received CCl4 (i.p.) and once daily 10 mg / kg s.c. of the compound according to the invention.

-

Group 5: experimental group that received CCl4 (i.p.) and once daily 20 mg / kg s.c. of the compound according to the invention.

The rats were labeled in the tail. Labels were checked and renewed, if necessary, after each injection of CCl4.

Process

CCl4 (Prolabo) was administered in olive oil every 3 days for three weeks by intraperitoneal injection (0.25 mL of CCl4 / kg body weight, diluted in oil at 1: 1 vol: vol for a total volume of 0.5 mL / kg) The animals were weighed daily. If the body weight decreased by more than 10% of the initial weight, the animal was excluded from the experiment.

The vehicles and compounds used were the following:

-

CCl4 was administered in olive oil (Prolabo) with a dilution of 1: 1;

-

The compound of the invention was suspended in 0.25% Tween-80 and 0.25% carboxymethyl cellulose in sterile solution with 0.9% NaCl. The solution was maintained at 4 ° C during the experiment and was used every day to prepare the suspensions.

The compound of the invention was administered daily by subcutaneous injection (s.c.) with an administration volume of 5 mL / kg. Groups 1 and 2 were dosed with 5 mL / kg of vehicle. Recently prepared solutions were used each day of the experiment. The administrations were made every day at the same time.

The treatment of the groups in this study was initiated for each animal at the time of the first administration of CCl4 and continued for 21 consecutive days. The last administration of the test substances or the vehicle was carried out 1 day before the animals were slaughtered.

Results

Death, date and alleged cause are reported.

Serum Enzyme Levels

Animals were sacrificed 21 days after the first administration of CCl4 by inhalation of isofuran. Blood was drawn individually at the time of sacrifice, that is, one day after the last administration of the test substance or vehicle. The blood was centrifuged at 4 ° C. Plasma was collected carefully and divided into 3 fractions. Plasma levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were measured in order to assess liver necrosis. Elevated levels of serum ASAT and ALAT are associated with liver impairment. The average levels of ASAT and ALAT are given in control animals and in those treated with the compounds of the invention at three different doses.

Histological evaluation of liver fibrosis

Liver fibrosis is evaluated by measuring the area of fibrosis in the liver using microcotomy. The results are given as a percentage of the area that was fibrotic.

The liver was removed, the three lobes were dissected and samples were extracted that were either fixed with 10% formaldehyde or frozen at -80 ° C.

The liver sections were submerged in paraffin blocks. Sectioning and staining with Sirius red was performed. The quantification of fibrosis in the liver was performed in a minimum of 3 sections taken from different places in the liver. Quantitative analysis was performed using an image analyzer (Imstar) and the Morphostar program.

The average percentages of area with fibrosis in the livers of the animals of the different groups were calculated.

Example 6: Chronic Obstructive Pulmonary Disease Model (COPD)

The ability of the compounds of the invention to prevent COPD induced by cigarette smoking can be evaluated.

Female AJ mice (Harlan, 17-25 g) were exposed to cigarette smoke (HC) for 11 consecutive days in groups of 5, in individual clean chambers. The animals were weighed before treatment, on the 6th day of exposure and on the 12th day. The HC was generated using 1R1 cigarettes obtained from the Institute of Tobacco Research, University of Kentucky, United States and allowed to be introduced into the chambers with a flow rate of 100 mL / min.

In order to minimize any potential problems caused by repeated exposure to a high level of daily HC, the exposure of mice to HC was gradually increased over time, to a maximum of 6 cigarettes from the 5th day to the 11th day ( approximately 48 minutes of exposure).

A white group of mice was also exposed to the air daily for an equivalent duration of time as controls (without exposure to HC).

Treatment

The compounds of the invention were prepared in 0.5% carboxymethylcellulose sodium salt (CMC, Sigma reference C4888) as a vehicle.

The animals were orally dosed twice daily by forced feeding with a dose volume of 5 mL / kg, 1 hour before exposure to air or HC and 6 hours after the end of exposure.

Target animals (n = 10) received a vehicle and were exposed to the air for up to 50 minutes per day. The control group (n = 10) received a vehicle and was exposed to HC (up to a maximum of 6 cigarettes per day). The groups

Additional were exposed to HC (up to 6 cigarettes per day) and treated with one of the test compounds or with the reference compound.

Bronchoalveolar lavage and cytospin analysis

Twenty-four hours after the last exposure to HC, bronchoalveolar lavage was performed as follows:

The trachea was dissected with deep anesthesia (sodium pentobarbitone) and cannulated with an intravenous cannula of Portex nylon trimmed to approximately 8 mm. Phosphate buffered saline (PBS, Gibco) containing 10 units / mL of heparin (0.4 mL) was gently instilled and extracted 3 times. The wash fluid was placed in an Eppendorf tube and kept on ice before subsequent determinations. Then, the wash fluid was separated from the cells by centrifugation. The supernatant was removed and frozen for subsequent analysis. The cell precipitate was resuspended in PBS and calculated in total number of cells by counting a stained aliquot (Turk reagent) in a microscope using a hemocytometer.

