KR20010089617A - ACETYLENIC β-SULFONAMIDO AND PHOSPHINIC ACID AMIDE HYDROXAMIC ACID TACE INHIBITORS - Google Patents

Abstract

The present invention relates to the use of hydroxamic acid of formula (B) useful for treating the symptoms of a disease mediated by TNF-a, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage damage . R ₅ , R ₆ , R ₇ , R ₈ , R ₁₁ , R ₁₂ , X, Y and Z have the meanings given in the specification.

Formula B

Description

Acetylenic beta-sulfonamido and phosphinic acid amide hydroxamic acid tiac inhibitor. ≪ Desc / Clms Page number 2 > < RTI ID = 0.0 >

TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane-bound TNF-α precursor protein. TNF- [alpha] is a well-established anti-tumor positive [Old, L. Science, 1985, 230, 630.], as well as rheumatoid arthritis [Shire, M. G .; Muller, G.W. Exp. Opin. Ther. Patents 1998, 8 (5), 531; Grossman, J. M .; Brahn, E.J. Women's Health 1997, 6 (6), 627; Isomaki, P .; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G .; Lupia, E. Drugs, 1998, 55 (5), 613.], septic shock [Mathison, et al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, P. F .; Grau, G. E .; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B .; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.], appetite deficiency, inflammation [Ksontini, R .; MacKay, S. L. D .; Moldawer, L.L. Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92 (6), 1379; Ferrari, R .; Bachetti, T .; et. al. Circulation, 1995, 92 (6), 1479.], sciatica reperfusion injury, inflammatory diseases of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G.S .; Shargill, N.S .; Spiegelman, B. M .; et. al. Science, 1993, 259, 87.] and HIV infection [Peterson, P. K .; Gekker, G .; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J .; Lopez-Soriano, F.J. Argiles, J. M. Med. Res. Reviews, 1995, 15 (6), 533.], which is a pro-inflammatory cytokine. For example, studies with anti-TNF- [alpha] antibodies and transgenic animals demonstrate that blocking TNF-alpha formation inhibits progression of arthritis (Rankin, E. C .; Choy, E. H .; Kassimos, D .; Kingsley, G. H .; Sopwith, A. M .; Isenberg, D. A .; Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), a197-M2Z.]. This observation has recently been expanded to humans as described in " TNF-a in Human Diseases ", Current Pharmaceutical Design, 1996, 2, 662.

Small molecule TACE inhibitors are expected to have potential for the treatment of various diseases. Although a variety of TACE inhibitors have been known, many of these molecules are peptide and peptide-like molecules with problems of bioavailability and pharmacokinetics. In addition, many of these molecules are non-selective and potent inhibitors of matrix metalloproteinases, particularly MMP-1. Inhibition of MMP-1 (collagenase 1) was assumed to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20]. Thus, long-acting, selective, orally bioavailable non-peptide inhibitors of TACE are highly desirable for the treatment of the aforementioned diseases.

As shown below, examples of sulfonamide hydroxamic acid MMP / TACE inhibitors wherein the two carbon chains separate hydroxamic acid and sulfonamide nitrogen are disclosed in WIPO International Publication Nos. WO 9816503, WO 9816506, WO 9816514, and WO 9816520 and U.S. Pat. 5,776,961.

The

US Patent Nos. 5,455,258, 5,506,242, 5,552,419, 5,770,624, 5,804,593, and 5,817,822 and European Patent Application EP606,046A1 and WIPO International Publication Nos. WO9600214 and WO9722587 disclose an aryl sulfonamide hydroxycarboxylic acid salt as shown below in which one carbon separates hydroxamic acid and sulfonamide nitrogen Desc / Clms Page number 3 > discloses non-peptide inhibitors of matrix metal metalloproteinases and / or TACE, which are typical of tri-acid. Further disclosures describing sulfonamide basic MMP inhibitors which are the variations of the sulfonamide-hydroxamates shown below or of the sulfonamide-carboxylates are described in European patent applications EP-757037-A1 and EP-757984-A1 and WIPO International Published pending WO9535275, WO9535276, WO9627583, WO9719068, WO9727174, WO9745402, WO9807697 and WO9831664, WO9833768, WO9839313, WO9839329, WO9842659 and WO9843963. The discovery of this type of MMP inhibitor is described in MacPherson, et. al., J. Med. Chem., (1997), 40, 2525 and in Tamura, et. al., J. Med. Chem. (1998), 41, 640.

The

As shown below, the disclosure of MMPs in which the carbon at the alpha position of the hydroxamic acid is bound in the ring to the sulfonamide nitrogen and / or the beta-sulfonamide-hydroxamate inhibitor of TACE is disclosed in U.S. Pat. Patent 5,753,653, WIPO International Publication WO9633172, WO9720824, WO9827069, WO9808815, WO9808822, WO9808823, WO9808825, WO9834918, WO9808827, Levin, et. al. Bioorg. & Med. Chem. Letters 1998, 8, 2657 and Pikul, et. al. J. Med. Chem. 1998, 41, 3568.

The

Patent applications DE19,542,189-A1, WO9718194 and EP803505 describe additional examples of cyclic sulfonamides as MMP and / or TACE inhibitors. In this case, the sulfonamide-containing ring is fused to an aromatic or heteroaromatic ring.

The

An analog of the sulfonamide is a phosphinic acid amide hydroxamic acid MMP / TACE inhibitor, represented by the following formula, which is described in WIPO International Publication No. WO9808853.

The

As shown below, the sulfonamide MMP / TACE inhibitor wherein the thiol is a zinc chelating group is described in WIPO International Application 9803166.

The

It is an object of the present invention to provide arylsulfonamides and phosphinic acid amide hydroxamic acid MMP / TACE inhibitors wherein Y (sulfonyl or phosphinylaryl) is para-substituted with substituted butyryl moieties or propargyl ethers, amines or sulfides . Such compounds provide enhanced levels of TACE activity inhibition and / or selectivity for MMP-1 in vitro and in cellular assays. Such compounds may therefore be used in the treatment of diseases mediated by TNF.

SUMMARY OF THE INVENTION

The TACE and MMP inhibiting ortho-sulfonamidohydroxamic acids or pharmaceutically acceptable salts thereof of the present invention are represented by Formula B:

In this formula,

C (= O) NHOH moiety and the -NR ₅ - moiety are bonded to an adjacent carbon and;

X is SO ₂ or -P (O) R ₁₀ ;

Y is a 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, phenyl or naphthyl ring; Provided that X and Z can not combine with adjacent atoms of Y;

Z is O, NH, CH ₂ or S;

R < ₅ > is hydrogen or alkyl of 1-6 carbon atoms;

R ₆ and R ₇ are each independently hydrogen or methyl;

R ₈ is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, N, NR ₉ , S And 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, and 5-7 membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR ₉ , S and O;

R ₉ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl;

R ₁₀ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl or 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O;

R ₁₁ and R ₁₂ are independently having 1 to 3 heteroatoms selected from hydrogen, 1-6 carbon atoms alkyl, 3-6 cycloalkyl carbon atoms, N, NR _9, S and O 5-7 Membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR < ₉ >, S and O, and wherein any double bond indicated by the dashed line is present;

R ₁₁ and R _{12 taken} together with the carbon to which they are attached form a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, , 5- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR ₉ , S and O, 5- to 10-membered saturated or unsaturated mono- or bicyclic rings optionally fused with one of the phenyl or naphthyl rings Form an alkyl ring;

R ₁₁ and R ₁₂ are taken together with the carbon they are bonded, N, NR _9, 5-7 membered monocyclic or acyclic having 1 to 3 heteroatoms selected from S, O-heteroaryl, 5-7 round of saturation or A 5-10 membered saturated or unsaturated mono- or bicyclic heterocycloalkyl having 1-2 heteroatoms selected from N, NR < ₉ >, S and O, optionally fused with an unsaturated cycloalkyl ring or one of the phenyl or naphthyl rings, Lt; / RTI >

The dotted line represents any double bond;

n = 0-2.

Preferred compounds of the present invention include compounds of formula (B) wherein X is SO ₂ .

More preferred compounds of the invention include compounds of formula (B) wherein X is SO ₂ and Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively.

More preferred compounds of the invention include compounds of formula (B) wherein X is SO ₂ , Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively, and Z is oxygen.

A more preferred compound of the present invention is a compound of formula B wherein X is SO ₂ and Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, Z is oxygen and R ₆ and R ₇ are hydrogen .

More preferred compounds of the present invention are those wherein X is SO ₂ , Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, Z is oxygen, R ₆ and R ₇ are hydrogen, and R ₈ ≪ / _RTI > is-CH2OH or methyl.

More preferred compounds of the invention are (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide;

(1 R, 2R) -2 - ({[4- (2-Butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide;

3 - {[[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxypropanamide;

3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) -N-hydroxypropanamide;

(1R, 2S) -2 - [{[4- (2-Butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclopentanecarboxamide;

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] N-hydroxycyclopentanecarboxamide;

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide;

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide;

(2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxybicyclo [2.2.1] Carboxamide; And

(Methyl) amino) -N-hydroxybicyclo [2.2.1] heptanecarboxylic acid dihydrochloride was prepared in the same manner as in Example 1, except that (1R, 2R, 3S, Heptane-2-carboxamide.

