KR100665761B1 - Hydroxamic and carboxylic acid derivatives - Google Patents

Abstract

For treating or preventing abnormal conditions associated with matrix metalloproteinases and / or mediated by enzymes involved in membrane exfoliation of TNFα or L-selectin, CD23, TNF receptor, IL-1 receptor or IL-6 receptor Formula (I) BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -W-COY compound for preparing a medicament.

Description

HYDROXAMIC AND CARBOXYLIC ACID DERIVATIVES}

The present invention relates to novel compounds comprising hydroxamic acid and carboxylic acid derivatives, and their use as medicaments.

Metalloproteinases containing matrix metalloproteinases (MMP), (human fibroblast) collagenase, gelatinase and TNF convertases (TACE) and their mode of action, and Their inhibitors and their clinical effects are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are hereby incorporated by reference. MMP inhibitors can also cause metalloproteinases and human joints in other mammals, such as the adamalysin family (or ADAMS) containing TNF convertase (TACE) and ADAM-10, which can cause the release of TNFα from cells. It has been demonstrated to be expressed by chondrocytes and is also useful for the destruction of myelin basic protein and for the inhibition of other enzymes associated with phenomena associated with multiple sclerosis.

Compounds that inhibit the action of metalloproteinases, such as collagenase, stromelysin and gelatinase, associated with connective tissue destruction, are known to inhibit the release of TNF both in vitro and in the body. appear. (See Gearing et al (1994), Nature 370 : 555-557; McGeehan et al (1994), Nature 370 : 558-561; GB-A-2268934; and WO-A-9320047). All of these reported inhibitors have a hydroxamic acid zinc-bonding group as the imidazole-substituted compound described in WO-A-9523790. Other compounds that inhibit MMP and / or TNF are WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A- 96035714.

WO-A-9839316 (which may be a prior art under EPC Article 54 Clause 3), wherein W is CHOH and B is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group bonded to X by carbon. Compounds of general formula (I) are described.

The present invention includes compounds of formula (I), many of which are novel, which are useful inhibitors of matrix metalloproteinases and / or TNFα-mediated diseases, including degenerative diseases and certain cancers.

The compounds according to the invention are the compounds represented by formula (I) and salts, solvates, hydrates, N-oxides, protective amino, protective carboxy and protective hydroxamic acid derivatives thereof.

BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -W-COY (I)

Where

m is 0-2;

n is 1-2 (where n = 2 if m = 0);

X is S (O) _0-2 ; Y is H, OH or NHOH;

W may be C═O or CHOH, or when Y is H, W may also be N—OR ⁸ ;

R ¹ is H or a C _1-6 alkyl group, C _2-6 alkenyl group, aryl group, C _1-6 alkyl-aryl group, heteroaryl group, C _1-6 alkyl-heteroaryl group, heterocycloalkyl group, C ₁ -A group selected from the group consisting of _-6 alkyl-heterocycloalkyl group, a cycloalkyl group and a C _1-6 alkyl-cycloalkyl group, optionally substituted with R ⁷ ; And

If (CR ¹ R ² ) _n is not (CH ₂ ) _n , then R ² is H or a C _1-6 alkyl group;

Or CR ¹ R ² is a cycloalkyl or heterocycloalkyl ring optionally substituted with R ⁷ , or a C _1-6 alkyl group, aryl group, C _1-6 alkyl-aryl group, heteroaryl group and C _1-6 alkyl-hetero A group selected from the group consisting of an aryl group (optionally substituted with R ⁷ );

B is C _1-6 alkyl-aryl group, C _1-6 alkyl group, cycloalkyl group, C _1-6 alkyl-cycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, C _1-6 alkyl-heteroaryl group, heterocyclo An alkyl group, a C _1-6 alkyl-heterocycloalkyl group, an aryl group or a heteroaryl group, these groups are R ³ , C _1-6 alkyl-R ³ , C _2-6 alkenyl-R ³ , aryl (optionally substituted with R ³ ), aryl-C _1-6 alkyl-R ³ , C _1-6 alkyl-aryl (optionally substituted with R ³ ), C _{1- 6} alkyl-heteroaryl (optionally substituted with R ³ ), aryl-C _2-6 alkenyl-R ⁵ , heteroaryl (optionally substituted with R ³ ), heteroaryl-C _1-6 alkyl-R ³ , cyclo Optionally substituted with a substituent selected from the group consisting of alkyl (optionally substituted with R ³ ), or heterocycloalkyl (optionally substituted with R ³ );

R ³ is a C _1-6 alkyl group, halogen, CN, NO ₂ , N (R ⁴ ) ₂ , OR ⁴ , COR ⁴ , C (= NOR ⁶ ) R ⁴ , CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ or SO ₂ N (R ⁴ ) ₂ ,

R ⁴ is H or a C _1-6 alkyl group, aryl group, C _1-6 alkyl-aryl group, heteroaryl group, C _1-6 alkyl-heteroaryl group, cycloalkyl group, C _1-6 alkyl-cycloalkyl group, hetero A cycloalkyl group and a C _1-6 alkyl-heterocycloalkyl group, wherein said group is optionally R ⁶ , COR ⁶ , SO _0-2 R ⁶ , CO ₂ R ⁶ , OR ⁶ , CONR ⁸ R ⁶ , NR ⁸ R ⁶ , halogen, CN, SO ₂ NR ⁸ R ⁶ or NO ₂ ,
In each of N (R ⁴ ) ₂ , R ⁴ groups are the same as or different from each other, or N (R ⁴ ) ₂ is optionally R ⁶ , COR ⁶ , SO _0-2 R ⁶ , CO ₂ R ⁶ , OR ⁶ , A heterocycloalkyl group substituted with CONR ⁸ R ⁶ , NR ⁸ R ⁶ , halogen, CN, SO ₂ NR ⁸ R ⁶ or NO ₂ ;

R ⁵ is COR ⁴ , CON (R ⁴ ) ₂ , CO ₂ R ⁶ or SO ₂ R ⁶ ,

R ⁶ is a C _1-6 alkyl group, an aryl group, a C _1-6 alkyl-aryl group, a heteroaryl group, or a C _1-6 alkyl-heteroaryl group,

R ⁷ is OR ⁴ , COR ⁴ , CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ , SO ₂ N (R ⁴ ) ₂ , halogen, CN or cyclo Imidyl group (optionally substituted with R ⁸ ); And

R ⁸ is H or a C _1-6 alkyl group.

