JP2003522723A - Metalloproteinase inhibitor - Google Patents

Abstract

  (57) [Summary] 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl] -5-methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide and similar compounds are It is a metalloproteinase inhibitor.

Description

Detailed Description of the Invention

This invention relates to therapeutically active derivatives of hydroxamic and carboxylic acids,
It relates to processes for their preparation, pharmaceutical compositions containing them and the use of such compounds as medicaments. In particular, the compound is a matrix metalloproteinase involved in tissue degeneration, in particular collagenases such as human fibroblast collagenase (MMP-1), human neutrophil collagenase (MMP-8) and collagenase-3 (MMP-13). It is an inhibitor of

BACKGROUND collagenase invention (known as matrix proteinases, where MMPs because) stromelysin and / or gelatinase compound having the property of inhibiting the action of metalloproteinases involved in disruption of such connective tissue as is
Symptoms including such tissue disruption, such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, osteopenia such as gingivitis, corneal, epidermal or gastric ulcer,
And is considered potentially useful for the treatment or prevention of tumor metastasis, invasion and growth. MMP inhibitors include the treatment of disorders involving degeneration of myelin, such as neuroinflammatory disorders including multiple sclerosis, as well as joint symptoms and solid tumor growth, as well as psoriasis, proliferative retinopathy, neovascular glaucoma, ocular There is potential value in the treatment of angiogenesis-dependent diseases, including tumors, angiofibromas and hemangiomas. However,
The relative contribution of individual MMPs in any of the above diseases is not yet fully understood.

Metalloproteinases are characterized by the presence of zinc (II) ionic sites in their structure. Human fibroblast collagenase (MMP-1), human neutrophil collagenase (MMP-8) and collagenase-3 (MMP-13)
, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin-1
, A wide variety of metalloproteinase enzymes, including Stromelysin-2 and PUMP-1, are known to exist (JF Woessner, FASEB J, 1991, 5, 214).
5-2154).

A group of known collagenase inhibitors is EP-A-0574758 (Roche), EP-A-
068240 (Roche), and those disclosed in WO 95/33731 (Roche). The compounds disclosed in these publications can be represented by the following structural formulas.

[Chemical 1] Where the X, Y and N-containing rings may vary according to the specific disclosure of the publication.

[0005] BRIEF DESCRIPTION our international patent pending inventions Application PCT / GB97 / 02891 (the disclosure of which is incorporated herein by reference), a new class of compounds are inhibitors of matrix proteinases available did. The present invention provides additional compounds to the class of compounds disclosed in PCT / GB97 / 02891, but has not been identified or exemplified therein. In general, like the group of compounds disclosed in PCT / GB97 / 02891, the compounds of the present invention include human fibroblast collagenase,
It is a selective inhibitor of collagenases such as overgelatinase, stromelysin and matrilysin, thus implying the treatment of diseases primarily mediated by collagenase.

The compounds of the invention conform to the general formula (IA), but differ from the prior art compounds of the general formula in structure, mainly in the identity of the group X. In the compound of the present invention, the group X is a sulfonamidoalkyl group, and EP-A-0574758, EP-A-
Not considered in either 068240 or WO95 / 33731.

According to the detailed description PCT / GB97 / 02891 of the invention, compounds of formula (I),

[0008]

[Chemical 2]

Wherein: V is HO— or HONH—, n is 1, 2, 3 or 4; R ₁ is C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ Alkynyl, perfluoroalkyl, phenyl (C ₁ -C ₆ alkyl)-, heteroaryl (C ₁ -C ₆ alkyl)-, non-aromatic heterocycle (C ₁ -C ₆ alkyl)-, cycloalkyl (C ₁ -C ₆ alkyl) -, cycloalkenyl (C ₁ -C ₆ alkyl) -, phenoxy (C ₁ -C ₆ alkyl) -, heteroaryloxy (C ₁ -C ₆ alkyl) -, phenyl (C ₁ -C ₆ alkyl) O (C ₁ -C ₆ alkyl) -, heteroaryl (C ₁ -C ₆ alkyl) O (C ₁ -C ₆ alkyl) -, phenyl (C ₁ -C ₆ alkyl) S (C ₁ -C ₆ alkyl) - or heteroaryl (C ₁ -C ₆ Alkyl) S (C ₁ -C ₆ alkyl) - group, any of which is, C ₁ -C ₆ alkyl, trifluoromethyl, C ₁ -C ₆ alkoxy, hydroxy, halo, cyano (-CN), Optionally substituted with phenyl, substituted phenyl or heteroaryl;

[0010] R₂Is a saturated 5-8 membered monocyclic or bridged attached through an N atom.
When N-heterocyclic and monocyclic, (i) optionally O, S, SO, SO as ring-constituting atoms ₂ Or NR_Five[Where R_FiveIs hydrogen, hydroxy, C₁-C₆Alkyl, (C₁-C ₆ Alkoxy) C₁-C₆Alkyl, benzyl, acyl, amino protecting group, or group-
SO₂R₆(Where R₆Is C₁-C₆Alkyl or substituted or unsubstituted phenyl
Or a heteroaryl group)] and / or
Is (ii) hydroxy having one or more carbon atoms, C₁-C₆Alkyl, C₁−
C₆Alkoxy, cyano, oxo, ketalized oxo, amino, mono (C₁
-C₆Alkyl) amino, di (C₁-C₆Alkyl) amino, carboxy, C₁-C₆A
Lucoxycarbonyl, hydroxymethyl, C₁-C₆Alkoxymethyl, carbamo
Il, Mono (C₁-C₆Alkyl) carbamoyl, di (C₁-C₆Alkyl) carbamoy
Or optionally substituted with hydroxyimino,

[0011] R₃Is hydrogen, C₁-C₆Alkyl, benzyl, acyl, amino protecting group, or group-(
CH₂)_mCOZ [where m is an integer from 1 to 6 and Z is OH, C₁-C ₆ Alkoxy or NR_xR_y(Where R_x, R_yAre each independently hydrogen or
C₁-C₆Represents alkyl)]; and

R ₄ is optionally substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₃ perfluoroalkyl, cycloalkyl, cycloalkyl (C ₁ -C ₆ alkyl)-, cycloalkenyl, cycloalkenyl (C ₁ -C ₆ alkyl)-, di- (C ₁ -C ₆ alkyl) amino, phenyl, phenyl (C ₁ -C ₆ alkyl)-, Biphenyl, phenyl-heteroaryl, naphthyl, non-aromatic heterocycle, non-aromatic heterocycle (C ₁ -C ₆ alkyl)-, heteroaryl or heteroaryl (C ₁ -C ₆ alkyl)-; heteroaryl -Phenyl; heteroaryl-heteroaryl; aryloxyaryl, or

R ₃ and R ₄ , taken together, may optionally be substituted with (i) an oxo group and / or (ii) (C ₁ -C ₆ ) alkoxy, hydroxy, mercapto, (
C ₁ -C ₆₎ comprising alkylthio, amino, halo (fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro, -COOH, -CONH ₂
, [Wherein, R ^A and R ^B are independently (C ₁ -C ₆₎ alkyl group] -CONHR ^A or -CONR ^A R ^B may be substituted by, and / or (iii) it Represents a divalent C ₃ -C ₆ alkylene or alkenylene group which may itself be fused to a phenyl or heteroaryl group which may be substituted; and pharmaceutically acceptable salts and hydrates thereof And solvates are provided.