Heteroaryl, used throughout, is a 5-10 membered mono- or bicyclic ring having 1-3 heteroatoms selected from N, NR ₉ , S and O. The heteroaryl is preferably

A (wherein, K is NR _9, O or S, R ₉ is hydrogen, 1-6 carbon atoms alkyl, 3-6 cycloalkyl or phenyl, a carbon atom). Preferred heteroaryl rings are pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, , Benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzdisasol and benzoxazole.

The heteroaryl groups of the present invention may be optionally mono- or di-substituted.

Heterocycloalkyl as used herein is N, NR _4, S or O 1 or 2 saturated 5-to 10-having a hetero atom or an unsaturated mono or selected from the non-refers to a cyclic ring. The heterocycloalkyl ring of the present invention is preferably

Is selected from (wherein, M is NR _4, O or S, R ₄ is hydrogen, 1-6 carbon atoms alkyl, 3-6 carbon atoms, cycloalkyl, phenyl, naphthyl, heteroaryl, - _{S (O) n R 2,} -COOR 2, -CONR 2 R 3, -SO ₂ R ₃ or NR a ₂ -COR _2). Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. The heterocycloalkyl groups of the present invention may be optionally mono- or di-substituted.

As used herein, aryl refers to phenyl or naphthyl, which may optionally be mono-, di-or tri-substituted.

Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight and branched chain moieties. The alkyl, alkenyl, alkynyl and cycloalkyl groups may be unsubstituted or mono- or poly-substituted (hydrogen or a carbon bonded to a carbon or other carbon of the ring). The cycloalkyl group may be mono or bicyclic. Examples of monocyclic cycloalkyl groups include cyclopentyl and cyclohexyl. Examples of bicycloalkylalkyl groups include bicycloheptane and adamantyl.

Halogen means bromine, chlorine, fluorine and iodine.

Suitable substituents for aryl, heteroaryl, alkyl, alkenyl, alkynyl and cycloalkyl include halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 3-6 carbon atoms, _{cycloalkyl, -OR 2, -CN, -COR 2} , 1-4 pieces of carbon atoms, perfluoroalkyl, alkyl with 1-4 -O- perfluoroalkyl carbon atoms, -CONR _{2 R 3, -S (O)} n R 2, -OPO (OR 2) OR 3, -PO (OR 2) R 3, -OC (O) NR 2 R 3, -C (O) NR 2 OR 3 , -COOR ₂ , -SO ₃ H, -NR ₂ R ₃ , -N [(CH ₂ ) ₂ ] ₂ NR ₂ , -NR ₂ COR ₃ , -NR ₂ COOR ₃ , -SO ₂ NR ₂ R ₃ , _{NO 2, -N (R 2)} SO 2 R 3, -NR 2 CONR 2 R 3, -NR 2 C (= NR 3) NR 2 R 3, -NR 2 C (= NR 3) N (SO 2) _{R 2 R 3, NR 2 C} (= NR 3) N (C = O) R 2 R 3, -SO 2 NHCOR 4, -CONHSO 2 R 4, - tetrazol-5-yl, -SO ₂ NHCN, - SO ₂ NHCONR ₂ R ₃ , phenyl, naphthyl, heteroaryl or heterocycloalkyl, wherein -NR ₂ R ₃ is selected from pyrrolidine, piperidine, morpholine, thiomorpholine , Four Jolly Dean, thiazolidine, pyrazolidine Jolly Dean, piperazine, or azetidine may form a ring, and; R ₂ and R ₃ are each independently hydrogen, alkyl of 1-6 carbon atoms, 3-6 carbon atoms R ₄ is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl, - _{S (O) n R 2,} -COOR 2, -CONR 2 R 3, -SO 2 NR 2 R 3 or -COR _2, and; n is 0 to 2).

Suitable substituents of the heterocycloalkyl groups of the present invention include, but are not limited to, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, heteroaryl and heterocycloalkyl.

If the moieties contain one or more substituents of the same designation, then each of these substituents may be the same or different.

Pharmaceutically acceptable salts are those salts of the compounds of the invention which contain basic moieties such as organic and inorganic acids such as acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, For example, be formed from malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and similar known acids. Salts may also be formed from organic bases and inorganic bases, preferably alkali metal salts, such as sodium, lithium or potassium, when the compounds of the present invention contain acidic moieties.

The compounds of the present invention may contain asymmetric carbon atoms and some of the compounds of the present invention may contain one or more asymmetric centers to form optical isomers and diastereomers. Without considering the stereochemistry, the present invention relates to such optical isomers and diastereomers; And enantiomerically pure R and S stereoisomers separated from racemic; And other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that optical isomers or stereoisomers, including diastereomers and enantiomers, may have favorable properties over others. Thus, when describing and claiming the present invention, it is clearly understood that when a racemic mixture is described, the others describe and claim optical isomers or stereoisomers that include both substantially free diastereomers and enantiomers.

The compounds of the present invention inhibit the enzymes MMP-1, MMP-9, MMP-13, and TNF-a converting enzyme (TACE) and inhibit the proliferation of arthritis, metastatic tumors, tissue ulcers, abnormal wound healing, periodontal disease, Bone diseases and HIV infections. In particular, the compounds of the present invention are particularly useful in the treatment of diseases mediated by TNF, providing enhanced levels of inhibition of TACE activity and / or increased selectivity for MMP-1 in vitro and in cellular assays.

The present invention relates to acetylenic arylsulfonamides and phosphinic acid amide hydroxamic acids which act as inhibitors of TNF-alpha converting enzyme (TACE). The compounds of the present invention are useful in the treatment of conditions mediated by TNF-a, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage damage.

Accordingly, the present invention provides a process for preparing a compound of formula (I) as described above, which comprises:

a) reacting a compound of formula 5 or a reactive derivative thereof with a hydroxylamine to provide the corresponding compound of formula B;

b) deprotecting the compound of formula 6 to provide the corresponding compound of formula B;

c) decomposing a mixture of optically active isomers of the compound of formula B (e. g., racemic) to separate one enantiomer or diastereomer substantially absent of the other enantiomer or diastereomer;

d) Acidifying the basic compound of formula (B) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt.

In this formula,

R ₅ , R ₆ , R ₇ , R ₈ , R ₁₁ , R ₁₂ , X, Y, Z and the dotted line are as described above,

Q is OH,

R ₃₀ is a suitable protecting group such as t-butyl, benzyl and trialkylsilyl.

In the case of process a), the reaction can be carried out by methods known in the art, for example by reaction of an acid chloride reactive derivative with a hydroxylamine.

Removal of the protecting group, as described in method b), may be carried out in a manner known in the art to provide the hydroxamic acid.

In case of process c) standard separation techniques can be used to separate certain enantiomeric or diastereomeric forms. For example, the racemic mixture can be converted to a mixture of optically active diastereomers by reaction with a single enantiomer of the " dissociation " (e.g., by formation of diastereomeric salts or covalent bonds) . The resulting mixture of optically active diastereoisomers can be separated by standard techniques (e. G., Crystallization or chromatography), and each optically active diastereomer is then treated to remove " Releases a single enantiomer of the invention compound. Chiral chromatography (using a chiral support, eluent or ion-pairing agent) can also be used to directly isolate the enantiomer mixture.

The compound of formula (B) can be isolated by treatment with an acid as described above in the form of a pharmaceutically acceptable acid, for example an organic or inorganic acid salt.

The present invention further relates to a process for the preparation of a compound of formula (B) comprising at least one of the following reactions:

1) alkylating a compound of formula (I) or a salt or solvate thereof with a compound of formula (II)

2) reacting the compound of formula 2, or a salt or solvate thereof, with a chlorinating agent such as thionyl chloride, chlorosulfonic acid, oxalyl chloride, phosphorus pentachloride or a halogenating agent such as fluorosulfonic acid or thionyl bromide, ≪ / RTI >

In this formula,

J is fluorine, bromine, or chlorine.

The resulting sulfonyl chloride, fluoride or bromide can be prepared by reacting the compound with a 1,2,4-triazole, imidazole or benzotriazole, respectively, so that J is 1,2,4-triazolyl, imidazolyl or benzotriazole Lt; / RTI > can be further converted into a triazolidinedione, zolyl, triazolid, imidazolide or benzothiazolide derivative. R ₆ , R ₇ and R ₈ are as described above.

The present invention further relates to a process for the preparation of a compound of formula (B) comprising at least one of the following reactions:

1) alkylating phenol or a salt or solvate thereof with a compound of formula 4;

2) The compound of formula (4) or its salt or solvate is reacted with chlorosulfonic acid to prepare the compound of formula (2).

Particularly preferred intermediates are compounds of formulas (2) and (3), with the proviso that R < ₆ >

The compounds of the present invention are prepared using conventional techniques known to those skilled in the art of organic synthesis. The starting materials used in the preparation of the compounds of the present invention are known and are prepared or marketed by known methods.