Combinations of substituents and / or variables are permissible only when such combinations produce stable compounds.

Preferred compounds of the present invention are those in which one or more of the following definitions apply.

X is SO ₂ ,

R ¹ is an optionally substituted C _1-6 alkyl group, C _1-6 alkyl-heteroaryl group, or C _1-6 alkyl-heterocycloalkyl group; Or CR ¹ R ² forms the optionally substituted ring,

B is a cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, these groups are selected from the group consisting of R ³ , aryl group (optionally substituted with R ³ ) and heteroaryl group (optionally substituted with R ³ ) Optionally substituted with substituents,

R ³ is OR ⁴ or COR ⁴ ;

R ⁴ is an optionally substituted aryl group, C _1-6 alkyl-aryl group, heteroaryl group, or C _1-6 alkyl-heteroaryl group; And

R ⁷ is CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ , SO ₂ N (R ⁴ ) ₂ or an optionally substituted cycloimidyl group.

Particular preference is given to the compounds of the examples.

The compounds according to the invention may comprise one or more asymmetrically substituted carbon atoms. The presence of one or more such asymmetric centers in the compound of general formula (I) may result in the formation of stereoisomers, in each case the invention comprising both stereoisomers, including enantiomers and diastereomers, and racemic mixtures thereof. It can be understood to extend to the mixture.

It can also be seen that the compounds according to the invention may comprise oximes. This oxime can produce geometric isomers, and in each case it can be understood that the compounds of the invention extend to all of these isomers and mixtures thereof.                 

When used alone or in combination in this specification, “C _1-6 alkyl” refers to 1-6 carbon sources, including, for example, methyl, ethyl, propyl, isopropyl, butyl, tert -butyl, pentyl, hexyl, and the like. Straight or branched chain alkyl moieties having a moiety.

"C _2-6 alkenyl" means a straight or branched chain alkyl moiety having 2 to 6 carbon atoms and in addition having one double bond, to which E or Z stereochemistry may be applied. This term includes, for example, vinyl groups, 1-propenyl groups, 1- and 2-butenyl groups, 2-methyl-propenyl groups, and the like.

"Cycloalkyl" means a saturated alicyclic moiety having 3 to 6 carbon atoms, which is optionally benzofused at the position where it is available. This term includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an indanyl group, a tetrahydronaphthyl group, and the like.

“Heterocycloalkyl” means a saturated heterocyclic moiety having 3 to 6 carbon atoms and one or more heteroatoms selected from N, O, S and their oxidation forms, which are optionally benzofused at the positions where they are available. This term includes, for example, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, an indolinyl group, a tetrahydroquinolinyl group, and the like.

"Cycloalkenyl" refers to an alicyclic moiety having 3 to 6 carbon atoms and one other double bond. This term includes, for example, a cyclopentenyl group, a cyclohexenyl group, and the like.                 

"Heterocycloalkenyl" refers to an alicyclic moiety having 3 to 6 carbon atoms and at least one heteroatom selected from N, O, S and their oxidation forms, and having one double bond. This term includes, for example, dihydropyranyl groups.

"Aryl" refers to an aromatic carbocyclic radical having a single ring or two condensed rings. This term includes, for example, a phenyl group or a naphthyl group.

"Heteroaryl" consists of 5 to 10 atoms, where at least one atom is an aromatic ring system selected from O, N and S, for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl And the like.

"Cycloimidyl" refers to a saturated ring of 5 to 10 atoms having an atomic arrangement of -C (= 0) NC (= 0), which ring may optionally be benzofused at available positions. Examples include succinimidoyl, phthalimidoyl and hydantoinyl groups.

"Benzo fusion" means the addition of a benzene ring that shares a common bond with a defined ring system.

“Optionally substituted” means optionally substituted with one or more specific groups at available positions or positions.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Protected amino", "protected carboxy" and "protected hydroxamic acid" refer to amino groups, carboxyl groups and hydroxamic acid groups which can be protected by methods well known to those skilled in the art. For example, the amino group may be protected by a benzyloxycarbonyl group, tert -butoxycarbonyl group, acetyl group, or the like, or may be in the form of a phthalimido group. Carboxyl groups may be protected in the form of esters such as methyl, ethyl, benzyl or tert -butyl esters. Hydroxamic acid is O- benzyl or O- tert - may be protected as, N or O- substituted derivatives such as butyldimethylsilyl.

Salts of the compounds of formula (I) are pharmaceutically acceptable salts, for example hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate Acid addition salts derived from inorganic or organic acids such as citrate, malonate, succinate, lactate, oxalate, tartarate and benzoate.

The salts can also be formed with bases. Such salts include, for example, alkali metal salts such as magnesium salts or calcium salts, and salts derived from inorganic or organic salts such as organic amine salts such as morpholine salts, piperiline salts, dimethylamine salts or dimethylamine salts. do.

When the "protected carboxy" group in the compounds of the invention is an etherified carboxyl group, this protected carboxyl group may be a metabolically labile ester of the general formula CO ₂ R ⁹ , wherein R ⁹ is an ethyl group, benzyl group, phenethyl group , Phenylpropyl group, α- or β-naphthyl group, 2,4-dimethylphenyl group, 4- tert -butylphenyl group, 2,2,2-trifluoroethyl group, 1- (benzyloxy) benzyl group, 1- ( Benzyloxy) ethyl group, 2-methyl-1-propionyloxypropyl group, 2,4,6-trimethylbenzyloxymethyl group or pivaloylmethyl group.