According to the invention, 2S-[[(5-dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl]-
5-Methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 3R-cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]-4-oxo-4- Piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]-4-morpholin-4-yl-4-oxo-butyramide, 3R-cyclopentyl Methyl-N-hydroxy-2S-[[(4-benzenesulfonyl) -methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S- [[(4-Benzenesulfonyl) -methyl-amino] -methyl] -4-morpholin-4-yl-4-oxo-butyramide, 2S-[(methanesulfonyl-methyl-amino) -methyl] -5-methyl- 3R- (morpholine-4
-Carbonyl) -hexanoic acid hydroxyamide, 2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide, 3R-cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -N-hydroxy-4-oxo-4 -Morpholin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4-oxo -Butylamide, 3R-Cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl
) -Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl)
) -Methyl-amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4-oxo-butyramide, 2S-[[(5-dimethylaminonaphthalene-1-sulfonyl) -ethyl-amino] -methyl ]-
5-Methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl]-
5-Methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide, 3R-Cyclopentylmethyl-2S-[(ethanesulfonyl-methyl-amino) -methyl] -N
-Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (propane-2-sulfonyl) -amino] -methyl] -4-oxo- 4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (octane-1-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl -Butylamide, 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methyl-trifluoromethanesulfonyl-amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 2S-[[4-chloro- Benzenesulfonyl) -methyl-amino] methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- ( Quinoline-8-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl-butyla Amido, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (naphthalene-1-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl-butylamide, 3R-cyclopentylmethyl- N-hydroxy-2S-[[isoquinoline-5-sulfonyl)-
Methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[6-dimethylamino-naphthalene-1-sulfonyl)
-Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[dimethylsulfamoyl-methyl-amino] -methyl] -N -Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 2S-[(butyl-methanesulfonyl-amino) -methyl] -3R-cyclopentylmethyl-N
-Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-Cyclopentylmethyl-N-hydroxy-2S-[(isopropyl-methanesulfonyl) -amino] -methyl] -4-oxo-4-piperidine- 1-yl-butyramide, 2S-[(tert-butyl-methanesulfonyl) -amino) -methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentyl Methyl-N-hydroxy-2S-[(cyclopropyl-methanesulfonyl) -amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 2S-[(Cyclopentyl-methanesulfonyl) -amino)- Methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, a compound which is a member of the group consisting of, and pharmaceutically acceptable salts, hydrates and solvents thereof Japanese food is provided.

As mentioned above, the compounds of the present invention are active as inhibitors of MMPs, and are therefore useful in human or veterinary medicine. Enzyme inhibition assays useful in measuring the activity of certain compounds of the invention on MMPs are known, eg, the assays described in Biological Example A below, and the "Background of the Invention" section above. See the MMP inhibition evaluations described in the patent publications listed in the section.

Therefore, from another aspect, the present invention provides: (i) a method of treatment (meaning treatment or prevention) of a disease or condition mediated by MMPs in a mammal, especially a human being, The method comprises administering to a mammal an effective amount of a compound that is a member of the above group, or a pharmaceutically acceptable salt thereof; and (ii) treatment (treatment) of diseases or conditions mediated particularly by MMPs. A compound which is a member of the above group for use in human or veterinary medicine (in which means prevention or prevention); and (iii) treatment of diseases or conditions mediated by MMPs (meaning treatment or prevention) For the use of a compound which is a member of the above group in the manufacture of a medicament for.

Diseases or conditions mediated by MMPs are those associated with tissue destruction such as bone resorption, inflammatory diseases, cutaneous conditions and tumor invasion by secondary metastases, especially rheumatoid arthritis, osteoarthritis, periodontal disease. Tumor invasion due to inflammation, gingivitis, corneal ulcers and secondary metastases, and diseases associated with myelin degeneration, including neuroinflammatory diseases including multiple sclerosis.

According to a further aspect of the invention, there is provided a pharmaceutical or veterinary composition comprising a compound which is a member of the above group and a pharmaceutically or veterinarily acceptable additive or carrier. The specific dosage for an individual patient will be determined by the activity of the particular compound used, age, weight, general health, sex, diet, time of administration, route of administration, degree of excretion, pharmaceutical combination and treatment. It will be understood that it will depend on various factors, including the severity of the particular disease.

The compounds of the present invention can be formulated for administration by routes consistent with their pharmacokinetic properties. Orally administrable compositions can be in the form of solutions or gels such as tablets, capsules, powders, granules, lozenges, oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in the form of single-dose formulations, with binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl-pyrrolidone; excipients such as lactose, sugar. , Corn starch, calcium phosphate, sorbitol or glycine; lubricants for tablets, such as magnesium stearate, talc, polyethylene glycol or silica; disintegrants, such as acceptable wetting agents such as potato starch or sodium lauryl sulfate. It may contain conventional additives. The tablets may be coated by methods well known in normal pharmaceutical practice. Oral solutions can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or dry products for reconstitution in water or other suitable vehicle before use. Can also be provided as. Such solutions include suspending agents such as sorbitol, syrup, methylcellulose, glucose syrup, gelatin, hydrogenated edible oils; emulsifiers such as lecithin, sorbitan monooleate or acacia; non-aqueous media (which may include edible oils. ), For example almond oil, fractionated coconut oil, glycerin, oily esters such as propylene glycol, or ethyl alcohol; preservatives, for example conventional additives such as methyl or propyl p-hydroxybenzoate or sorbic acid, And, if desired, conventional flavors or colorants may be included.

For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which can be used in medicine are the usual preparations well known in the art, for example described in standard textbooks of medicine such as the British Pharmacopoeia.

For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non-aqueous medium. Additives, for example buffering agents such as sodium metabisulfite or disodium edetate; preservatives containing fungicides and antifungal agents such as acetic acid or phenylmercuric nitrate, benzalkonium chloride or chlorhexidine, and hypromellose. Thickeners such as (hypromellose) may also be included. The active ingredient may also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration employed, can either be suspended or dissolved in the vehicle. Preferably, auxiliary agents such as local anesthetics, preservatives and buffers are dissolved in the medium.