One of ordinary skill in the art will perceive that a particular reaction is best carried out when other potentially reactive functional groups on the molecule are masked or protected to avoid and / or avoid undesired side reactions or to increase the yield of the reaction. For this purpose, the skilled artisan can use a protecting group. An example of such a protection group moieties may be found in TW Greene, PGM Wuts "Protective Groups in Organic Synthesis", 2 nd Edition, 1991, Wiley & Sons, New York. The reactive side chain functional group on the amino acid starting material is preferably protected. The need and choice of a protecting group for a particular reaction depends on the nature of the functional group (hydroxy, amino, carboxy, etc.) that is known and well-known to those skilled in the art and depends on the structure and stability of the molecule do.

When preparing or synthesizing a compound of the present invention containing an aryl, heteroaryl or heterocyclic ring, one of ordinary skill in the art will perceive that the substituent on the ring can be prepared before, after, or simultaneously with formation of the ring. For clarity, such cyclic substituents have been omitted from the reaction formula hereinbelow.

One skilled in the art will appreciate that the nature and sequence of the synthetic steps provided may vary for the purpose of optimizing the formation of the compounds of the present invention.

The hydroxamic acid compound (1) of the present invention can be obtained by converting the carboxylic acid (2) in which A = R ₁₁ and R ₁₂ into the corresponding acid chloride or anhydride according to Scheme 1, reacting it with a suitable peptide coupling agent, Is reacted with a hydroxylamine to provide (1), or reacting with a protected hydroxylamine derivative to provide (3). Compounds (3) wherein R < ₃₀ > is t-butyl, benzyl, trialkylsilyl or other suitable protecting groups can then be deprotected in a known manner to provide the hydroxamic acid (1).

The carboxylic acid (2) can be prepared as shown in Scheme 2. The amino acid derivative (4) wherein R ₄₀ is hydrogen or a suitable carboxylic acid protecting group can be sulfonated or phosphorylated by reaction with a compound (5) wherein J is a suitable leaving group including, but not limited to chlorine. The NH compound 6 is then alkylated with a base such as R ₃ J and potassium carbonate or sodium hydride in a polar aprotic solvent such as acetone, N, N-dimethylformamide (DMF) or tetrahydrofuran (THF) (7). ≪ / RTI > Compound (7) is also available through direct reaction of (5) with an N-substituted amino acid derivative (8). (7) to the carboxylic acid is carried out by acid, base hydrolysis or other methods consistent with the choice of protecting group R ₄₀ and the presence of a carbon-carbon triple bond.

The method for preparing the sulfonylating agent (5) is shown in Scheme 3. Thus, a sulfonic acid salt (9) wherein ZR ₅₀ is a hydroxy, thiol or substituted amino residue is alkylated with acetylen (10), where J is a suitable leaving group such as a halogen mesylate, tosylate or triflate to provide (11) can do. Acetylene 10 is a commercially available or known compound, or they can be synthesized by methods known to those skilled in the art. The sulfonate (11) is reacted with the corresponding sulfonyl chloride or other sulfonylating agent (5) in a known manner such as by reaction with oxalyl chloride or the substituents R ₆ , R ₇ and R ₈ and other reactants compatible with acetylene, . ≪ / RTI > Alternatively, the disulfide 12 can be converted to diacetylene 13 by reduction of the disulfide bond followed by reaction with the compound 10 to provide a similar thiol which can be converted to (5) by known methods have. (15) with an alkylation of phenol, thiophenol, aniline or protected aniline (14) to (10), then the reaction with chlorosulfonic acid is carried out in the presence of an oxalyl chloride or a similar reactant, P-toluenesulfonic acid. Thiophenol (17) is also a precursor of (5) through protection of the thiol, alkylation of ZH where Z is O, N or S and deprotection of the sulfur followed by oxidation to the sulfonic acid (16).

Analogs containing phosphorus of formula (8) can be prepared using a similar methodology, as shown in Scheme 4.

Acetylene side chains can also be added after sulfonylation or phosphorylation of amino acid derivatives, as shown in Scheme 5. Thus, the amino acid derivatives 4 and 8 can be sulfonated or phosphorylated with a compound (20) wherein ZR ₅₀ is hydroxy or protected hydroxy, thiol or amine and, if necessary, alkylated with R ₇ J as in Scheme 2 (21). Subsequent alkylation of the resulting phenol, thiol, or amine with (10) to give an R < ₅₀ > blocking group to give (22) provides (7). If ZR ₅₀ is significant for OH, then a deprotection step to provide (22) is not required.

(7) can be synthesized as shown in Scheme 6 starting with amino acid derivatives (4 and / or 8). Subsequent to sulfonylation or phosphorylation with the para-nitroaryl compound (23), for example 4-nitrobenzenesulfonyl chloride, R ₅ J (4) using a base such as potassium carbonate or sodium hydride in DMF (24). ≪ / RTI > Hydrogenation of the nitro moiety to give aniline (25) and reduction to palladium, tin chloride or other known methods on carbon and subsequent alkylation to (10) provides (7). Aniline 25 can be converted to an appropriate nitrogen protecting group such as t-butoxycarbonyl to provide (26), prior to alkylation with (10) and subsequent deprotection after the alkylation step.

Acetylene derivatives 7 are also available from fluoro compounds 27 which are readily prepared from the amino acid derivatives 4 and / or 8 by reaction with fluoroaryl 26, as shown in Scheme 7. Thiol or amino group (R ₇₀ is a suitable protecting group HZR ₇₀ ) in a polar aprotic solvent such as DMF in the presence of a base such as sodium hydride and then deprotected (28), which in turn can be alkylated (10) to provide (7). Z is of the 27 conversion to sulfur 28 may also be accomplished with _{Na 2 S, K 2 S,} NaSH or KS (C = S) OEt. Fluorine of formula (27) can also be directly substituted (7) in a polar aprotic solvent in the presence of a base such as sodium hydride with a propargyl derivative (29) wherein Z is O, S or NH.

Compound (7) wherein Z is a methylene group is available through (30) as shown in Scheme (8). Benzyl bromination of (30) to N-bromosuccinimide in a chlorinated hydrocarbon solvent provides bromide (31). Substitution of the bromide with a suitable propynyl cufrate then provides the sulfonamide (8).

The compounds of the present invention may also be prepared by modifying the substituents on the acetylene side chain at any stage after sulfonylation or phosphorylation of the starting amino acid derivative (4 or 8). Functional groups such as halogen, hydroxy, amino, aldehyde, ester, ketone and the like can be manipulated by standard methods to form the moiety defined by R ₁ -R ₈ of compound (1). It will be appreciated by those skilled in the art of organic synthesis that the successful use of such methods depends on the compatibility of the substituents on other parts of the molecule. Changes in the protection group and / or step sequence described herein may be necessary.

Part of the methods available for the derivatization of compounds of formula (32) (equivalents of compounds (7) wherein R ₁₂ is hydrogen) are shown in Scheme 9. Following metallization of the terminal acetylene 32, addition of an aldehyde or alkyl halide, sulfonate or triflate provides derivatives 33 and 34. (32) with formaldehyde and amine provides the Mannich adduct (35). The addition of cyanogen bromide to compound (35) provides propargyl bromide (36) which can be substituted with various nucleophiles to provide, for example, ethers, thioethers and amines (37). Palladium catalyzed coupling reaction of (32) provides aryl or heteroaryl acetylene (38). Successful use of such methods is dependent on the compatibility of the substituents on different parts of the molecule and is perceived by those skilled in the art of organic synthesis. And may require a protecting group and / or changes in the sequence of steps described herein, R _35, R _45, R _55, R ₆₅ and R ₇₅ is methyl, for alkyl, for example.

The following specific examples illustrate the preparation of exemplary compounds of the invention. Starting materials, intermediates and reactants are either commercially available or can be readily prepared according to standard literature procedures by those skilled in the art of organic synthesis.

Example 1

(Trans) -2- (4-methoxybenzenesulfonyl) aminocyclohexanecarboxylic acid

To a room temperature solution of trans-2-amino-1-cyclohexylcarboxylic acid 1 g (6.8 mmol) in 50 ml of dioxane: H ₂ O (1: 1) containing 1.7 ml (12.2 mmol) 1.54 g (7.46 mmol) of methoxybenzenesulfonyl chloride are added. The mixture is stirred at 25 < 0 > C for 18 hours. The resulting mixture was diluted with pentane to give 1.119 g (51%) of the desired sulfonamide product as a white solid. _{^{1 H NMR (DMSO-d 6}} ): 7.7 ppm (dd, 2H, Ar), 7.4 ppm (d, 1H, NH), 7.0 ppm (dd, 2H, Ar), 3.8 ppm (s, 3H, OMe), 3.5 ppm (m, 1H, N-CH), 1.0-1.7 ppm (m, 9H, hydrocarbon).

Example 2

(Cis) -2- (4-methoxybenzenesulfonyl) aminocyclohexanecarboxylic acid

In the same manner as described in example 1, 2.5 g (17 mmol) of cis-2-amino-1-cyclohexylcarboxylic acid provides 3.283 g (60%) of the desired carboxylic acid. Electrospray mass spectrum 314.1 (M + H) < ⁺ & gt ^; .