Compounds of formula (I) may be prepared by suitable methods known in the art and / or by the following methods.

Where specific stereoisomers of Formula (I) are desired, the synthetic methods described herein may employ suitable homochiral starting materials, or the isomers may be prepared using conventional separation techniques (e.g., HPLC). Can be disassembled.

The compound according to the present invention can be prepared by the following method. In the following description and general formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , B, W, X and Y, unless otherwise indicated, As defined. It can be seen that functional groups, such as amino groups, hydroxyl groups and carboxyl groups, which are preferably maintained and which need to be in protected form prior to initiating a particular reaction, may be present in the various compounds described below. In such cases, removal of the protecting group may be the last step of a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. See Greene et al., “Protective Groups in Organic Synthesis,” Wiley Interscience.

Compounds of general formula (I) wherein W is CHOH and Y is OH can be exemplified by hydrolyzing the compound of general formula BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -CHOH-CN (II). For example, it may be prepared by treatment with an inorganic acid such as 7M hydrochloric acid at a suitable temperature such as 80 ° C.

The compound of the general formula (II) is potassium cyanide or the like in an appropriate solvent such as an aldehyde of the general formula BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -CHO (III) and an aqueous NaHSO ₃ solution, for example. It can be prepared by reaction with an inorganic cyanide.

The compound of the general formula (III) may be an ester of the general formula BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -CO ₂ R ¹⁰ (IV), wherein R ¹⁰ is a suitable group such as a methyl group or an ethyl group. In a suitable solvent such as toluene, for example, by reduction with a reducing agent such as diisobutylaluminum hydride.

The compound of formula (IV) (X = S) is obtained by alkylation of a B-SH compound with an alkylating agent of Z- (CH ₂ ) _m- (CR ₁ R ₂ ) _n -CO ₂ R ¹⁰ (V) type. Easily prepared, where Z is a leaving group (e.g., halogen, such as bromine, or alkylsulfonate ester, such as methane sulfonate). Many compounds of formula (V) and B-SH are commercially available or may be prepared from commercially available materials by standard chemistry known to those skilled in the art.

Compounds of formula (I) (W is C = O and Y is OH) are described in Tetrahedron Lett ., 1992 , 33 , 6003 and J. Org. A three-step sequence consisting of (i) reaction with cyanomethylene-triphenylphosphorane, (ii) oxidation by ozone, and (iii) aqueous hydrolysis, as described in Chem ., 1994 , 59 , 4364. By formula (IV) (R ¹⁰ = H).

Compounds of formula (IV) (m = 1, n = 1 and R ² = H) are also prepared by reaction of compound B-SH with an acrylate of formula H ₂ CCR ¹ CO ₂ H (VI). Can be. The compound of formula (VI) was reacted with paraformaldehyde in a suitable organic solvent, such as 1,4-dioxane, in a Mannick reaction of dicarboxylic acid of formula HO ₂ C-CHR ¹ -CO ₂ H (VII). To ferridine). This reaction includes a removable decarboxylation process that directly forms α, β-unsaturated carboxylic acids.

The dicarboxylic acid of the general formula (VIII) is, for example, alkylated with dialkylmalonate with an alkylating agent of the general formula R ¹ -Z (VIII), wherein Z is as defined above, followed by hydrolysis under basic conditions. It can manufacture by decomposing. Many alkylating agents of the general formula are commercially available or can be prepared from commercially available materials by methods known to those skilled in the art.

The compound of formula (I) (Y is H and W is N-OR ⁸ ) is a compound of formula BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -NHOR ⁸ (VII). It may be prepared by formylation. Compounds of formula (VII), wherein m = 1, n = 1 and X = SO ₂ , are prepared by adding R ⁸ ONH ₂ to vinylsulfone of general formula B-SO ₂ -CHCR ¹ R ² (VII). can do. This reaction can be carried out in a suitable organic solvent such as tetrahydrofuran in the presence of an organic base such as triethylamine. Compounds of formula (VII) may be prepared by the condensation of sulfones of formula B-SO ₂ -CH ₃ (XI) with ketones of formula R ₁ COR ₂ (XII). Conditions suitable for this reaction are a suitable base such as sodium hydride in an inert solvent such as THF. Many sulfones (XI) and ketones (XII) are known or can be readily prepared by methods known to those skilled in the art.

The compound of formula (VII) reacts (i) free amine with aldehyde to produce appropriate imine, ii) reaction of imine with an oxidizing agent such as meta-chloroperbenzoic acid to produce the corresponding oxaziridine, And (iii) cleaving the oxaziridine to hydroxylamine to produce the desired hydroxylamine of the general formula (VII), with the general formula BX- (CH ₂ ) _m (CR ¹ R ² ) _n NH may optionally be prepared by the oxidation of N- amine ₂ (XIII) (see, for example, Synthesis, 1987, 1115).

The amines of formula (XIII) are (if X is SO ₂ and B is bonded to X via nitrogen) B and the formula Z-SO _2- (CH ₂ ) _m (CR ¹ R ² ) _n NHR ¹¹ ( By reaction of an acylating agent of XIX) or (if X is S and B is bonded to X via carbon) sulfanyl compound of formula B-SH and formula Z- (CH ₂ ) _m (CR ¹ R ² ) _n NHR ¹¹ (XX), wherein R ¹¹ is a suitable amine protecting group that can be removed after conversion, can be prepared by reaction with an alkylating agent (Greene et al , "Protecting Groups in Organic Synthesis", Wiley Interscience). The compound of formula (XIX) reacts a compound of formula (XX) with a compound of formula Q-SH, where Q is a suitable labile group such as acetyl, and then, for example, with chlorine and water It can be prepared sequentially from the compound of the general formula (XX) by a reaction which produces a compound of the general formula (XIX), wherein Z is Cl.