The differential cell count was then performed as follows: the residual cell precipitate was diluted to approximately 105 cells per mL. A volume of 500 mL was placed in a funnel of a cytospine sample and centrifuged for 8 minutes at 800 rpm. The sample was air dried and stained using "Kwik-Diff" (Shandon) solutions following the supplier's instructions. The sheets were dried and covered and differential cell counting was performed using an optical microscope. Up to 400 cells were counted for each sample. The cells were differentiated using conventional morphometric techniques.

Statistical analysis

The mean ∋ desv. its T. for each experimental group.

The results were analyzed using one-way analysis of variance (ANOVA) followed by a Bonferroni correction for multiple comparisons. Statistical significance was considered with p <0.05.

Example 7: Experimental allergic encephalomyelitis (EAE) model.

The activity of the compounds according to the invention can be evaluated in a model for multiple sclerosis in mice.

Animals

C57BL / 6NCr1BR female mice were used. The mice were stored in wire cages (32 x 14 x 13 cm) with stainless steel feeders and fed with a conventional diet (4RF21, Charles River, Italy) and water ad libitum. As of the 7th day, feed was also placed in wet granules every day at the bottom of the cage. In addition to the automatic water system, plastic bottles were used.

Experimental procedure

Mice were immunized (day = 0) by injection s.c. on the left flank of 0.2 mL of an emulsion composed of 200 Mg of MOG35-55 peptide (Neosystem, Strasbourg, France) in complete Freund's adjuvant medium (CFA, Difco, Detroit, United States) containing 0.5 Mycobacterium tuberculosis mg. Immediately after, they received an i.p. 500 ng pertussis toxin (List Biological Lab., Campbell, CA, United States) dissolved in 400 ∃L of buffer solution (0.5M NaCl, 0.017% Triton X-100, 0.015M Tris, pH = 7.5 ). On the 2nd day, the animals were given a second injection of 500 ng pertussis toxin.

On the 7th day, the mice received a second dose of 200 mg of MOG35-55 peptide in CFA by injection s.c. on the right flank. Starting approximately on the 8th-10th day, this procedure produces a progressive paralysis, starting in the tail and ascending to the front extremities.

The animals were weighed individually and the presence of paralysis that was rated according to the following scoring system (1) was examined:

0 = no signs of illness

0.5 = partial tail paralysis

1 = tail paralysis

1.5 = tail paralysis + unilateral partial paralysis of the hind limb

2 = tail paralysis + partial paralysis or bilateral weakness of the hind limbs

2.5 = tail paralysis + partial paralysis of the hind limbs (lower pelvis)

3 = tail paralysis + total paralysis of the hind limbs

3.5 = tail paralysis + hind limb paralysis + incontinence

4 = tail paralysis + paralysis of the hind limbs + weakness or partial paralysis of the forelimbs

5 = dying or dead

Mortality and clinical signs are monitored daily in each treatment group, by a technician who does not know the treatments.

Daily treatment with the compounds, their vehicle or with a reference compound was started on the 7th day and continued for 15 or 21 consecutive days in all groups.

Histopathological examination

At the end of the treatment period, each animal was anesthetized with sodium pentobarbital and pre-fixed-transcardially fixed with 4% paraformaldehyde through the left ventricle. Then the spinal cord was dissected carefully.

Spinal cord samples were immersed in paraffin blocks. Sectioning and staining with hematoxylin and eosin and staining CD45 for inflammation, and with Kluver-PAS (rapid Luxol blue staining with Schiff's periodic acid) and Bielchowski staining for the detection of demyelination and axonal loss were performed.

In the spinal cord, the total area of all samples for each animal was measured as intersection points of a 10x10 network with a magnification of 0.4 x 0.4 mm per network. Perivascular inflammatory infiltrates in each sample were counted in order to obtain a total value for each animal and were evaluated as the number of infiltrates per mm2. The areas of demyelination and axonal loss were measured for each animal as intersection points of a 10x10 network with a magnification of 0.1 x 0.1 mm per network and expressed as a percentage of the total demyelination area over the Total area of the samples.

Data evaluation and statistical analysis

The results of the clinical and histopathological observations are expressed as the mean results (∋ SEM, standard error of the mean) in each treatment group. The values obtained in the groups treated with the test drug are compared with those in the positive control group. The significance of the differences between groups with respect to the clinical score were analyzed by one-way ANOVA, followed in the case of significance (p <0.05) by the Fisher trial.

Differences between groups for the presence of perivascular inflammatory infiltrates and the extent of demyelination and axonal loss in the spinal cord as well as body weight data were analyzed by one-way ANOVA, in the case of significance (p <0, 05) by Fisher's essay.

Example 8: Preparation of a pharmaceutical formulation

The following formulation examples show representative pharmaceutical compositions according to the present invention, without being restricted thereto.

Formulation 1 - Tablets

A compound of the invention is mixed with a dry powder with a dry gelatin binder in a ratio of approximately 1: 2 by weight. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active N-hydroxyamide derivative per tablet) in a tablet press.