Example 3

(Trans) -2- (4-methoxybenzenesulfonyl) aminocyclohexanecarboxylic acid t-butyl ester

1 ml (4 mmol) of N, N-dimethylformamide di-tert-butyl acetal is added to a solution of 0.313 g (1 mmol) of the product from Example 1 in 5.0 ml of toluene. The resulting mixture is heated under nitrogen at < RTI ID = 0.0 > 110 C < / RTI > for 4 hours and then cooled to room temperature. The solution is then poured onto the top of a silica gel column. Chromatography on silica gel, eluting with 10-20% ethyl acetate / hexanes, gives 353 mg (96%) of the desired ester as a white solid. _{^{1 H NMR (CDCl 3):}} 7.8 ppm (dd, 2H, Ar), 7.0 ppm (dd, 2H, Ar), 5.7 ppm (d, 1H, NH), 3.9 ppm (s, 3H, OMe), 3.4 ppm (m, 1H, N-CH), 2.5 ppm (m, 1H, CH-CO ₂ -), 1.0-2.0 ppm (m, 17H, hydrocarbon).

Example 4

(Cis) -2- (4-methoxy-benzenesulfonylamino) -cyclohexanecarboxylic acid tert-butyl ester

In a manner similar to that described in Example 3, 1.438 g (4.59 mmol) of the product from Example 2 gives the desired tert-butyl ester as a colorless oil, 0.739 g (44%). Electrospray mass spectrum 370.1 (M + H) < ⁺ & gt ^; .

Example 5

(Trans) -2- [benzyl- (4-methoxybenzenesulfonyl) amino] -cyclohexanecarboxylic acid t-butyl ester

To a solution of 1.146 g (3.1 mmol) of the product from Example 3 in 31 ml of DMF is added 0.137 g (3.42 mmol) of 60% sodium hydride. The resulting mixture is stirred at 25 < 0 > C for 30 minutes and then 0.42 ml (3.50 mmol) of benzyl bromide are added all at once. The solution mixture is stirred at 55 占 폚 for 10 hours, then poured into water and extracted with ether. Washed combined organics with water and brine, dried over MgSO _4, filtered and concentrated in vacuo to give a white solid which was recrystallized from ethyl acetate / hexane to give the desired product 1.364 g (95%) of . _{^{1 H NMR (CDCl 3):}} 7.7 ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9 ppm (dd, 2H, Ar), 4.5-4.7 ppm (AB quartet, 2H, _{CH 2 -Ar), 3.9 ppm (} s, 3H, OMe), 4.0 ppm (m, 1H, N-CH), 2.9 ppm (m, 1H, CH-CO 2 -), 1.0-2.3 ppm (m, 17H , Hydrocarbon protons).

Example 6

(Cis) -2- [benzyl- (4-methoxy-benzenesulfonyl) -amino] -cyclohexanecarboxylic acid tert-butyl ester

In the same manner as described in example 5, 0.600 g (1.62 mmol) of the product from example 4 gave 0.310 g (42%) of the desired benzylated ester as a colorless oil. Electrospray mass spectrum 460.1 (M + H) < ⁺ & gt ^; .

Example 7

(Trans) -2- [benzyl- (4-methoxy-benzenesulfonyl) -amino] -cyclohexanecarboxylic acid

To a solution of 1.364 g (2.97 mmol) of the product from example 5 in 10 ml of dichloromethane is added 10 ml of trifluoroacetic acid and the mixture is stirred at room temperature for 4 hours. The solvent was then concentrated in vacuo and chromatography on silica gel, eluting with 10-100% ethyl acetate / hexanes as the residue, gave 1.092 g (73%) of the desired product as a white solid. Electrospray mass spectrum 404.2 (M + H) < ⁺ & gt ^; .

Example 8

(Cis) -2- [benzyl- (4-methoxy-benzenesulfonyl) -amino] -cyclohexanecarboxylic acid

In the same manner as described in Example 7, 0.240 g (0.522 mmol) of the product from Example 6 gave 0.207 g (98%) of the desired carboxylic acid as a white solid. Electrospray mass spectrum 404.0 (MH) ^- .

Example 9

4-But-2-ynyloxy-benzenesulfonic acid sodium salt

59.96 g (0.45 mol) of 1-bromo-2-butyne are added to a solution of 52.35 g (0.225 mmol) of 4-hydroxybenzenesulfonate sodium salt in 225 ml of a 1 L isopropanol and 1.0 N solution of sodium hydroxide. The resulting mixture is heated to 70 < 0 > C for 15 hours, then the isopropanol is removed by evaporation under vacuum. The resulting white precipitate was collected by filtration, washed with isopropanol and ether, and then dried in vacuo to give 56.0 g (100%) of butinyl ether as a white solid.

Example 10

4-But-2-ynyloxy-benzenesulfonyl chloride

To a 0 ° C solution of 43.8 ml (0.087 mol) of a 2 M oxalyl chloride / dichloromethane solution in 29 ml of dichloromethane is added dropwise 6.77 ml (0.087 mol) of DMF followed by 7.24 g (0.029 mol) of the product of example 9. The reaction mixture is stirred at 0 < 0 > C for 10 minutes, then warmed to room temperature and stirred for 2 days. The reaction mixture is then poured into ice and extracted with 150 ml of hexane. Sikimyeo wash the organics with water and brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo to give the sulfonyl chloride 6.23 g (88%) as a yellow solid; mp 63-65 [deg.] C, EI mass spectrum: 243.9 (M ^< ^{+ &} gt ^; ).

Example 11

But-2-ynyloxy-benzene

To a solution of 6.14 g (0.023 mol) of triphenylphosphine dissolved in 100 ml of benzene and 40 ml of THF is added 1.75 ml (0.023 mol) of 2-butyn-1-ol. After 5 minutes, 2.00 (0.023 mol) of phenol dissolved in 10 ml of THF is added to the reaction mixture, and 3.69 ml (0.023 mol) of diethyl azodicarboxylate are added. The resulting reaction mixture is stirred at room temperature for 18 hours and then concentrated in vacuo. Chromatography on silica gel eluting with ethyl acetate / hexane (1: 10) as a residue gives 2.18 g (70%) of butynyl ether as a clear liquid. EI mass spectrum: 146.0 MH ^< ^{+ &} gt ^; .

Example 12

4-But-2-ynyloxy-benzenesulfonyl chloride

To a solution of 0.146 g (1.0 mmol) of the product of example 11 in 0.3 ml of dichloromethane in an N ₂ under acetone / ice bath is added dropwise a solution of 0.073 ml (1.1 mmol) of dichlorosulfonic acid in 0.3 ml of dichloromethane. After the addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. 0.113 ml (1.3 mmol) of oxalyl chloride and then 0.015 ml of DMF are added dropwise to the reaction mixture. The reaction mixture is heated to reflux for 2 hours, then diluted with hexane and poured into ice water. The organic layer is washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 0.130 mg (53%) of the desired product as a pale brown solid.

Example 13

(1R, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -cyclohexanecarboxylic acid

To a room temperature solution of trans-2-amino-1-cyclohexylcarboxylic acid 1.5 g (10.2 mmol) in 75 mL of dioxane: H ₂ O (1: 1) containing 2.55 mL (18.3 mmol) 3.0 g (11.2 mmol) of neooxybenzenesulfonyl chloride are added. The mixture is stirred at 25 [deg.] C for 18 hours. The resulting mixture is diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid (3 times). The organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo to give (lR, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylic acid as a white solid. Electrospray mass spectrum 352.2 (M + H) < ⁺ & gt ^; .

Example 14

(1R, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -cyclohexanecarboxylate

To a solution of 2.1 g (6 mmol) of (lR, 2R) -2 - ({[4- (2-butynyloxy) phenyl] -sulfonyl} amino) cyclohexanecarboxylic acid in 30 ml of toluene was added N, N-dimethylformamide 6 ml (24 mmol) of di-tert-butyl acetal are added. The resulting mixture is heated under nitrogen at < RTI ID = 0.0 > 110 C < / RTI > for 4 hours and then cooled to room temperature. The solution is then poured onto the top of a silica gel column. Chromatography on silica gel, eluting with 10-20% ethyl acetate / hexanes, gave tert-butyl (1R, 2R) -2- ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) 1.7 g of cyclohexanecarboxylate are provided. Electrospray mass spectrum 408.3 (M + H) < ⁺ & gt ^; .

Example 15

(1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -cyclohexanecarboxylate

To a solution of 1.38 g (3.4 mmol) of tert-butyl (1R, 2R) -2 - {[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylate in 20 ml of DMF was added 60% 0.164 g (4.1 mmol) of rye are added. The resulting mixture is stirred for 30 min at 25 < 0 > C and then 0.26 ml (4.1 mmol) of iodomethane are added all at once. The reaction mixture is stirred at 25 < 0 > C for 0.5 h, then water and ethyl acetate are added. The organic material was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo to give tert-butyl (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (Methyl) amino] cyclohexanecarboxylate. Electrospray mass spectrum 422.2 (M + H) < ⁺ & gt ^; .