Compounds of formula (XX) are commercially available or can be prepared by methods known to those skilled in the art. For example, compound (XX) (m = 1 and n = 1) is a compound of formula (HCH) in which an amino acid of general formula HO ₂ CCR ¹ R ² NHR ¹¹ (XXI) is used in an inert solvent with a suitable reagent such as borane. Reducing ₂ CR ¹ R ² NHR ¹¹ (XXII) to a primary alcohol, and (ii) reacting the primary alcohol with methanesulfonyl chloride in the presence of an organic base such as triethylamine, for example in an inert solvent. Can be prepared from amino acids of the formula HO ₂ CCR ¹ R ² NHR ¹¹ (XXI) by a two-step continuous process converting to a leaving group by means of which a compound of formula (XX) (Z is methanesulfonate) is produced. have. Compounds of general formula (XXI) are known or can be prepared by known methods.

In addition, compounds of formula (I) or any suitable intermediate may be prepared by interconversion of compounds of the same formula. Thus, for example, a compound of formula (I) wherein R ¹ is a C _1-6 alkyl group is a hydrogenated compound of formula (I) wherein R ¹ is a C _2-6 alkenyl group (such as an alcohol such as ethanol). Carbon-based palladium in a suitable solvent). Compounds of general formula (I) wherein W is C═O can be prepared by oxidizing a compound wherein W is CHOH with, for example, oxalyl chloride and dimethyl sulfoxide in the presence of an organic base such as trimethylamine. Compounds of general formula (I) wherein Y = NHOH can be selected from compounds having Y = OH, using standard chemistry known to those skilled in the art, where R ¹² is a suitable protecting group such as benzyl, tert -butyl or tert -butyldimethylsilyl (TBDMS). , An intermediate of hydroxyamide NHOR ¹² can be prepared.

으로 산화시켜 제조할 수 있다.Similarly, a compound of Formula (I), (IV), (XIII), (XIII), (XIX), or other suitable intermediate, wherein X = SO ₂ , may be selected from a suitable solvent such as methanol-water. For example, Oxone

It can be prepared by oxidation.

The resulting final product or mixture of intermediates can be prepared on the basis of differences in the physico-chemical properties of the components, either by known methods, for example by chromatography, distillation, fractional crystallization or by the formation of salts under suitable or possible conditions, thereby making the pure final material Or as an intermediate.

The compounds according to the present invention exhibit inhibitory activity against stromelysin, collagenase and gelatinase in vitro. The compounds according to the invention can also be used in vitro teloproteinases such as α-APP, ACE, TGF-α, TNF-α, Fas ligand, TNFR-I, TNFR-II, CD30, Il-6R Inhibition of membrane shedding known to be mediated by, CD43, CD44, CD16-I, CD16-II, folate receptor, CD23, or IL-1RII.

The activity and selectivity of the compounds can be determined using, for example, the appropriate enzyme inhibition test described in Example AM of WO-A-9805635, or for the inhibition of CD23 shedding described in PCT / GB98 / 03395 or TNF RI. Can be determined by post analysis of divergence.

The efficacy of the compound of formula (I), which acts as an inhibitor of TNF RI production, is determined by the following procedure. 100 μM solution of the inhibitor to be tested or a dilution thereof was incubated at 37 ° C. in an atmosphere of 5% CO ₂ using peripheral blood mononuclear cells (PBMC). PBMCs were isolated from buffer coats by standard methods using ficoll. 100 μM solution of the inhibitor to be tested or a dilution thereof was incubated at 37 ° C. for 22 hours in an atmosphere of 5% CO ₂ using PBMC 1 × 10 ⁶ / ml stimulated with LPS. The cells were centrifuged to settle and the supernatants were analyzed for TNF RI using a commercial ELISA kit (R & D Systems). In the presence of a 0.1 mM inhibitor or a diluent thereof, the activity was compared to that of a control without any inhibitor, and the results were reported as inhibitor concentrations that inhibit 50% of the production of TNF RI.

The invention also relates to a method of treating a patient suffering from a disease or condition that may be attributable to such a stromelysin (including mammals raised for human and / or dairy, meat or fur industries or pets), more specifically The present invention relates to a therapeutic method comprising administration of a matrix metalloproteinase inhibitor of general formula (I) as an active ingredient.

Therefore, the compounds of formula (I) can be used, inter alia, for the treatment of osteoarthritis and rheumatoid arthritis, and for diseases and indications due to overexpression of these matrix metalloproteinases found in certain metabolic tumor cell lines.

As mentioned above, the compounds of general formula (I) are effective as inhibitors of TNF and MMPs and are therefore useful in human medicine or veterinary medicine. Therefore, in another aspect, the present invention relates to the following:

Management (treatment or treatment of a disease or condition mediated by TNF and / or MMPs in a mammal, in particular a human, comprising administering to the mammal an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof Means prevention); And

Compounds of formula (I) for use in the management (meaning treatment or prevention) of diseases or abnormalities mediated by human medicine or veterinary medicine, in particular TNF and / or MMPs; And

Use of a compound of formula (I) in the manufacture of a medicament for the management (meaning treatment or prevention) of a disease or condition mediated by TNF and / or MMPs.