[0022]

【Example】

Preparations A, B and C below describe the synthetic methods used to prepare the compounds of the invention. The products of Preparations A, B and C are described in PCT / GB97 / 02891. Examples 1-29 relate to compounds of the invention. The following abbreviations are used throughout: DMF N, N-dimethylformamide EDC N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide HOBt 1-hydroxybenzotriazole THF tetrahydrofuran ¹ H and ¹³ C NMR spectra. Were recorded using a Bruker AC250E spectrometer at 250.1 and 62.9 MHz, respectively. Elemental microanalysis was performed by Medac Ltd. (Brunell Scien Spark, Cooper's Hill Lane, Inglefield Green, Egham, Surrey TW200JZ). Preparative HPLC was performed using a Gilson automated preparative HPLC system. Electrospray mass spectrometry is PE-Sciex
It was performed at the turbo ion spray interface using the AP165 system. Infrared spectra were acquired on a Perkin Elmer 1600 FTIR instrument using a reflective disc.

Preparation Example A 2S- [3- (4-Methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide The title compound is shown in Formula 1. Prepared according to the route given. The details will be described below.

[0024]

[Chemical 3]

[0025]Process A : 2S-allyl-3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl
ester   2S-allyl-3R-isobutyl-succinic acid 1-tert-butyl ester dicyclohexyl
The amine salt (31.6 g, 70 mmol) was partitioned between dichloromethane and 1M hydrochloric acid. Organic layer
It was washed with water, dried, filtered and concentrated to dryness. The obtained free acid (18.6 g) was added to acetone (2
50 ml) and placed this solution under an argon atmosphere. Potassium carbonate (19g, 138
mmol) and benzyl bromide (7.4 ml, 62.2 mmol) were added and the reaction mixture was stirred up.
Stirred at night. The solvent was removed under reduced pressure and the residual oil was dissolved in ethyl acetate. this
The solution was washed with water (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. The filtrate
Concentrate to dryness and flash chromatograph the residue (silica gel, ethyl acetate-hexane).
Purification with xane, 1: 9) gave the title compound as a colorless oil (21.7g, 88%). ¹ H-NMR: δ (CDCl₃), 7.41-7.30 (5H, m), 5.70 (1H, m), 5.14 (2H, d, J =
1.3 Hz), 5.06 -4.94 (2H, m), 2.75 (1H, m), 2.60 (1H, m), 2.45 (1H, m), 2
.12 (1H, m), 1.71 (1H, m), 1.43 (9H, s), 1.32-1.11 (2H, m), 0.88 (3H,
d, J = 6.5 Hz) and 0.86 (3H, d, J = 6.6 Hz)

Step B : 2S- (3-Hydroxypropyl) -3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl ester 2S-allyl-3R-isobutyl-succinic acid 4-benzyl ester 1-tert-butyl ester The ester (7.42 g, 20.6 mmol) was dissolved in a 0.5 M solution of 9-BBN in THF (100 ml, 50 mmol) at room temperature and stirred for 3 days. The solution was added with 3M sodium hydroxide solution (10 ml, 30 mmol), followed by 30
Treated with% w / v hydrogen peroxide (slow) and the reaction mixture was stirred for an additional 2 hours. T
HF was distilled off under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with water (3 x 50 ml), dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave an oil which was purified by flash chromatography (silica gel, ethyl acetate-hexane, 3: 7) to give a colorless oil (5.3 g, 68%).

Step C : 3R-isobutyl-2S- (3-methanesulfonyloxy-propyl) -succinic acid 4-
Benzyl ester 1-tert-butyl ester 2S- (3-hydroxypropyl) -3R-isobutyl-succinic acid 4-benzyl ester 1-te
rt-Butyl ester (5.3 g, 14 mmol) was dissolved in dry THF (150 ml) and the solution was cooled to 0 ° C.
Cooled to. Triethylamine (2.1 ml, 15.1 mmol) was added followed by methanesulfonyl chloride (1.2 ml, 15.5 mmol) and the reaction mixture was slowly warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (150 ml). The organic solution was washed with water (3 × 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (6.1 g, 95%). This compound was used in the next step without further purification.

Step D : 2S- (3-azido-propyl) -3R-isobutyl-succinic acid 4-benzyl ester 1
-tert-Butyl ester 3S-isobutyl-2R- (3-methanesulfonyloxy-propyl) -succinic acid 4-benzyl ester 1-tert-butyl ester (6.1 g, 14 mmol) was dissolved in toluene (100 ml) and tetrabutyl was added. Ammonium iodide (4.9 g, 14 mmol) was added, followed by sodium azide (8.7 g, 140 mmol) in water (100 ml). The reaction mixture was heated under reflux for 8 hours, stirred at room temperature for 3 days, then heated under reflux for a further 6 hours. The reaction mixture was diluted with ethyl acetate (100 ml), the organic layer was separated, washed with water (3 × 80 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product obtained (5.5 g, 95%
Was used in the next step without further purification.

[0029]Process E : 2S- (3-Amino-propyl) -3R-isobutyl-succinic acid 1-tert-butyl ester
Le   2S- (3-Azido-propyl) -3R-isobutyl-succinic acid 4-benzyl ester 1-tert-
Butyl ester (5.5 g, 12.7 mmol) was dissolved in ethanol (100 ml), and this solution was dissolved.
I placed it in the atmosphere of Lugon. Add 10% palladium on carbon (800 mg) and add hydrogen in suspension
It was introduced by bubbling. The reaction mixture was stirred under hydrogen atmosphere overnight.
The system was replaced with argon and the catalyst was filtered off. When the solution was concentrated under vacuum, ¹ The reaction was found to be incomplete by 1 H-NMR analysis. Hydrocracking is
The title compound (3.7 g, approximately quantitative
) Got.¹ H-NMR: δ (CDCl₃), 5.19-4.85 (2H, br s), 3.17-2.93 (2H, m), 2.69 (1
H, m), 2.44 (1H, m), 1.89-1.40 (6H, m), 1.46 (9H, s), 1.12 (1H, m), 0.
89 (3H, d, J = 6.2 Hz) and 0.88 (3H, d, J = 6.2 Hz).