Example 16

(1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -cyclohexanecarboxylic acid

To a solution of tert-butyl (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} - (methyl) amino] cyclohexanecarboxylate in 20 ml of dichloromethane was added trifluoroacetic acid 5 Is added and the mixture is stirred at room temperature for 3 hours. The solvent is then removed in vacuo and the residue is chromatographed on silica gel, eluting with methanol / dichloromethane. Trituration with ethyl acetate / hexane affords 1.04 g of (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) -amino] cyclohexanecarboxylic acid as a white solid . Electrospray mass spectrum 364.3 (MH) ^- .

Example 17

(1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide

To a solution of oxalyl chloride (1.42 mL of a 2M solution in dichloromethane) in dichloromethane is added dimethylformamide (0.22 mL) at 0 < 0 > C. After 15 minutes a solution of (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] cyclohexanecarboxylic acid in dimethylformamide was added and the resulting reaction mixture was stirred at room temperature Lt; / RTI > for 1 hour.

In a separate flask, 3 ml of triethylamine are added to a mixture of 7.6 ml of THF and 0.987 g of hydroxylamine hydrochloride in 3.2 ml of water at 0 [deg.] C. After stirring the mixture for 15 minutes at 0 < 0 > C, the acid chloride solution is added to it in one portion and the resulting solution is warmed to room temperature and then stirred for 18 hours. Ethyl acetate and aqueous sodium bicarbonate are then added to the reaction flask. The organic phase is washed with aqueous sodium bicarbonate and dried over anhydrous potassium carbonate. Concentration in vacuo and trituration with diethyl ether gave (1R, 2R) -2 - {[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] - N-hydroxycyclohexanecarboxamide. Electrospray mass spectrum 381.2 (M + H) < ⁺ & gt ^; .

Example 18

(1R, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N- hydroxycyclohexanecarboxamide

0.50 g (1.42 mmol) of (1R, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylic acid was obtained as a white solid To give 0.32 g of (1R, 2R) -2 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide. Electrospray mass spectrum 367.2 (M + H) < ⁺ & gt ^; .

Example 19

tert-butyl 3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) propanoate

(6.75 mL, 48.4 mmol) was added to tert-butyl-2-aminopropanoate (2.0 g, 11.0 mmol) in 20 mL of dichloromethane followed by 4- (2-butynyloxy) phenylsulfonyl chloride g, 12.1 mmol) at 0 < 0 > C. Additional 10 mL of dichloromethane is added to the thick slurry. The mixture is stirred overnight, then diluted with dichloromethane, washed successively with water, 2 N aqueous citric acid and brine, and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provided a solid which was triturated with hexane / ethyl acetate to give tert-butyl 3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) propanoate 3.88 g) is obtained (mp 63-65 < 0 > C). Analysis of C ₁₇ H ₂₃ NO ₅ S: Calculated: C, 57.77; H, 6.56; N, 3.96. Measured: C, 57.68; H, 6.42; N, 3.90. Electrospray mass spectrum 354.2 (M + H) < ⁺ & gt ^; .

Example 20

N - {[4- (2-butynyloxy) phenyl] sulfonyl} -beta-alanine

({[4- (2-butynyloxy) phenyl] sulfonyl} amino) propanoate (1.0 g, 2.83 mmol) was obtained as a white solid from N- {[4- (2-butynyloxy) phenyl] sulfonyl} -beta-alanine (1.12 g). Electrospray mass spectrum 296.2 (MH) ^- .

Example 21

3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxypropanamide

Hydroxybenzotriazole (0.436 g, 3.23 mmol) was added to N - {[4- (2-butynyloxy) phenyl] sulfonyl} -beta-alanine (0.80 g, 2.69 mmol) in dimethylformamide mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.67 g, 3.5 mmol). After 1 h, 50% hydroxylamine in water (1.3 mL) is added. The reaction mixture is stirred overnight and concentrated in vacuo. Ethyl acetate is added and the organic phase is washed with water (twice) and brine then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provided a white solid which was triturated with ethyl acetate to give 3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxypropanamide 0.30 g) is obtained (mp 118-128 [deg.] C). Electrospray mass spectrum 313.3 (M + H) < ⁺ & gt ^; .

Example 22

tert-butyl-3 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] propanoate

To a solution of tert-butyl 3 - ({[4- (2-butynyloxy) phenyl] -sulfonyl} amino) -propanoate (1.0 g, 2.83 mmol) in dimethylformamide (5 ml) was added sodium hydride 3.39 mmol) followed by iodomethane (211 [mu] L, 3.39 mmol) at 0 [deg.] C. After 72 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afford tert-butyl-3 - [{[4- (2-butynyloxy) phenyl] -sulfonyl} (methyl) amino] -propanoate (1.0 g) as a colorless oil . Electrospray mass spectrum 368.2 (M + H) < ⁺ & gt ^; .

Example 23

N - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-methyl-beta-alanine

Phenyl] sulfonyl} (methyl) amino] propanoate (0.863 g, 2.34 mmol) was obtained as white in a similar manner to that described in Example 16. < Affords N - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-methyl-beta-alanine (0.760 g) as a solid (mp 90-110 [deg.] C). Electrospray mass spectrum 312.1 (M + H) < ⁺ & gt ^; .

Example 24

3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino} -N-hydroxypropanamide

Methyl-beta-alanine (0.7 g, 2.25 mmol) was reacted with 3 - ({[4- (2-methoxyphenyl) -Butyryloxy) phenyl] sulfonyl} (methyl) amino) -N-hydroxypropanamide (0.525 g white solid). Analysis for _{C 14 H 18 N 2 O 5} S: Calculated: C, 51.52; H, 5.56; N, 8.58. Measured: C, 51.38; H, 5.16; N, 8.28. Electrospray mass spectrum 327.2 (M + H) < ⁺ & gt ^; .

Example 25

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylic acid

To a solution of cis-2-amino-1-cyclopentane (1.0 g, 7.74 mmol) in 1: 1 water: dimethylformamide (10 mL) was added sodium carbonate (2.7 g, 25.5 mmol) followed by 4- Phenylsulfonyl chloride (2.08 g, 8.5 mmol) at 0 < 0 > C. The reaction mixture is allowed to warm to room temperature. After stirring overnight, water and ethyl acetate are added and the mixture is acidified to pH = 1 with 6 N aqueous hydrochloric acid. The organic phase is washed with water and brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo affords (1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylic acid (1.58 g) as a white solid 135 [deg.] C). Electrospray mass spectrum 336.4 (M + H) < ⁺ & gt ^; .

Example 26

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclopentanecarboxamide

(0.506 g, 1.5 mmol) was added to a solution of (1R, 2S) - {[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylic acid (0.18 g) was obtained by conversion to 2-amino-2- {[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclopentanecarboxamide (0.28 g) -145 [deg.] C). Electrospray mass spectrum 353.4 (M + H) < ⁺ & gt ^; .

Example 27

butyl (1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanetetate

(1R, 2S) - ({[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylic acid (0.80 g) Converted into 2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylate to give white crystals (0.60 g) (mp 97-100 ° C). Analysis of C ₂₀ H ₂₇ NO ₅ : Calculated: C, 61.05; H, 6.92; N, 3.56. Measured: C, 61.04; H, 6.79; N, 3.72. Electrospray mass spectrum 394.2 (M + H) < ⁺ & gt ^; .

Example 28

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) aminocyclopentanecarboxylate

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylate (0.50 g, 1.27 mmol) in dimethylformamide (4 mL) Carbonitrile (0.527 g, 3.81 mmol) and iodomethane (95 [mu] L, 1.53 mmol). After 18 hours, the reaction mixture is concentrated in vacuo, diluted with ethyl acetate, washed with water and brine, then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded tert-butyl (1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) aminocyclopentanecarboxylate (Mp 131-133 [deg.] C). Electrospray mass spectrum 408.2 (M + H) < ⁺ & gt ^; .

Example 29

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] cyclopentanecarboxylic acid

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclopentanecarboxylate - (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] cyclopentanecarboxylic acid as described in Example 16 to give a white solid (0.375 g). Electrospray mass spectrum 352.2 (M + H) < ⁺ & gt ^; .

Example 30

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] N-hydroxycyclopentanecarboxamide

(1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] cyclopentanecarboxylic acid (0.320 g) Amino} N-hydroxycyclopentanecarboxamide to give white crystals (0.105 g) (mp 160- < RTI ID = 0.0 > 164 [deg.] C). Analysis of C ₁₇ H ₂₂ N ₂ O ₅ S: Calculated: C, 55.72; H, 6.05; N, 7.64. Measured: C, 55.40; H, 6.15; N, 7.50. Electrospray mass spectrum 367.25 (M + H) < ⁺ & gt ^; .