The diseases or abnormal conditions mentioned above include inflammatory diseases, autoimmune diseases, cancer, cardiovascular diseases and rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer's disease, stroke, vasculitis, Crohn's disease, ulcerative colitis, multiple sclerosis, and periostitis Diseases including bone destruction, gingivitis, and bone resorption, bleeding, flocculation, acute phase reactions, cachexia, anorexia, acute infections, HIV infection, fever, shock conditions, graft-versus-host reactions, skin abnormalities, surgical wound healing , Psoriasis, atopic dermatitis, bullous skin mycosis, tumor growth, angiogenesis and secondary metastasis invasion, eye disease, retinopathy, corneal ulceration, perfusion injury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis, eczema, ana Diseases including tissue destruction such as phloxil, recurrent stenosis, congestive heart failure, endometriosis, atherosclerosis, endometriosis and aspirin-independent antithrombolysis The.                 

In addition, compounds of formula (I) are also useful for the treatment of pelvic inflammatory disease (PID), age-related macular degeneration and cancer-induced aggregate absorption. In addition, the compounds may be pulmonary diseases such as cystic fibrosis, adult respiratory distress syndrome (ARDS), emphysema, obstructive bronchitis-derived pneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolar injury, pulmonary Langer It can also be used to treat Langerhan's cell granulomatosis, pulmonary lymphangiomyopathy (LAM) and chronic obstructive pulmonary disease (COPD).

Diseases and signs caused by excessive expression of matrix metalloendoproteinases found in rheumatoid arthritis, osteoarthritis and certain metastatic tumor cell lines or by matrix metalloendoproteinases or increased TNF production For the treatment of other mediated diseases, the compound of formula (I) is orally, topically, parenterally and also by spray inhalation in a dosage unit formulation containing a nontoxic pharmaceutically acceptable carrier, adjuvant and excipient. By or rectally. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, arterial injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats and the like, the compounds of the present invention are effective in the treatment of humans.

Pharmaceutical compositions containing the active ingredient include, for example, tablets, troches, sugar-containing tablets, water-soluble or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. It may be in a form suitable for oral use. Oral compositions can be formulated by known methods for the manufacture of pharmaceutical compositions, which compositions are selected from the group consisting of sweetening, flavoring, coloring and preservatives to provide pharmaceutical formulations with excellent pharmaceutical preferences. It may contain one or more agents. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the formulation of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; For example, granulating agents or disintegrating agents, such as corn starch or alginic acid; Binders such as, for example, starch, gelatin or acacia rubber, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be coated with known techniques to provide a sustained action for longer periods of time by not coating or delaying disintegration and absorption in the gastrointestinal tract. For example, a time delay substance such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated with the techniques described in US Pat. No. 4,256,106, US Pat. No. 4,166,452, and US Pat. No. 4,265,874 to form an osmotic therapeutic tablet for controlled release.

Oral formulations may also be formulated in hard gelatin capsules, wherein the active ingredient may be mixed, for example, with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in a soft gelatin capsule, where the effective The ingredients are mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions are mixed with the active ingredient with excipients suitable for the preparation of aqueous suspensions. Such excipients include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate polyvinyl-pyrrolidone, tragacanth rubber and acacia rubber, for example lecithin. Naturally occurring phosphatides, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene Condensation products of oxycetanol, ethylene oxide with partial esters derived from fatty acids and hexitols, condensation products of polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxy ethylene sorbitan monorate Dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, such as ethyl, or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Can be.

Oily suspensions can be formulated by suspending the active ingredient in, for example, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil such as liquid paraffin. Oily suspensions may contain, for example, thickening agents of beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents such as those described above may be added to provide the oral formulations to suit your preference. Such a composition can be preserve | saved by adding antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspension and one or more preservatives. Suitable dispersing or wetting agents and suspending agents include, for example, sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase can be, for example, vegetable oils such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers are, for example, natural rubbers which are acacia rubbers or tragacanth rubbers, for example natural phosphatides such as soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example Sorbitan monooleate, a condensation product of said partial ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain thickeners, preservatives, flavors and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectables can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as, for example, solutions in 1,3-butane diol. Among the acceptable excipients and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, mild nonvolatile oils including synthetic mono- or diglyceramides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. Such a medicament may be formulated by mixing the drug with a non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and is therefore suitable for melting in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellys, solutions or suspensions containing the compounds of formula (I) are used. For this purpose, topical applications include mouthwashes and gargles.

Doses of about 0.05 to about 140 mg / kg body weight per day (about 2.5 mg to about 7 g per patient per day) are useful for the treatment of such abnormal conditions. For example, inflammation can be effectively treated by administration of about 0.01-50 mg / kg body weight / day (about 0.5 mg to about 3.5 g per patient per day).

The amount of active ingredient mixed with the carrier material to produce a single formulation will vary depending upon the host treated and the particular mode of administration. For example, in formulations for oral administration in humans, the amount of active ingredient may vary from about 5 to about 95% of the total composition. Dosage unit forms generally contain about 1 to about 500 mg of the active ingredient.

However, the specific dosage level of a particular patient may vary, including the activity, age, weight, overall health, sex, duration of administration of administration, route of administration, rate of excretion, drug combination and depth of specific disease being treated for the specific compound used. Depends on the factor

The following examples illustrate the invention. In the examples, the following abbreviations were used.

 DMF: Dimethylformamide;                 

 RT: room temperature;

 THF: tetrahydrofuran

Intermediate 1 2-[(4-methoxybenzenesulfonyl) methyl] -5-phenylpentanoic acid

The title compound (2.5 g) was prepared according to the method described in WO-A-9805635, which was a colorless solid.