Formulation 2 - Capsules

A compound of the invention is mixed with a dry powder with a starch diluent in a ratio of about 1: 1 by weight. A smaller amount of magnesium stearate is added as a lubricant. 250 mg capsules (125 mg of active N-hydroxyamide derivative per capsule) are filled with the mixture.

Formulation 3 - Liquid

A compound of the invention (1,250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed, passed through a 10 mesh screen and then mixed with a previously prepared cellulose solution

microcrystalline and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then enough water is added to produce a total volume of 5 mL.

Formulation 4 - Tablets

A compound of the invention is mixed with a dry powder with a dry gelatin binder in a ratio of approximately 1: 2 by weight. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active N-hydroxyamide derivative per tablet) in a tablet press.

Formulation 5 - Injection

A compound of the invention is dissolved in an injectable aqueous medium of sterile buffered saline solution to a concentration of approximately 5 mg / mL.

Claims (14)

1.-A derivative of N-hydroxyamide according to formula (I), in which: 5 A is chosen between –C (B) - and N; B is H or B forms a bond with the carbon atom that supports either R5 or R7; R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C3-C8 cycloalkyl-C1-C6 alkyl, heterocyclylalkyl-C1-C6 alkyl, heteroaryl -C1-C6 alkyl, amino and alkoxy; R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, alkoxy, aryl10 and heteroaryl; R3 is selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R4, R5, R6 and R7 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; or R4 and R7 together form a link -CH2-; n is an integer chosen from 1, 2, 3, 4, 5 and 6; The carbon atoms (2) and (3) are two chiral centers, in which the chiral center (2) has a configuration chosen between "S" and "R" and where the chiral center (3) has a " S ”, as well as its pharmaceutically acceptable salts. 2. An N-hydroxyamide derivative according to claim 1, which has a formula (Ia): 20 in which A is chosen between CH and N; R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C3-C8 cycloalkyl-C1-C6 alkyl, heterocyclylalkyl-C1-C6 alkyl, heteroaryl -C1-C6 alkyl, amino and alkoxy; R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, alkoxy, aryl and heteroaryl; R3 is selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; R4, R5, R6 and R7 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl; or R4 and R7 together form a link -CH2-; n is an integer chosen from 1, 2, 3, 4, 5 and 6; the carbon atoms (2) and (3) are two chiral centers, in which the chiral center (2) has a configuration chosen between "S" and "R" and where the chiral center (3) has a "S" configuration ”, As well as its pharmaceutically acceptable salts. 3. An N-hydroxyamide derivative according to any of the preceding claims, wherein R1 is selected from aryl and heteroaryl. 4. An N-hydroxyamide derivative according to any of the preceding claims, wherein R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl. 5.-A derivative of the N-hydroxyamide according to any of the preceding claims, wherein A is N. 6. An N-hydroxyamide derivative according to any of the preceding claims, wherein R1 is selected from aryl and heteroaryl; R2 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl and alkoxy; R3, R4, R5 and R7 are H; R6 is chosen from H and methyl; A is N; and n is an integer chosen between 1, 2 and 3. 7. An N-hydroxyamide derivative according to any one of the preceding claims, chosen from the following group:

-

hydroxy ((2S) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentyl) formamide;

-

{(2S) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentyl} hydroxyformamide.

8. A compound according to any of claims 1 to 7 for use as a medicament. 9. Use of a compound according to claims 1 to 8, as well as mixtures thereof, for the preparation of a medicament for the prophylaxis and / or treatment of inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, stroke, cancer, premature delivery. , endometriosis, fibrosis and respiratory disorders. 10. The use according to claim 9, wherein said diseases are chosen from inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, asthma, emphysema, chronic obstructive pulmonary disorders, pulmonary fibrosis, pancreatic fibrosis, skin fibrosis and fibrosis Hepatic 11. A pharmaceutical composition comprising at least one N-hydroxyamide derivative according to any one of claims 1 to 7 and one of its pharmaceutically acceptable carriers, diluents or excipients. 12. A process for the preparation of an N-hydroxyamide derivative according to any of claims 1 to 7, comprising the step of reacting a compound of formula (II) with a formulating agent of formula (FA): wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined in the preceding claims; PG1 is H or a protecting group chosen from benzyl, t-butyl, THP, TMS and TBS; and LG1 is a leaving group chosen from –OH, -OAc, -OPiv, -OCH2CN, -OCH2CF3, -OPh and –OPfp. 13.-A compound according to formula (II): wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined in the preceding claims; and PG1 is H or a protective group chosen from benzyl, t-butyl, THP, TMS and TBS. 14. A compound according to claim 13 chosen from the following group: - (2S) -N- (benzyloxy) -2 - {[4- (4-methoxyphenyl) piperazin-1-yl] carbonyl} -4-methylpentan-1-amine; - (2S) -N- (benzyloxy) -2 - [(4-biphenyl-4-ylpiperazin-1-yl) carbonyl] -4-methylpentan-1-amine.