Example 31

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclohexanecarboxylic acid

(1.2 g, 8.38 mmol) was added to a solution of (cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclo Hexanecarboxylic acid to give a white solid (0.825 g) (mp 172-175 < 0 > C). Analysis of C ₁₇ H ₂₁ NO ₅ S: Calculated: C, 58.10; H, 6.02; N, 3.99. Measured: C, 58.32; H, 5.92; N, 3.87. Electrospray mass spectrum 350.1 (MH) ^- .

Example 32

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} aminocyclohexanecarboxylic acid (0.300 g, 0.854 mmol) [4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide to give an off-white foam (0.210 g). Electrospray mass spectrum 367.2 (M + H) < ⁺ & gt ^; .

Example 33

(Cis) -tert-butyl-2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylate

(0.38 g, 1.08 mmol) was added to a solution of (cis) -tert-butyl-2-aminocyclohexanecarboxylic acid 2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylate to give a white solid (0.450 g). Electrospray mass spectrum 408.2 (M + H) < ⁺ & gt ^; .

Example 34

(Cis) -tert-butyl-2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) cyclohexanecarboxylate

(0.390 g, 0.956 mmol) was added to a solution of (cis) -tert-butyl-2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) cyclohexanecarboxylate ) -tert-butyl-2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) cyclohexanecarboxylate to give a colorless oil (0.260 g). Electrospray mass spectrum 422.2 (M + H) < ⁺ & gt ^; .

Example 35

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) cyclohexanecarboxylic acid

(Methyl) amino) cyclohexanecarboxylate (0.220 g, 0.522 mmol) was added to a solution of (cis) -tert-butyl-2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} Sulfonyl} (methyl) amino) cyclohexanecarboxylic acid to give a white solid (0.190 g) as a yellow solid. Electrospray mass spectrum 366.2 (M + H) < ⁺ & gt ^; .

Example 36

(Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide

(0.165 g, 0.45 mmol) was added to a solution of (cis) - ({[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) cyclohexanecarboxylic acid (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide to yield an off-white solid (0.50 g). Electrospray mass spectrum 381.2 (M + H) < ⁺ & gt ^; .

Example 37

(2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [2.2.1] heptane-

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2- (1-benzyloxy) phenyl] -sulfonyl} amino) bicyclo [2.2.1] heptane-2-carboxylic acid as described in Example 25 to give 1.32 g of white solid (mp 195-215 C) . Electrospray mass spectrum 364.3 (M + H) < ⁺ & gt ^; .

Example 38

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N- hydroxybicyclo [2.2.1] - carboxamide

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [2.2.1] heptane- , 1 mmol) was added to a solution of (1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxybicyclo [2.2. 1] heptane-2-carboxamide as described in Example 21 to yield a white solid (0.30 g). Analysis of C ₁₈ H ₂₂ N ₂ O ₅ S: Calculated: C, 57.13; H, 5.86; N, 7.4. Measured: C, 57.76; H, 6.12; N, 7.6. Electrospray mass spectrum 379.3 (M + H) < ⁺ & gt ^; .

Example 39

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [2.2.1] heptane- Rate

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [2.2.1] heptane- , 2.2 mmol) was reacted with tert-butyl (lR, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [ Heptane-2-carboxylate as described in Example 14 to give a white solid (0.69 g) (mp 94-99 [deg.] C). Analysis of C ₂₂ H ₂₉ NO ₅ S: Calculated: C, 62.98; H, 6.97; N, 3.34. Measured: C, 62.25; H, 6.95; N, 3.7. Electrospray mass spectrum 420.3 (M + H) < ⁺ & gt ^; .

Example 40

(methyl) amino) bicyclo [2.2.1] heptane-2-carboxylic acid ethyl ester was obtained in the same manner as in Example 1, except that tert-butyl (1R, 2R, 3S, 2-carboxylate

(1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) bicyclo [2.2.1] heptane- (0.55 g, 1.31 mmol) was added to a solution of tert-butyl (1 R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} Bicyclo [2.2.1] heptane-2-carboxylate as described in Example 28 to give a white solid (0.54 g) (mp 120-125 [deg.] C). Analysis of C ₂₃ H ₃₁ NO ₅ S: Calculated: C, 63.72; H, 7.21; N, 3.23. Measured: C, 63.34; H, 7.11; N, 3.55. Electrospray mass spectrum 434.2 (M + H) < ⁺ & gt ^; .

Example 41

(Methyl) amino) bicyclo [2.2.1] heptane-2-carboxylic acid (1R, 2R, 3S, 4R)

(methyl) amino) bicyclo [2.2.1] heptane-2-carboxylic acid ethyl ester was obtained in the same manner as in Example 1, except that tert-butyl (1R, 2R, 3S, 2-carboxylate (0.45 g, 1.04 mmol) was added to a solution of (1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} Bicyclo [2.2.1] heptane-2-carboxylic acid as described in Example 16 to give a white solid (0.37 g) (mp 153-158 [deg.] C). Analysis of C ₁₉ H ₂₃ NO ₅ S: Calculated: C, 60.46; H, 6.14; N, 3.71. Measured: C, 60.71; H, 5.94; N, 3.97. Electrospray mass spectrum 378.1 (M + H) < ⁺ & gt ^; .

Example 42

(Methyl) amino) -N - hydroxybicyclo [2.2.1] heptanecarboxylic acid dihydrochloride was obtained in the same manner as in (1R, 2R, 3S, Heptane-2-carboxamide

(Methyl) amino) bicyclo [2.2.1] heptane-2-carboxylic acid (1R, 2R, 3S, 4R) (0.30 g, 0.79 mmol) was added to a solution of (1R, 2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) 2-carboxamide (0.137 g) as described in Example 21. Electrospray mass spectrum 393.2 (M + H) < ⁺ & gt ^; .

Pharmacology

The ability of a compound of the invention or a pharmaceutically acceptable salt thereof to inhibit matrix metalloproteinase or TACE and to be efficacious in the treatment of a disease modulated by a matrix metalloproteinase or TACE is demonstrated by the following in vitro assay .

Test procedure for measuring MMP-1, MMP-9 and MMP-13 inhibition rates

This standard pharmacological test procedure is based on Ac-Pro-Leu-Gly (2-mercaptoacetic acid), which results in the release of a substrate product that is colorimetrically reactive with DTNB (5,5'-dithiobis Cleavage by a matrix metalloproteinase MMP-1, MMP-13 (collagenase) or MMP-9 (gelatinase) of a thiopeptide substrate such as L-glutamic acid It is basically. Enzyme activity is measured by the rate of staining. The thiopeptide substrate is freshly composed of 20 mM stock in 100% DMSO and DTNB is 100 mM stock dissolved in 100% DMSO and stored in a dark room at room temperature. Both substrate and DTNB are diluted together with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl ₂ ) to 1 mM before use. The enzyme stock is diluted to the desired final concentration with buffer (50 mM HEPES, pH 7.5, 5 mM CaCl ₂ , 0.02% Brij). The buffer, enzyme, vehicle or inhibitor and DTNB / substrate are added in this order to a 96-well plate (200 μl total reaction volume) and the color is monitored by a spectrophotometer at 405 nm for 5 minutes on a plate reader, Floating.

Alternatively, a fluorescent peptide substrate is used. In this test procedure, the peptide substrate contains a fluorescent group and a quenching group. Upon cleavage of the substrate by MMP, the resulting fluorescence is quantified on a fluorescent plate reader. Analysis is performed with human recombinant MMP-1, MMP-9 or MMP-13 in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca ⁺² , 0.02% Brij, 0.5% cysteine). The substrate is dissolved in methanol and stored frozen in 1 mM fractions. For analysis, the substrate and enzyme are diluted to the desired concentration with HCBC buffer. The compound is added to a 96 well plate containing the enzyme and the reaction is initiated by the addition of the substrate. The reaction is read for 10 min (excitation 340 nm, emission 444 nm) and the increase in fluorescence over time is plotted as a straight line.

For the thiopeptide or fluorescent peptide test procedure, the slope of the line is calculated, which indicates the rate of the reaction. The linearity of the reaction rate is confirmed (r ² > 0.85). The mean of the control rate (x ± sem) was calculated and compared with the drug-treated rate using the Dunnett multiple comparison test (p <0.05). The dose-response relationship can be obtained using different doses of the drug and the IC ₅₀ values to 95% CI are evaluated using linear regression.

Test procedure for measuring TACE inhibition rate

Using a 96-well black microtiter plate, 10 μl of TACE (final concentration 1 μg / ml), 70 μl of Tris buffer (final concentration 10 mM) of pH 7.4 containing 10% glycerol and a test in DMSO 10 μl of the compound solution (final concentration 1 μM, DMSO concentration <1%) is injected and incubated at room temperature for 10 minutes. The reaction is initiated by the addition of a fluorescent peptidyl substrate (final concentration 100 [mu] M) to each well and then shaking for 5 seconds in the shaker.

The reaction is read for 10 min (excitation 340 nm, emission 420 nm) and the increase in fluorescence over time is plotted in a straight line. The slope of the straight line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r ² > 0.85). The mean of the control rate (x ± sem) was calculated and compared with the drug-treated rate using the Dunnett multiple comparison test (p <0.05). The dose-response relationship can be obtained using different doses of the drug and the IC ₅₀ values to 95% CI are evaluated using linear regression.