Step F : 2S- (3-Benzyloxycarbonylamino-propyl) -3R-isobutyl-succinic acid 1-tert-butyl ester 2S- (3-Amino-propyl) -3R-isobutyl-succinic acid 1-tert -Butyl ester (3.7
g, 12.9 mmol) was dissolved in THF (150 ml) and the solution was cooled to 0 ° C. Triethylamine (3.8 ml, 27.3 mmol) and Z-ONSu (3.5 g, 14 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), and 1M hydrochloric acid (50
ml), followed by water (2 × 30 ml), dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave the title compound mixed with excess Z-ONSu. This impurity could not be separated by column chromatography or acid-base extraction. Therefore, the crude mixture was dissolved in THF (100 ml) and N, N-dimethylethylenediamine (0.18 ml, 1 ml) was added.
.6 mmol) at room temperature with stirring overnight. The by-product was conveniently removed by acid extraction from ethyl acetate and, after removing the solvent, pure title compound (2.43 g, 66%)
Remained.

Step G : 2S- (3-benzyloxycarbonylamino-propyl) -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid tert-butyl ester 2S- (3-benzyloxycarbonylamino-propyl) ) -3R-isobutyl-succinic acid 1
-tert-Butyl ester (2.43 g, 5.8 mmol) was dissolved in DMF (150 ml) and this solution was added to 0.
Cooled to 0 C and added HOBt (0.9 g, 6.6 mmol) and EDC (1.3 g, 6.8 mmol). After stirring the reaction mixture for 1 hour, piperidine (1.1 ml, 11.1 mmol) was added and stirring was continued overnight. The solvent was removed under vacuum and extraction followed by flash chromatography (
Silica gel, ethyl acetate-hexane, 4: 6) gave the title compound (2.34 g, 83%)
Was isolated as a colorless oil.

Step H : 2S- (3-Amino-propyl) -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid tert-butyl ester 2S- (3-Benzyloxycarbonylamino-propyl) -5 -Methyl-3R- (piperidine
-1-Carbonyl) -hexanoic acid tert-butyl ester (2.34 g, 4.8 mmol) was added to Step E
Z-deprotection by hydrogenolysis as described in to give the title compound (1.70 g, quantitative) as a colorless oil.

Step I : 2S- [3- (4-Methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid tert-butyl ester 2S- (3-amino-propyl) -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid tert-butyl ester (1.70 g, 4.8 mmol) was converted to the title sulfonamide in the same manner as described in Step C, substituting 4-methoxybenzenesulfonyl chloride for methanesulfonyl chloride. The desired product was isolated as a colorless gum by extraction followed by flash chromatography (silica gel, ethyl acetate-hexane, 6: 4).

Step J : 2S- [3- (4-Methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid 2S- [3- (4-methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid tert-butyl ester (1.53 g, 2.9 mmol) was dissolved in dichloromethane (15 ml) and TFA (15 ml) was added. The reaction mixture was stored overnight at 4 ° C. The solvent was removed under reduced pressure and the remaining TFA was removed azeotropically with toluene then diisopropyl ether. The resulting white waxy solid (1.37 g, with residual solvent) was used in Step K without further purification.

Step K : 2S- [3- (4-Methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide 2S- [3- (4-methoxybenzenesulfonyl-amino) -propyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid (2.9 mmol) in DMF (25 ml), and the solution is 0
Cooled to ° C and added HOBt (0.6g, 4.4mmol) and EDC (0.85g, 4.4mmol). The reaction mixture was stirred for 30 minutes and then hydroxylamine hydrochloride (0.4 g, 5.7 mmol) and NMM (0.64 ml, 5.9 mmol) were added. The reaction mixture was warmed to room temperature and then stirred for 3 days. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The desired product was removed by flash chromatography (acid washed silica gel, 5% methanol in dichloromethane) followed by removal of residual traces of HOBt to give a colorless gum (300 mg, 21%).
Got as.

Production Example B 2 S-[[(4-methoxybenzenesulfonyl) -methyl-amino] -methyl] -5-methyl-3R
-(Piperidin-1-carbonyl) -hexanoic acid hydroxyamide The title compound was prepared according to the route shown in Formula 2. The details will be described below.

[0037]

[Chemical 4]

[0038]Process A : 2-carboxy-3R-isobutyl-succinic acid 4-tert-butyl ester   2-benzyloxycarbonyl-3R-carboxy-5-methyl-hexanoic acid 1-benzyl
Ester 4-tert-butyl ester (55.53g, 126mmol) dissolved in ethyl acetate (500ml)
Under the same conditions as described in Production Example 1, Step E.
Subjected to hydrogenolysis in the presence of 5 g). After 3 days, TLC analysis showed that deprotection was complete.
Was shown. The catalyst was filtered off and the solution was concentrated under reduced pressure to give a clear oil.
The compound (about 33 g, quantitative) was obtained. This compound was used without further purification. ¹ H-NMR: δ (CDCl₃), 3.73 (1H, d, J = 9.1 Hz), 3.09 (1H, m), 1.75-1.58
(2H, m), 1.45 (9H, s), 1.31 (1H, m), 0.96 (3H, d, J = 6.5 Hz) and 0.92 (
3H, d, J = 6.5Hz).

Step B : 3R-isobutyl-2-methylene-succinic acid 4-tert-butyl ester 2-carboxy-3R-isobutyl-succinic acid 4-tert-butyl ester (33 g, 126 mmol
Was dissolved in ethanol (300 ml) and the solution was cooled in an ice bath while piperidine (14.95 ml, 151 mmol) followed by 37% aqueous formaldehyde (47.17 ml, 630 mmol) was added. The reaction mixture was warmed to room temperature and then stirred overnight. The resolvent was evaporated and the residue was dissolved in ethyl acetate, washed successively with 1M hydrochloric acid (400ml) and brine (400ml), dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure to give the title compound (28.11 g, 97%) as a colorless oil.

Step C : 3R-isobutyl-2-methylene-succinic acid 1-benzyl ester 4-tert-butyl ester 3R-isobutyl-2-methylene-succinic acid 4-tert-butyl ester (28.11 g, 122 mmo
l) was dissolved in acetone (500 ml) and this solution was placed under an argon atmosphere. Solid calcium carbonate (67.34 g, 488 mmol) was added and the suspension was stirred for 30 minutes. Benzyl bromide (13.13 ml, 110 ml) was added and the reaction mixture was kept stirring at room temperature overnight. The inorganics were filtered off and the solvent removed under reduced pressure to give the title compound as a yellow oil.

Step D : 3R-isobutyl-2-methylene-succinic acid 1-benzyl ester 3R-isobutyl-2-methylene-succinic acid 1-benzyl ester 4-tert-butyl ester (35.5 g, 111 mmol) Deprotection was carried out by TFA acid decomposition according to the method (Production Example 1, Step J). After 16 hours, the solvent was distilled off under reduced pressure, and the remaining TFA was removed by azeotropic distillation with toluene. The desired product was isolated as a yellow oil (32.5 g, containing residual solvent).