Intermediate 2 Methyl 2-[(4-methoxybenzenesulfonyl) methyl] -5-phenylpentanoate

Using a diazomethane kit, the reaction vessel was charged with potassium hydroxide (2.50 g), ethanol (5 ml) and water (4 ml) and the mixture was heated in a water bath maintained at 65-70 ° C. In solution in diethyl ether (25 ml), diazal (2.50 g) was added dropwise to the reaction vessel (with care), and the effluent was collected in a trap cooled with carbon dioxide / acetone. After the addition was finished, the diazal addition flask was rinsed with diethyl ether (2 x 1 ml) and placed in the reaction vessel until the effluent was colorless. The pale yellow diazomethane solution thus obtained was carefully added to a stirred ice-cooled solution of intermediate 1 (2.00 g) in tetrahydrofuran (25 ml). The mixture was then stirred in ice for 1 hour, then warmed to room temperature and washed with nitrogen until colorless. The solution was treated with a few drops of acetic acid to remove traces of diazomethane, concentrated in vacuo and dried to give the title compound (2.23 g, 100%) as a colorless oil.

TLC R _f 0.67 (ethyl acetate with 50% hexanes / trace acetic acid)

Intermediate 3 2-[(4-methoxybenzenesulfonyl) methyl] -5-phenylpentanal

Stirring of intermediate 2 (2.82 g) in anhydrous toluene (30 ml) while confirming that the temperature is maintained at -65 ° C. over about 45 minutes with 1.5 M toluene solution (7.5 ml). The solution was added dropwise using a syringe. The mixture was further held at this temperature for 45 minutes, after which methanol (5 ml) was added dropwise, and then 1M hydrochloric acid (4 ml) was added. After warming to room temperature, diethyl ether (25 ml) and 1 M hydrochloric acid (45 ml) were added, and after the layers were separated, the aqueous layer was extracted with diethyl ether (2 × 25 ml). The combined organic extracts were washed with water (2 × 10 ml), brine (15 ml), dried (MgSO ₄ ) and reduced in vacuo to give a colorless oil (2.63 g). Purification by chromatography on silica gel using 3% diethyl ether / dichloromethane as eluent gave the title compound (1.84 g, 71%) as a colorless oil.

TLC R _f 0.47 (3% diethyl ether / dichloromethane)

MS 364 (M + NH4 ⁺ )

Intermediate 4 1-cyano-2-[(4-methoxybenzenesulfonyl) methyl] -5-phenylpentanol

Intermediate 3 (1.724 g) was stirred vigorously with sodium metabisulfite (1.703 g) in water (10 ml) and ethanol (2 ml), and after 30 minutes the resulting suspension was dissolved in potassium cyanide (10 ml) ( 0.486 g) was treated with solution (with care). After 2 h the mixture was extracted with diethyl ether (2 × 25 ml) and the combined extracts washed with water (20 ml), dried (MgSO ₄ ) and reduced to give the title compound (1.463 g, 79 as a colorless oil). %) Was obtained.

TLC R _f 0.24 (3% diethylether / dichloromethane).

Intermediate 5   4- (4-methoxybenzenesulfonylmethyl) -3-oxo-7-phenyl-2- (triphenylphosphanyl-idene) heptanitrile

Oxalyl chloride (3.50 g) was added to a stirred solution of intermediate 1 (2.00 g) in dichloromethane (50 ml) and DMF (1 drop) at 0 ° C. Stirring was continued for 15 minutes at 0 ° C. and then for 45 minutes at room temperature. The solvent was removed in vacuo. The residue was taken up in dichloromethane (10 ml) and added to a solution of triphenylphosphoranylideneacetonitrile (1.84 g) and bistrimethylacetamide (1.68 g) in dichloromethane (80 ml) under nitrogen at 0 ° C. Stirring was continued at 0 ° C. for 10 minutes, then at room temperature for 3 hours. The reaction mixture is diluted with dichloromethane (100 ml), washed with water (3 x 50 ml), sodium hydroxide solution (0.5 M; 50 ml), water (2 x 50 ml), brine (50 ml) and dried ( MgSO ₄ ). The residue was filtered off, the solvent was evaporated and the residue was purified by silica gel column chromatography using a 1: 1 hexane / ethyl acetate mixture containing traces of acetic acid as eluent to give the title compound (1.24 g, 35) as a colorless foam. %) Was obtained.

TLC R _f 0.32 (1: 1 hexanes / ethyl acetate, traces of acetic acid).

Intermediate 6   Methanesulfonic acid, 2S- tert -Butoxycarbonylamino-3-methyl-butyl ester

After ice-cooling L-Boc-Valinol (5 g) in dichloromethane (100 ml), triethylamine (3.8 ml) and methanesulfonyl chloride (2.0 ml) were added dropwise. The cooled solution was stirred for 2 hours, washed with water and brine, dried over MgSO ₄ and evaporated to afford the title compound (6.2 g, 95%) as a colorless solid.

TLC R _f 0.75 (ether)

Intermediate 7   Thioacetic Acid, S -(2S- tert -Butoxycarbonylamino-3-methyl-butyl) ester

A solution of intermediate 6 (6.0 g) was stirred with potassium thioacetate (4.0 g) in dimethylformamide (50 ml) for 18 hours at room temperature. The resulting thick suspension was diluted with water, extracted with ether (2 × 100 ml), the solvent was washed with water, aqueous sodium bicarbonate solution and brine, dried over MgSO ₄ and evaporated to give the title compound as a beige solid ( 5.2 g, 88%).

TLC R _f 0.43 (1: 1 ether / hexane)

Intermediate 8   (1S-chlorosulfonylmethyl-2-methylpropyl) carbamic acid, tert -Butyl ester

Chlorine gas was bubbled at 0 ° C. for 20 minutes in a solution of intermediate 7 (2.0 g) in water (50 ml) and dichloromethane (50 ml), followed by vigorous stirring for 20 minutes. After separating the layers, the organic layer was washed with ice water and brine, dried over MgSO ₄ and evaporated to afford the title compound (2.20 g, 100%) as a colorless solid.