Human mononuclear cell THP-1 cell differentiation assay for soluble protein (THP-1 soluble protein assay)

The mitogen stimulation of THP-1 cells is particularly important in the treatment of TNF-α and TNF receptors (TNF-R p75 / 80 and TNF-R p55 / 60) and interleukin-8 (IL-8) Secretion and differentiation into macrophage-like cells. In addition, non-stimulated THP-1 cells release both the p75 / 80 and p55 / 60 receptors over time. The release of membrane-bound TNF- [alpha] and possibly TNF-R p75 / 80 and TNF-R p55 / 60 (but not IL-8) is mediated by an enzyme called TNF-alpha converting enzyme or TACE. This assay can be used to demonstrate the inhibitory or irritant compound potency of this TACE enzyme and the cytotoxicity results of such compounds.

THP-1 cells (from ATCC) are human mononuclear cell lines obtained from peripheral blood of 1-year-old boy suffering from acute mononuclear cell leukemia. They can grow in culture and differentiate into macrophage-like cells by stimulation with mitotic material.

For analysis, and the THP-1 cells already growing were inoculated from frozen stock back to 5 × 10 ⁶ / ㎖ / vial ATCC. One vial is 10% fetal calf serum, penicillin 100 units / ㎖, streptomycin 100 ㎍ / ㎖ and 5 × 10 ^-5 M 2- Mercapto-ethanol article containing rutile Max (Gibco) medium, and RPMI-1640 16 Ml &lt; / RTI &gt; (THP-1 medium). Cells of each vial are incubated for approximately 2 weeks prior to use for analysis and then used for 4 to 6 weeks to screen for compounds. Cells are cultured at a concentration of 1x10 &lt; ⁵ &gt; / ml on Monday and Thursday.

To perform the analysis, if the THP-1 cells in 24-well plates polysaccharide (LPS) (Calbiochem Lot # B13189 ) 24 mg / ㎖ stock 50 ㎖ / well with 5% CO ₂ and 37 ℃ 1.091 × 10 ⁶ cells of / Ml (1.1 ml / well) for a total of 24 hours. At the same time, 50 ml / well of drug, vehicle or THP-1 medium are plated in the appropriate wells to provide a final volume of 1.2 ml / well. The standard and test compounds were dissolved in DMSO at a concentration of 36 mM and diluted to the appropriate concentration in THP-1 medium and then added to the wells at the start of culture to give 100 mM, 30 mM, 10 mM, 3 mM, 1 mM, 300 nM and a final concentration of 100 nM. Cell exposure to DMSO is limited to a final concentration of 0.1%. The positive control wells to which the mitogen was added without agent were included in the experiment. The same vehicle control wells as the positive control wells are also included, except that DMSO is added to provide a final concentration of 0.083%. Negative control wells containing vehicles with no mitogen or agent added to the cells are included in the experiment. Compounds can be evaluated for their efficacy over basic (non-stimulated) release of the receptor by replacing LPS with 50 ml / well of THP-1 medium. The plates are placed in an incubator set at 5% CO ₂ and 37 ° C. After 4 hours of incubation, tissue culture supernatant (TCS) 300 ml / well is removed for use in TNF-α ELISA. After 24 hours of incubation, TCS 700 ml / well is removed and used for analysis in TNF-R p75 / 80, TNF-R p55 / 60 and IR-8 ELISA.

At the 24 hour time point, the cells of each treatment group were collected by resuspending in 500 μl / well of THP-1 medium and transferred to a FACS tube. Add 2 ml / tube of 0.5 mg / ml of propidium iodide (PI) (Boerhinger Mannheim cat. # 1348639). Run the sample on a Becton Dickinson FaxCaliber FLOW blood count calculator and measure the amount of dye taken by each cell as red high wavelength (FL3). Only cells with damaged membranes (cells that die or die) can take PI. Percentage of viable cells is calculated by dividing the number of cells that are not stained with PI by the total number of cells in the sample. The calculated percent viability of the drug treated group is compared to the calculated viability of the vehicle treated mitotic material stimulation group (" vehicle positive control ") to determine the% change from control. This "percent change from control" value is an indicator of drug toxicity.

The amounts of soluble TNF-α, TNF-R p75 / 80 and TNF-R p55 / 60 and IL-8 in THP-1 cell culture were determined by extrapolation from a standard curve generated by kit standards, using commercially available ELISA . The number of cells that take or exclude PI is measured by a FLOW blood count calculator and visualized with a histogram of each treatment group containing all control groups using commercially available Cytologic software.

The biological diversity of the degree of response of the THP-1 cell culture requires that the experiment be compared on a% change from the " vehicle positive control " for each drug concentration. The percent change of each soluble protein evaluated from the " vehicle positive control " is calculated for each compound concentration by the following equation:

For study of soluble proteins (TNF-a, p75 / 80, p55 / 60, IL-8) under stimulated conditions, the average pg / ml of replicate wells was measured and the results were expressed as percent change from "vehicle positive control" do. For studies of soluble proteins (p75 / 80 and p55 / 60 receptors) under non-stimulating conditions, the average pg / ml of replicate wells was measured and the results are expressed as percent change from "vehicle positive control" :

The IC ₅₀ values of each compound are calculated by non-linear regression analysis using conventional software using the JUMP statistical package.

For cell viability studies, viability (PI exclusion) of pooling replicate wells was measured and the results are expressed as percent change from "vehicle positive control". The calculated vital force of the compound treated group is compared with the vital force calculated value of the " vehicle positive control " to determine " percent change from control " This value "% change from control " is an indicator of drug toxicity.

Reference literature:

The results of the above in vitro matrix metalloproteinase inhibition, TACE inhibition and THP standard pharmaceutical test procedures are shown in Table 1.

Based on the standard pharmaceutical test procedures described above, the compounds of the present invention are useful for the treatment of disorders such as arthritis, metastatic tumors, tissue ulcers, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone diseases and HIV infection .

The compounds of the present invention may also be used in the treatment of atherosclerosis, atherosclerotic plaque formation, coronary arterial thrombosis from atherosclerotic plaque destruction, restenosis, MMP-mediated osteopenia, inflammatory diseases of the central nervous system, skin aging, , Degenerative cartilage damage resulting from traumatic joint injury, neurodegenerative diseases of the nervous system, liver cirrhosis, renal glomerular disease, premature rupture of the tongue, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcer, proteinuria, aortic aneurysm disease, , Inflammatory bowel disease, age speckle deterioration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy caused by prematurity, eye inflammation, keratoconus, sgrenic syndrome, myopia, eye tumor, ocular angiogenesis / angiogenesis and corneal graft rejection It is useful for treating or inhibiting pathological changes mediated by the same matrix metalloproteinases .

The compounds of the invention may be administered to a patient in need thereof with a nitro or pharmaceutical carrier. The pharmaceutical carrier may be a solid or a liquid.

The solid carriers applicable may also include one or more substances which may act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compressing agents, binders or tablet-disintegrating or capdising agents. In powders, the carrier is a finely divided solid mixed with the finely divided active component. In tablets, the active ingredient is mixed with the carrier having the necessary compressibility in suitable proportions and compacted to the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, .

Liquid carriers may be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspensions, thickeners, colorants, viscosity modifiers, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (especially those containing the abovementioned additives, for example cellulose derivatives, the preferred sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as glycols) And derivatives thereof and oils (e. G., Fractionated coconut oil and peanut oil). The carrier for parenteral administration may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile carrier may be used in the composition in sterile liquid form for parenteral administration.

Liquid pharmaceutical compositions that are sterile liquid or sterile suspensions may be used, for example, intramuscularly, intraperitoneally or subcutaneously. The sterile liquid may also be administered intravenously. Oral administration can be in the form of a liquid or solid composition.

The compounds of the present invention may be administered rectally in the form of conventional suppositories. For administration by nasal or bronchial inhalation or insufflation, the compounds of the invention may be formulated as an aqueous solution or as a partial aqueous solution, which may then be used in the form of an aerosol. The compounds of the present invention can also be administered via the use of transdermal patches that are inert to the active compound and the active compound and that are non-toxic to the skin and that contain a carrier that allows delivery of the agent for systemic absorption into the blood stream through the skin It can be administered to the skin. The carrier may take many forms such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments may be viscous liquids or semi-solid emulsions in the oil-in-water or water-in-oil form. Pastes comprising absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices, such as a semi-permeable membrane covering a reservoir containing the active ingredient, with or without a carrier, or a matrix containing the active ingredient, may be used to release the active ingredient into the blood stream. Other occlusion devices are known in the literature.

The dosage used for the treatment of a particular patient suffering from MMP or TACE dependent symptoms should be determined subjectively by the primary care physician. The relevant variables include the severity of the dysfunction and the body shape, age and response pattern of the patient. The treatment will generally be initiated at low doses below the optimal dose of the compound. The dosage is then increased until optimum efficacy is achieved in the environment. The exact dosage for oral, parenteral, nasal, or intravenous administration will be determined by the individual to be treated and the physician administering it on a standard medical basis.