Step E : 2- [3-Methyl-1R- (piperidine-1-carbonyl) -butyl] -acrylic acid benzyl ester 3R-isobutyl-2-methylene-succinate 1-benzyl in ethyl acetate (500 ml). To the ester solution was added HOBt (14.99 g, 111 mmol) followed by EDC (21.31 g, 111 mmol). The solution was stirred at room temperature for 1 hour and piperidine (16.44 ml, 167 mmol) was added slowly. The reaction mixture was stirred at room temperature for 3 days, 1M hydrochloric acid (500ml), 1M sodium carbonate (500ml)
And washed successively with brine (300 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give an orange oil. Flash chromatography
Purification with (silica gel, ethyl acetate-hexane, 1: 4) gave the title compound (19.3 g, 52%) as a yellow oil.

Step F : 5-Methyl-2S-methylaminomethyl-3R- (piperidine-1-carbonyl) -hexanoic acid benzyl ester Methylamine (33% in methanol; 6.21 ml, 50 mmol) in methanol (50 ml) of
2- [3-Methyl-1R- (piperidine-1-carbonyl) -butyl] -acrylic acid benzyl ester (8.3 g, 25 mmol) was added to the solution and the mixture was stirred at room temperature for 90 minutes. The solvent was removed under vacuum to give the title compound (15: 1 mixture of diastereoisomers by ¹ H-NMR) as a yellow oil (8.865 g, 98%).

Step G : 5-Methyl-2S-methylaminomethyl-3R- (piperidine-1-carbonyl) -hexanoic acid The title compound was prepared by the method described above (Preparation Example A, Step E) using the benzyl ester (550).
mg, 1.52 mmol) was prepared by hydrogenolysis. The product was a white amorphous solid (410 mg, 99%).
Isolated as.

Step H : 2S-[[(4-methoxybenzenesulfonyl) -methyl-amino] -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid 5-methyl-2S-methylamino Methyl-3R- (piperidine-1-carbonyl) -hexanoic acid
(1.51 mmol) was dissolved in dichloromethane (5 ml) and converted to the title sulfonamide by the same method as in (Example 1, Step I) above. The solution was washed with 1M hydrochloric acid (25 ml) and brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed to isolate the desired product (500 mg, 75%) as a white foam.

Step I : 2S-[[(4-Methoxybenzenesulfonyl) -methyl-amino] -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide 2S-[[((4 -Methoxybenzenesulfonyl) -methyl-amino] -methyl] -5-methyl-3R
-(Piperidin-1-carbonyl) -hexanoic acid (500 mg, 1.13 mmol) was converted to the title hydroxamic acid by the method described in Example 1. The product is flash chromatographed (silica gel washed with acid, 3% methanol in dichloromethane).
Was isolated as a white amorphous solid (26 mg, 5%). mp. 147 ° C

Production Example C 2 S-[(Methanesulfonyl-methyl-amino) -methyl] -5-methyl-3R- (piperidine-1
-Carbonyl) -hexanoic acid hydroxyamide The title compound was prepared according to the route shown in Formula 3 and summarized below.

[0048]

[Chemical 5]

Step A : 3-isobutyl-2-methylaminomethyl-succinic acid 1-benzyl ester 4-te
rt-Butyl ester 3R-isobutyl-2-methylene-succinic acid 1-benzyl ester 4-tert-butyl ester (Example 7, step C) (10.0 g, 30.1 mmol) was dissolved in methanol (50 ml) and methylamine was added. (33% in methanol; 7.5 ml, 60.2 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound as an oil. This was used without further purification.

Step B : 3R-isobutyl-2-[(methanesulfonyl) -methyl-amino) -methyl] -succinic acid 1-benzyl ester 4-tert-butyl ester 3-isobutyl-2-methylaminomethyl-succinic acid 1-Benzyl ester 4-tert-butyl ester (5.0 g, 13.8 mmol) was dissolved in dichloromethane and the solution was cooled in an ice bath. Triethylamine (3.9 ml, 28 mmol) followed by methanesulfonyl chloride (1.01 ml, 13.1 mmol) was added dropwise and after stirring the mixture at 0 ° C. for 90 minutes a thick white precipitate formed. The mixture was further diluted with dichloromethane (25 ml) and stirred at room temperature overnight. The suspension was washed successively with water, citric acid, sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the desired product (6.10 g, almost quantitative). Got

Step C : 3R-isobutyl-2-[(methanesulfonyl) -methyl-amino) -methyl] -succinic acid 1-benzyl ester 3R-isobutyl-2-[(methanesulfonyl) -methyl-amino) -methyl ] -Succinic acid 1-
The benzyl ester 4-tert-butyl ester was converted to the title compound by acidolysis with TFA as described above (Example 1, Step J).

Step D : 2S-[(Methanesulfonyl) -methyl-amino) -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid benzyl ester 3R-isobutyl-2-[(methanesulfonyl -Amino) -methyl] -succinic acid 1-benzyl ester was coupled with piperidine under standard conditions (see Preparation A, Step G).

Step E : 2S-[(Methanesulfonyl) -methyl-amino) -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid Hydrogenolysis of the title compound (benzyl ester) A, method of step E).

Step F : 2S-[(Methanesulfonyl) -methyl-amino) -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide Standard procedure (Example 1, step According to K), 2S-[(methanesulfonyl) -methyl-
Coupling of amino) -methyl] -5-methyl-3R- (piperidine-1-carbonyl) -hexanoic acid with hydroxyamine gave the title compound as a colorless oil. Using the method described in Preparation C, 3R-isobutyl-2-methylene-succinic acid 1-
Benzyl ester 4-tert-butyl ester or 3R-cyclopentyl-2-methylene-
The following compounds were prepared starting from succinic acid 1-benzyl ester 4-tert-butyl ester and the appropriate amine and sulfonamide. The product was purified by preparative HPLC.

Example 1 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl]-
5-Methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide (trifluoroacetate)

[0056]

[Chemical 6]

Yellow solid mp 88-94 ^o C. ¹ H-NMR: δ (CD ₃ OD), 8.57 (1H, d, J = 9.0 Hz),
8.54 (1H, d, J = 8.8 Hz), 8.16 (1H, d, J = 7.4 Hz), 7.67 (2H, m), 7.47
(1H, d, J = 7.7 Hz), 3.73-3.37 (8H, br m), 3.14-2.82 (3H, m), 3.02
(6H, s), 2.75 (3H, s), 2.69 (1H, m), 1.64 (1H, m), 1.36 (1H, m), 1.18 (1
H, m) and 0.86 (6H, d, J = 6.5 Hz). ¹³ C-NMR: δ (CD ₃ OD), 174.8, 171.1,
135.4, 131.9, 131.6, 131.0, 129.7, 125.6, 123.1, 117.9, 68.2, 52.0, 48.
3, 46.6, 44.1, 42.5, 40.3, 36.8, 27.4, 24.6 and 22.7. IR: v _max 2959, 2
358, 1675, 1614, 1456, 1332, 1140, 1042, 966, 795, 723, 622 and 578 cm ^{- 1} Measured: C 49.68% H 5.93% N 8.23%; C ₂₈ H ₃₉ N ₄ O ₈ SF ₃ .1.6 H ₂ O Calculated: 49
.64% H 6.26% N 8.27%.