TLC R _f 0.35 (1: 1 ether / hexane)

Intermediate 9  {1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl] -2-methylpropyl} carbamic acid, tert -Butyl ester

A suspension of 4-chlorophenylpiperazine dihydrochloride (2.0 g) and triethylamine (3.3 ml) in dichloromethane (100 ml) is stirred for 10 minutes, then cooled in ice and the solution of intermediate 8 is added dropwise It was. The mixture was stirred vigorously for 3 hours and then washed with water, saturated aqueous sodium bicarbonate solution and brine. The organic layer was then dried over MgSO ₄ and evaporated to afford the title compound (2.50 g, 73%) as a colorless crystalline solid.

TLC R _f 0.63 (ether)

Intermediate 10   1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl] -2-methylpropylamine

A solution of intermediate 9 (2.50 g) in dichloromethane (60 ml) was treated with trifluoroacetic acid (30 ml), then the mixture was stirred for 2 hours. The mixture was then evaporated to dryness and azeotropic with dichloromethane and hexanes. The residue is taken up in water (100 ml) and the solution is washed with ether. The aqueous layer was basified with 48% aqueous NaOH solution and the resulting suspension was extracted with EtOAc (3 × 100 ml). The solvent was washed with brine, dried over MgSO ₄ and evaporated to afford the title compound (1.85 g, 95%) as a colorless solid.

TLC R _f 0.15 (ether)

Intermediate 11  {1S- [4- (4-chlorophenyl) piperazin-1-sulfonylmethyl] -2-methylpropyl}-(4-methoxybenzylidene) amine

A solution of intermediate 10 (1.80 g) and para -anisaldehyde (1.2 ml) in methanol (100 ml) was stirred with solid sodium carbonate (2 g) at room temperature for 18 hours. After the suspension was filtered, the filtrate was evaporated and treated with ethyl acetate (200 ml). The mixture was filtered and the filtrate was evaporated to give the title compound (2.50 g, 100%) as a viscous pale yellow oil.

TLC R _f 0.54 (ether / hexane 1: 2)

Intermediate 12 1- (4-chlorophenyl) -4- {2S- [3- (4-methoxyphenyl) oxaziridin-2-yl] -3-methylbutane-1-sulfonyl} piperazine

A solution of meta -chloroperbenzoic acid (1.2 g) in dichloromethane was dried over magnesium sulfate and added dropwise to a solution of intermediate 11 (2.5 g) dissolved in dry dichloromethane at -10 ° C over 30 minutes. The mixture was stirred for 2 hours, then washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried over MgSO ₄ and evaporated to give the product (2.50 g, 95%) as a viscous oil.

TLC R _f 0.34 (2: 1 hexanes / ether)

Intermediate 13 N -{1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl] -2-methylpropyl} -hydroxylamine

To a solution of intermediate 12 (2.5 g) in methanol (50 ml) was added hydroxylamine hydrochloride (2.0 g) at room temperature. The solution was stirred overnight and then evaporated in vacuo, then the residue was dissolved in water and washed with ether (2 × 50 ml). The aqueous layer was basified with solid sodium bicarbonate and then extracted with ethyl acetate (2 x 50 ml) and then evaporated to give crude hydroxylamine (1.2 g, 70%), which was used without purification.

TLC R _f 0.20 (EtOAc)

Example 1   2-hydroxy-3-[(4-methoxybenzenesulfonyl) methyl] -6-phenylhexanoic acid

Intermediate 4 (1.443 g) was heated to reflux with 7M hydrochloric acid (30 ml) for 2 hours. Then the mixture was cooled and extracted with dichloromethane (2 x 20 ml). The dichloromethane extract was reduced to 20 ml, diluted with diethyl ether (100 ml) and extracted with 1 M sodium carbonate solution (2 x 10 ml). The combined basic extracts were washed with ethyl acetate (10 ml), acidified with 12 M hydrochloric acid and extracted with dichloromethane (2 x 15 ml). The dichloromethane extract was then washed with water (10 ml), dried (MgSO ₄ ) and the title compound (0.888 g, 59%) as an off-white solid.

TLC R _f 0.35 (5% Methanol / Dichloromethane)

MS 410 (M + NH4 ⁺ )

Example 2   Methyl 3- (4-methoxybenzenesulfonylmethyl) -2-oxo-6-phenylhexanoate

At −78 ° C., ozone was introduced until a blue color remained in a stirred solution of intermediate 5 (330 mg) in dichloromethane / methanol (7: 3; 10 ml). Nitrogen gas was passed through the solution until the solution was colorless, and then warmed to room temperature. Stirring was continued for 30 minutes before the solvent was removed in vacuo and the residue was purified by silica gel column chromatography using hexane / ethylacetate (2: 1) as eluent to give the title compound (89 mg, 43%). m.p. 95 ° C.

TLC R _f 0.31 (2: 1 hexanes / ethyl acetate)

Example 3    3- (4-Methoxy-benzenesulfonylmethyl) -2-oxo-6-phenylhexanoic acid

To a stirred solution of Example 2 (47 mg) in dioxane (5 ml) in an ice salt bath was added a solution of lithium hydroxide (24 mg) in water (2 ml). The mixture was stirred for 90 minutes, then diluted with water (30 ml) and washed with dichloromethane (2 × 10 ml). The aqueous layer was acidified (2 M HCl) and extracted with ethyl acetate (4 × 10 ml). The combined ethyl acetate extracts were washed with water (2 × 10 ml), brine (10 ml) and dried (MgSO ₄ ). After filtration, the solvent was evaporated and the residue was purified by silica gel column chromatography using hexanes / ethylacetate / acetic acid (1: 1: 0.002) as eluent to give the title compound (30 mg; 67% as colorless oil). )

TLC R _f 0.36 (1: 1 hexanes / ethylacetate and 0.2% acetic acid)

MS 390 (M ⁺ )

Example 4 N -{1S- [4- (4-chlorophenyl) piperazine-1-sulfonylmethyl] -2-methylpropyl}- N Hydroxyformamide

Intermediate 13 (1.2 g) was stirred under reflux for 3 hours in a mixture of THF (50 ml), ethylformate (2 ml) and triethylamine (1 ml). The solvent was then evaporated in vacuo and the residue was purified by flash chromatography on silica gel using 5% methanol in dichloromethane as the eluent to afford the title compound (0.15 g; 11%) as a colorless solid.                 