Preferably, the pharmaceutical compositions are in unit dosage form, for example tablets or capsules. In this form, the composition is again separated into unit doses containing an appropriate amount of the active ingredient; The unit dosage form may be a packaging composition, for example, a packed powder, vial, ampoule, pre-filled syringe, or a fresh package containing liquid. The unit dosage form may be, for example, a capsule or tablet itself, or it may be a suitable number of such compositions in packaged form.

Claims (13)

Hydroxamic acid of formula (B) or a pharmaceutically acceptable salt thereof. Formula B In this formula, C (= O) NHOH moiety and -NR ₅ - moiety are bonded to adjacent carbons; X is SO ₂ or -P (O) R ₁₀ ; Y is a 5- to 10-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, NR ₉ , S and O, phenyl or naphthyl provided that X and Z are not capable of bonding to adjacent atoms of Y; Z is O, NH, CH ₂ or S; R &lt; ₅ &gt; is hydrogen or alkyl of 1-6 carbon atoms; R ₆ and R ₇ are each independently hydrogen or methyl; R ₈ is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, N, NR ₉ , S and 5-7 membered heteroaryl having 1-3 heteroatoms selected from O, 5-7 membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR ₉ , S and O; R ₉ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl; R ₁₀ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl or 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O; R ₁₁ and R ₁₂ are independently having 1 to 3 heteroatoms selected from hydrogen, 1-6 carbon atoms alkyl, 3-6 cycloalkyl carbon atoms, N, NR _9, S and O 5-7 Membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, and wherein any double bond indicated by the dashed line is present; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, , 5-7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, 5- to 10-membered saturated or unsaturated mono- or non-aromatic heterocycle optionally fused with one of the phenyl or naphthyl rings Form a cyclic cycloalkyl; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5-7 membered mono or non-cyclic heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, Saturated or unsaturated mono- or polyunsaturated radical having 1 to 2 heteroatoms selected from N, NR ₉ , S and O, optionally fused with one of a saturated or unsaturated cycloalkyl ring or a phenyl or naphthyl ring, Form heterocycloalkyl; The dotted line represents any double bond; n = 0-2. The compound according to claim 1, wherein X is SO ₂ . 3. A compound according to claim 1 or 2, wherein Y is a phenyl ring substituted at the 1- and 4-positions by X and Z, respectively. 4. The compound according to any one of claims 1 to 3, wherein Z is oxygen. 5. The compound according to any one of claims 1 to 4, wherein R &lt; ₆ &gt; and R &lt; ₇ &gt; are hydrogen. The method according to any one of claims 1 to 5, wherein, R ₈ is -CH ₂ OH or methyl. 2. The compound of claim 1 which is (1R, 2R) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide; (1 R, 2R) -2 - ({[4- (2-Butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide; 3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxypropanamide; 3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino) -N-hydroxypropanamide; (1R, 2S) -2 - [{[4- (2-Butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclopentanecarboxamide; (1R, 2S) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] N-hydroxycyclopentanecarboxamide; (Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxycyclohexanecarboxamide; (Cis) -2 - [{[4- (2-butynyloxy) phenyl] sulfonyl} (methyl) amino] -N-hydroxycyclohexanecarboxamide; (2R, 3S, 4R) - (cis) -3 - ({[4- (2-butynyloxy) phenyl] sulfonyl} amino) -N-hydroxybicyclo [2.2.1] Carboxamide; And (Methyl) -amino) -N-hydroxybicyclo [2.2.1 &lt; RTI ID = 0.0 &gt; ] Heptane-2-carboxamide. &Lt; / RTI &gt; A process for the preparation of a compound as claimed in claim 1, which comprises one of the following: a) reacting a compound of formula 5 or a reactive derivative thereof with a hydroxylamine to provide the corresponding compound of formula B; b) deprotecting the compound of formula 6 to provide the corresponding compound of formula B; c) resolving a mixture of optically active isomers of the compound of formula B (e. g., racemic) to separate one enantiomer or diastereomer substantially absent of the other enantiomer or diastereomer; d) Acidifying the basic compound of formula (B) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt. Formula 5 6 In this formula, R ₅ , R ₆ , R ₇ , R ₈ , R ₁₁ , R ₁₂ , X, Y, Z and the dotted line are as defined in claim 1, Q is OH, R ₃₀ is a suitable protecting group. &Lt; / RTI &gt; (2) In this formula, R ₆ and R ₇ are each independently hydrogen, alkyl of 1-6 carbon atoms, -CN, -CCH 2; R ₈ is alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, N, NR _9, O or a 5-to 10-membered having from 1 to 3 heteroatoms selected from S-heteroaryl or N, NR _9, O or a 5-to 9 source having one or two heteroatoms selected from S, Lt; / RTI &gt; &Lt; / RTI &gt; (3) In this formula, R ₆ and R ₇ are each independently hydrogen, alkyl of 1-6 carbon atoms, -CN, -CCH 2; R ₈ is alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl, naphthyl, N, NR _9, O or a 5-to 10-membered having from 1 to 3 heteroatoms selected from S-heteroaryl or N, NR _9, O or a 5-to 9 source having one or two heteroatoms selected from S, Heterocycloalkyl; J is fluorine, bromine, chlorine, 1,2,4-triazolyl, benzotriazolyl or imidazolyl. (TACE) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula B or a pharmaceutically acceptable salt thereof. Formula B In this formula, C (= O) NHOH moiety and -NR ₅ - moiety are bonded to adjacent carbons; X is SO ₂ or -P (O) R ₁₀ ; Y is a 5- to 10-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, NR ₉ , S and O, phenyl or naphthyl provided that X and Z are not capable of bonding to adjacent atoms of Y; Z is O, NH, CH ₂ or S; R &lt; ₅ &gt; is hydrogen or alkyl of 1-6 carbon atoms; R ₆ and R ₇ are each independently hydrogen or methyl; R ₈ is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, N, NR ₉ , S and 5-7 membered heteroaryl having 1-3 heteroatoms selected from O, 5-7 membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR ₉ , S and O; R ₉ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl; R ₁₀ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl or L; R ₁₁ and R ₁₂ are independently having 1 to 3 heteroatoms selected from hydrogen, 1-6 carbon atoms alkyl, 3-6 cycloalkyl carbon atoms, N, NR _9, S and O 5-7 Membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, and wherein any double bond indicated by the dashed line is present; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, , 5- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and 0, 5- to 10-membered saturated or unsaturated mono- or disubstituted heterocycloalkyl optionally fused with one of the phenyl or naphthyl rings, Form an acyclic alkyl; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5-7 membered mono or non-cyclic heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, a 5-7 membered saturated or unsaturated A 5-10 membered saturated or unsaturated mono- or bicyclic heterocycle having 1-2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, optionally fused with an unsaturated cycloalkyl ring or one of the phenyl or naphthyl rings Alkyl; The dotted line represents any double bond; n = 0-2. 12. The method of claim 11, wherein the condition to be treated is rheumatoid arthritis, graft rejection, cachexia, inflammation, heat, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection. A pharmaceutical composition comprising a compound of formula (B) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Formula B In this formula, C (= O) NHOH moiety and -NR ₅ - moiety are bonded to adjacent carbons; X is SO ₂ or -P (O) R ₁₀ ; Y is a 5- to 10-membered heteroaryl ring having 1 to 3 heteroatoms selected from N, NR ₉ , S and O, phenyl or naphthyl provided that X and Z are not capable of bonding to adjacent atoms of Y; Z is O, NH, CH ₂ or S; R &lt; ₅ &gt; is hydrogen or alkyl of 1-6 carbon atoms; R ₆ and R ₇ are each independently hydrogen or methyl; R ₈ is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, N, NR ₉ , S And 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, and 5-7 membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR ₉ , S and O; R ₉ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or phenyl; R ₁₀ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, phenyl or L; R ₁₁ and R ₁₂ are independently having 1 to 3 heteroatoms selected from hydrogen, 1-6 carbon atoms alkyl, 3-6 cycloalkyl carbon atoms, N, NR _9, S and O 5-7 Membered heterocycloalkyl or phenyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, and wherein any double bond indicated by the dashed line is present; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5 to 7 membered saturated or unsaturated cycloalkyl ring, a 5-7 membered heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, , 5- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, NR &lt; ₉ &gt;, S and O, 5- to 10-membered saturated or unsaturated mono- or non-aromatic rings optionally fused with one of the phenyl or naphthyl rings Form a cyclic cycloalkyl; R ₁₁ and R ₁₂ together with the carbon to which they are attached form a 5-7 membered mono or non-cyclic heteroaryl having 1-3 heteroatoms selected from N, NR ₉ , S and O, a 5-7 membered saturated Or 5- to 10-membered saturated or unsaturated mono- or bicyclic heteroatoms having 1-2 heteroatoms selected from N, NR ₉ , S and O, optionally fused with an unsaturated cycloalkyl ring or a phenyl or naphthyl ring, Form cycloalkyl; The dotted line represents any double bond; n = 0-2.