Example 2 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]-4-oxo-4-piperidin-1-yl-butyramide

[0059]

[Chemical 7]

White foam mp 78-80 ^o C. ¹ H-NMR: δ (CD ₃ OD), 3.57 (4H, m), 3.40 (1H, dd
, J = 10.1, 13.5Hz), 3.31 (1H, m), 2.97 (1H, dd, J = 4.4, 13.5Hz), 2.82 (3H,
s), 2.79 (3H, s), 2.67 (1H, m), 1.55 (14H, br m), 1.35 (1H, m) and 1.1
0 (2H, m). ¹³ C-NMR: δ (CD ₃ OD), 174.3, 171.7, 52.1, 48.4, 46.2, 44.8,
41.9, 39.7, 39.2, 36.4, 36.0, 35.4, 34.2, 28.3, 27.3, 26.6 and 25.9. I
R: v _max (reflective disc) 3193, 2943, 1778, 1713, 1663, 1601, 1449, 1331, 1
154, 1022 and 967 cm ¹ .C ₁₈ H ₃₃ N ₃ O ₅ S (403.5); MS (Electrospray): 404.4 [
M + H] ⁺ , 426.2 [M + Na] ⁺ .

Example 3 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]-4-morpholin-4-yl-4-oxo-butyramide

[0062]

[Chemical 8]

White foam mp 82-84 ^o C. ¹ H-NMR: δ (CD ₃ OD), 3.71 (8H, br m), 3.32 (
1H, m), 3.10 (2H, m), 2.82 (3H, s), 2.78 (3H, s), 2.71 (1H, m), 1.58 (8H
, br m), 1.34 (1H, m) and 1.10 (2H, m). ¹³ C-NMR: δ (CD ₃ OD), 173.2, 16
9.9, 66.5, 50.5, 46.6, 42.4, 39.7, 38.0, 37.3, 34.3, 33.3, 32.0 and 24.
8. IR: v _max 3218, 2944, 2870, 1774, 1611, 1451, 1327, 1153, 1036 and
967 cm ¹ .

Example 4 3R-Cyclopentylmethyl-N-hydroxy-2S-[[(4-benzenesulfonyl) -methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[0065]

[Chemical 9]

White foam mp 64-65 ^o C. ¹ H-NMR: δ (CD ₃ OD), 7.69 (2H, d, J = 8.9 Hz)
, 7.10 (2H, d, J = 8.9 Hz), 3.87 (3H, s), 3.70 (2H, m), 3.47 (2H, m), 3.1
7 (2H, m), 2.64 (3H, s), 2.61 (2H, m) and 1.76 1.06 (17H, br m). ¹³ C-
NMR: δ (CD ₃ OD), 174.3, 171.6, 165.3, 131.3, 129.4, 115.9, 56.7, 52.8, 4
8.7, 48.3, 44.7, 41.5, 39.7, 39.1, 37.1, 35.0, 33.7, 28.4, 27.3, 26.6 and 25.8.IR v _max 3200, 2942, 2862, 1777, 1598, 1498, 1454, 1343, 1261,
1161 and 1024 cm ¹ .

Example 5 3R-Cyclopentylmethyl-N-hydroxy-2S-[[(4-benzenesulfonyl) -methyl-amino] -methyl] -4-morpholin-4-yl-4-oxo-butyramide

[0068]

[Chemical 10]

White foam mp 71-72 ^o C. ¹ H-NMR: δ (CD ₃ OD), 7.70 (2H, d, J = 8.9 Hz
), 7.11 (2H, d, J = 8.9 Hz), 3.88 (3H, s), 3.63 (8H, br m), 3.11 (2H, m
), 2.85 (1H, m), 2.72 (1H, m), 2.62 (3H, s) and 1.78 1.09 (11H, br m).
¹³ C-NMR: δ (CD ₃ OD), 174.9, 171.5, 165.3, 131.3, 129.4, 115.9, 68.2, 5
6.7, 52.9, 48.1, 44.1, 41.5, 39.7, 39.0, 37.1, 35.0, 33.7 and 26.6. IR
: v _max 3207, 2950, 1909, 1778, 1603, 1462, 1343, 1264, 1164, 1117, 1027
And 944 cm ¹ .

Example 6 2S-[(Methanesulfonyl-methyl-amino) -methyl] -5-methyl-3R- (morpholine-4
-Carbonyl) -hexanoic acid hydroxyamide

[0071]

[Chemical 11]

White foam mp 75-78 ^o C. ¹ H-NMR: δ (CD ₃ OD), 3.82 3.62 (8H, m), 3.43
3.35 (1H, m), 3.21 3.10 (2H, m), 2.85 (3H, s), 2.82 (3H, s), 2.75 2
.65 (1H, m), 1.74 1.63 (1H, m), 1.50 1.37 (1H, m), 1.29 1.18 (1H, m),
0.92 (3H, d, J = 6.4 Hz) and 0.91 (3H, d, J = 6.5 Hz). ¹³ C-NMR: δ (C
D ₃ OD), 174.9, 171.5, 68.2, 52.2, 48.3, 44.1, 42.6, 40.3, 36.1, 27.3, 24.
7 and 22.7.IR: v _max 3224, 2959, 1735, 1614, 1446, 1387, 1328, 1267, 1
243, 1153, 1116, 1068, 1040, 965, 782, 575 and 519 cm ^-1 .