TLC R _f 0.37 (5% MeOH / CH ₂ Cl ₂ )

MS 290 (MH ⁺ )

Claims (25)

A compound of formula (I), or a salt or N-oxide derivative thereof: BX- (CH ₂ ) _m- (CR ¹ R ² ) _n -N (OR ⁸ ) -COH (I) Where m and n are each 1; X is SO ₂ ; R ¹ is a C _1-6 alkyl group, C _1-6 alkyl-heteroaryl group, or C _1-6 alkyl-heterocycloalkyl group, optionally substituted with R ⁷ ; And If (CR ¹ R ² ) _n is not (CH ₂ ) _n , then R ² is H or a C _1-6 alkyl group; Or CR ¹ R ² forms a cycloalkyl or heterocycloalkyl ring, optionally substituted with R ⁷ ; B is C _1-6 alkyl-aryl group, C _1-6 alkyl group, cycloalkyl group, C _1-6 alkyl-cycloalkyl group, cycloalkenyl group, heterocycloalkenyl group, C _1-6 alkyl-heteroaryl group, heterocyclo An alkyl group, a C _1-6 alkyl-heterocycloalkyl group, an aryl group or a heteroaryl group, these groups are R ³ , C _1-6 alkyl-R ³ , C _2-6 alkenyl-R ³ , aryl (optionally substituted with R ³ ), aryl-C _1-6 alkyl-R ³ , C _1-6 alkyl-aryl (optionally substituted with R ³ ), C _{1- 6} alkyl-heteroaryl (optionally substituted with R ³ ), aryl-C _2-6 alkenyl-R ⁵ , heteroaryl (optionally substituted with R ³ ), heteroaryl-C _1-6 alkyl-R ³ , cyclo Optionally substituted with a substituent selected from the group consisting of alkyl (optionally substituted with R ³ ), or heterocycloalkyl (optionally substituted with R ³ ); R ³ is a C _1-6 alkyl group, halogen, CN, NO ₂ , N (R ⁴ ) ₂ , OR ⁴ , COR ⁴ , C (= NOR ⁶ ) R ⁴ , CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ or SO ₂ N (R ⁴ ) ₂ , R ⁴ is H or a C _1-6 alkyl group, aryl group, C _1-6 alkyl-aryl group, heteroaryl group, C _1-6 alkyl-heteroaryl group, cycloalkyl group, C _1-6 alkyl-cycloalkyl group, hetero A cycloalkyl group and a C _1-6 alkyl-heterocycloalkyl group, wherein said group is optionally R ⁶ , COR ⁶ , SO _0-2 R ⁶ , CO ₂ R ⁶ , OR ⁶ , CONR ⁸ R ⁶ , NR ⁸ R ⁶ , halogen, CN, SO ₂ NR ⁸ R ⁶ or NO ₂ , In each of N (R ⁴ ) ₂ , R ⁴ groups are the same as or different from each other, or N (R ⁴ ) ₂ is optionally R ⁶ , COR ⁶ , SO _0-2 R ⁶ , CO ₂ R ⁶ , OR ⁶ , A heterocycloalkyl group substituted with CONR ⁸ R ⁶ , NR ⁸ R ⁶ , halogen, CN, SO ₂ NR ⁸ R ⁶ or NO ₂ ; R ⁵ is COR ⁴ , CON (R ⁴ ) ₂ , CO ₂ R ⁶ or SO ₂ R ⁶ , R ⁶ is a C _1-6 alkyl group, an aryl group, a C _1-6 alkyl-aryl group, a heteroaryl group, or a C _1-6 alkyl-heteroaryl group, R ⁷ is OR ⁴ , COR ⁴ , CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ , SO ₂ N (R ⁴ ) ₂ , halogen, CN or cyclo Imidyl group (optionally substituted with R ⁸ ); And R ⁸ is H or a C _1-6 alkyl group. delete The compound of claim 1, wherein B is a cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, and these groups are R ³ , aryl group (optionally substituted with R ³ ) and heteroaryl group (optionally substituted with R ³ ) Compound optionally substituted by a substituent selected from. The compound of claim 1, wherein R ³ is OR ⁴ or COR ⁴ . The compound of claim 1, wherein R ⁴ is an optionally substituted aryl group, a C _1-6 alkyl-aryl group, a heteroaryl group, or a C _1-6 alkyl-heteroaryl group. The compound of claim 1, wherein R ⁷ is CO ₂ R ⁸ , CON (R ⁴ ) ₂ , NR ⁴ R ⁵ , S (O) _0-2 R ⁶ , SO ₂ N (R ⁴ ) ₂ or optionally substituted cycloimide A compound which is a dill group. delete delete 2. Compounds according to claim 1, wherein B is an optionally substituted heterocycloalkenyl group, heterocycloalkyl group or heteroaryl group and comprises heteroatoms N bonded to X. The compound according to claim 9, wherein B is an optionally substituted azetidinyl group, pyrrolidinyl group, tetrahydrofuranyl group, piperidinyl group, indolinyl group, tetrahydroquinolinyl group, pyridyl group, indolyl group or quinolyl group. The compound of claim 1, wherein the compound is N- {1S- [4- (4-chlorophenyl) piperazin-1-sulfonylmethyl] -2-methylpropyl} -N -hydroxyformamide. The compound of claim 1, wherein the compound is in the form of a single enantiomer or diastereomer. delete delete delete delete delete delete delete delete delete delete delete delete delete