Example 7 2S-[[Ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide

[0074]

[Chemical 12]

White foam mp 87-89 ^o C. ¹ H-NMR: δ (CDCl ₃ ), 10.26 (1H, br s), 7.72 (
2H, d, J = 8.9 Hz), 6.98 (2H, d, J = 8.9 Hz), 3.86 (3H, s), 3.73 3.59
(8H, m), 3.31 3.12 (4H, m), 3.10 2.96 (2H, m), 1.77 1.66 (1H, m), 1.5
0 1.37 (1H, m), 1.31 1.21 (1H, m), 0.98 (3H, t, J = 7.1 Hz), 0.89 (3H,
d, J = 6.4 Hz) and 0.88 (3H, d, J = 6.4 Hz). ¹³ C-NMR: δ (CDCl ₃ ), 174
.3, 169.9, 163.5, 130.2, 130.0, 114.8, 67.3, 67.2, 56.0, 48.3, 47.2, 46.
2, 45.0, 42.9, 40.1, 37.9, 26.5, 24.0, 22.5 and 13.7. IR: v _max 3229,
2959, 1612, 1496, 1463, 1386, 1336, 1303, 1260, 1182, 1154, 1092, 1067,
1024, 892, 838, 804, 730 and 560 cm ^-1 . Measured: C 53.47% H 7.22% N 8.49
%; C ₂₂ H ₃₅ N ₃ O ₇ S .0.5 H ₂ O Calculated: C 53.42% H 7.34% N 8.50%.

Example 8 2S-[[Ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide

[0077]

[Chemical 13]

White foam mp 88.5-90 ^o C. ¹ H-NMR: δ (CDCl ₃ ), 10.32 (1H, br s), 7.74
(2H, d, J = 8.8 Hz), 6.98 (2H, d, J = 8.9 Hz), 3.86 (3H, s), 3.62 3.60
(4H, m), 3.36 3.19 (4H, m), 3.12 2.93 (2H, m), 1.74 1.37 (8H, m), 1.
28 1.18 (1H, m), 0.99 (3H, t, J = 7.2 Hz), 0.90 (3H, d, J = 6.1 Hz) and 0.88 (3H, d, J = 6.2 Hz). ¹³ C-NMR: δ (CDCl ₃ ), 175.7, 172.0, 165.2
, 132.2, 131.9, 116.5, 57.9, 50.3, 49.6, 47.8, 46.9, 45.5, 41.7, 39.6, 2
9.0, 28.3, 28.0, 26.7, 25.9, 24.4 and 15.7. IR: v _max 3206, 2937, 159
7, 1496, 1451, 1336, 1257, 1182, 1153, 1022, 836, 804 and 729 cm ^-1 .
Measured: C 56.41% H 7.69% N 8.54%; C ₂₃ H ₃₇ N ₃ O ₆ S .0.3 H ₂ O Calculated: C 56.49%
H 7.75% N 8.59%.

Example 9 3R-Cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -N-hydroxy-4-oxo-4-morpholin-1-yl-butyramide

[0080]

[Chemical 14]

White foam ¹ H-NMR: δ (CD ₃ OD), 7.74 (2H, d, J = 8.9 Hz), 7.06 (2H, d,
J = 8.9 Hz), 3.87 (3H, s), 3.71 (2H, m), 3.52 (2H, m), 3.30 2.91 (5H,
m), 2.72 (1H, m), 1.87 1.38 (14H, m), 1.32 (1H, m) and 1.00 (6H, m)
^{. 13 C-NMR: δ (} CD 3 OD), 174.0, 171.4, 164.8, 131.6, 130.7, 115.5, 56.3,
48.0, 45.4, 44.4, 39.4, 38.8, 34.6, 33.4, 28.1, 27.1, 26.2, 25.5 and
13.4. IR: v _max 3211, 2948, 1736, 1598, 1497, 1453, 1335, 1261, 1156, 10
93 and 1024 cm ¹ .C ₂₅ H ₃₉ N ₃ O ₆ S (509.7); MS (Electrospray): 510.4 [M + H
] ⁺ , 532.2 [M + Na] ⁺ .

Example 10 3R-Cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4oxo-butyramide

[0083]

[Chemical 15]

White foam ¹ H-NMR: δ (CD ₃ OD), 7.72 (2H, d, J = 8.9 Hz), 7.08 (2H, d, J
= 8.9 Hz), 3.87 (3H, s), 3.65 (10H, br m), 3.21 (1H, m), 3.05 (1H, m)
, 2.89 (1H, m), 2.78 (1H, m), 1.89 1.49 (8H, br m), 1.39 (1H, m), 1.10
(2H, m) and 0.98 (3H, t, J = 7.1 Hz). ¹³ C-NMR: δ (CD ₃ OD), 174.9, 17
1.6, 165.2, 131.9, 131.6, 115.9, 68.4, 56.7, 48.7, 45.4, 44.2, 39.6, 39.
1, 35.0, 33.7, 26.6 and 13.7. IR: v _max 3228, 2952, 2862, 1778, 1600,
1497, 1463, 1340, 1263, 1160, 1115 and 1027 cm ¹ .

Example 11 3R-Cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl
) -Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide (trifluoroacetate)

[0086]

[Chemical 16]

[0087] Yellow foam¹H-NMR: δ (CD₃OD), 8.57 (1H, d, J = 8.6 Hz), 8.51 (1H, d, J
 = 8.7 Hz), 8.14 (1H, d, J = 7.4 Hz), 7.65 (2H, m), 7.45 (1H, d, J = 7.4
 Hz), 3.65 (4H, m), 3.42 (1H, m), 3.08 (1H, m), 3.01 (6H, s), 2.75 (3H,
s), 2.71 (2H, m), 1.59 (13H, br m), 1.28 (2H, m) and 1.01 (2H, m).^{1 3} C-NMR: δ (CD₃OD), 174.2, 171.5, 150.9, 135.2, 132.0, 131.0, 129.7, 12
5.5, 123.0, 117.8, 52.1, 48.6, 48.4, 46.6, 44.7, 41.5, 39.6, 39.1, 36.6,
 35.0, 33.7, 28.3, 27.3, 26.4 and 22.6. IR: v_max 3202, 2944, 1606,
1454, 1332, 1249, 1141, 1048, 1024, 946 and 796 cm¹. C₂₉H₄₃N_FourO_FiveS.C₂F ₃ O₂ (558.7); MS (Electrospray): 559.4 [M + H]⁺.

Example 12 3R-Cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl
) -Methyl-amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4-oxo-butyramide trifluoroacetate

[0089]

[Chemical 17]

Yellow foam ¹ H-NMR: δ (CD ₃ OD), 8.56 (1H, d, J = 4.5 Hz), 8.54 (1H, d,
J = 4.6 Hz), 8.14 (1H, d, J = 6.3 Hz), 7.68 (2H, m), 7.49 (1H, d, J = 7
.5 Hz), 3.61 (8H, m), 3.41 (1H, m), 3.04 (7H, m), 2.91 (1H, m), 2.75 (4H
, m), 1.65 (8H, br m), 1.31 (1H, m) and 1.01 (2H, m). ¹³ C-NMR: δ (CD ₃ OD), 174.8, 171.4, 150.5, 135.2, 132.0, 131.9, 130.9, 129.7, 125.7, 123.
3, 118.0, 68.3, 52.1, 48.4, 46.7, 44.1, 41.5, 39.6, 39.0, 36.7, 35.0, 33
.7 and 26.6. IR: v _max 3207, 2943, 2862, 1636, 1516, 1458, 1333, 1267
, 1140, 1042, 946 and 796 cm ¹ measurements:.. C 53.54% H 6.11 % N 8.33% C 3 0 H 41 F 3 N 4 O 8 S Calculated: C 55.35% H 6.44% N 8.33%.

Example 13 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -ethyl-amino] -methyl] -5-
Methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide (trifluoroacetate)

[0092]

[Chemical 18]

[0093] Yellow foam¹H-NMR: δ (CD₃OD), 8.60 (1H, d, J = 8.5 Hz), 8.40 (1H, d, J
 = 8.7 Hz), 8.22 (1H, d, J = 8.5 Hz), 7.65 (2H, dd, J = 8.6, 7.5 Hz), 7.
38 (1H, d, J = 7.3 Hz), 3.75 3.24 (11H, m), 3.18 3.00 (2H, m), 2.97 (6H,
 s), 2.79 2.70 (1H, m), 1.75 1.64 (1H, m), 1.45 1.32 (1H, m), 1.23 1
.13 (1H, m) and 0.91 0.81 (9H, m).¹³C-NMR: δ (CD₃OD), 174.7, 171.
5, 152.3, 136.6, 131.8, 131.5, 131.4, 129.7, 125.2, 122.0, 117.4, 68.3,
48.8, 46.4, 44.2, 44.0, 42.3, 40.5, 27.4, 24.6, 22.6 and 13.2.IR: v _max  3194, 2955, 1609, 1458, 1319, 1267, 1198, 1139, 1042, 932, 892, 794,
 717 cm^-1.

Example 14 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl]-
5-Methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide (trifluoroacetate)

[0095]

[Chemical 19]

Yellow foam ¹ H-NMR: δ (CD ₃ OD), 8.60 (1H, d, J = 8.5 Hz), 8.39 (1H, d, J
= 8.7 Hz), 8.22 (1H, d, J = 8.5 Hz), 7.67 7.61 (2H, m), 7.38 (1H, d, J
= 7.5 Hz), 3.75 3.41 (6H, m), 3.31 3.03 (3H, m), 2.96 (6H, s), 2.77
2.67 (1H, m), 1.73 1.33 (8H, m), 1.21 1.10 (1H, m) and 0.90 0.83
(9H, m). ¹³ C-NMR: δ (CD ₃ OD), 174.2, 171.6, 136.6, 131.8, 131.5, 129.6,
125.2, 117.3, 111.4, 44.0, 42.4, 41.5, 40.0, 26.0, 25.1, 23.5, 22.3, 20
.3 and 10.8.IR: v _max 3359, 3360, 3198, 2938, 1777, 1642, 1606, 1465
, 1389, 1322, 1251, 1227, 1199, 1140, 1056, 1019, 989, 931 cm ^-1 .
: C 58.55% H 7.62% N 9.69%; C ₃₀ H ₄₂ N ₄ O ₇ SF ₃ .1.5 H ₂ O Calculated: C 58.62% H
7.91% N 9.76%. The following additional compounds were prepared by the parallel synthesis in solution using the method described in Preparation B, 2- [2-cyclopentyl-1R- (piperidine-1-carbonyl)- Prepared from ethyl] -acrylic acid benzyl ester. Briefly, for the Michael addition of the appropriate amine, sulfonylation with the desired sulfonyl chloride, catalytic transfer hydrogenolysis (4.4% formic acid in methanol, 10% palladium on carbon at room temperature,
4 hours) and direct coupling of hydroxylamine follows. The product was generally isolated by preparative reverse phase HPLC with 90-95% purity and characterized by electrospray mass spectroscopy.

Example 15 3R-Cyclopentylmethyl-2S-[(ethanesulfonyl-methyl-amino) -methyl] -N-
Hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[0098]

[Chemical 20] C ₂₀ H ₃₇ N ₃ O ₄ S (415.6); MS (Electrospray): 416.6 [M + H] ⁺ , 438.6 [M + Na] ⁺ .

Example 16 3R-Cyclopentylmethyl-N-hydroxy-2S-[[methyl- (propane-2-sulfonyl)
-Amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical 21] C ₂₁ H ₃₉ N ₃ O ₄ S (429.6); MS (Electrospray): 430.6 [M + H] ⁺ , 452.6 [M + Na] ⁺ .

Example 17 3R-Cyclopentylmethyl-N-hydroxy-2S-[[methyl- (octane-1-sulfonyl)
-Amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical formula 22] C ₂₆ H ₄₉ N ₃ O ₄ S (499.8): MS (Electrospray): 500.8 [M + H] ⁺ , 522.8 [M + Na] ⁺ .

Example 18 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methyl-trifluoromethanesulfonyl-amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical formula 23] C ₁₉ H ₃₂ F ₃ N ₃ O ₄ S (455.5); MS (Electrospray): 456.5 [M + H] ⁺ , 478.5 [M + Na] ⁺ .

Example 19 2S-[[4-Chloro-benzenesulfonyl) -methyl-amino] methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical formula 24] C ₂₄ H ₃₆ ClN ₃ O ₄ S (498.1); MS (Electrospray): 499.1, 501.1 [M + H] ⁺ , 521.1, 52
3.1 [M + Na] ⁺ .

Example 20 3 R-Cyclopentylmethyl-N-hydroxy-2S-[[methyl- (quinoline-8-sulfonyl)
-Amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical 25] C ₂₇ H ₃₈ N ₄ O ₄ S (514.7); MS (Electrospray): 515.7 [M + H] ⁺ , 537.7 [M + Na] ⁺ .

Example 21 3R-Cyclopentylmethyl-N-hydroxy-2S-[[methyl- (naphthalene-1-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical formula 26] C ₂₈ H ₃₉ N ₃ O ₄ S (513.7); MS (Electrospray): 514.7 [M + H] ⁺ , 536.7 [M + Na] ⁺ .

Example 22 3R-Cyclopentylmethyl-N-hydroxy-2S-[[isoquinoline-5-sulfonyl) -methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical 27] C ₂₇ H ₃₈ N ₄ O ₄ S (514.7); MS (Electrospray): 515.7 [M + H] ⁺ , 537.7 [M + Na] ⁺ .

Example 23 3R-Cyclopentylmethyl-2S-[[6-dimethylamino-naphthalene-1-sulfonyl)-
Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical 28] C ₃₀ H ₄₅ N ₄ O ₄ S .C ₂ F ₃ O ₂ (556.8); MS (Electrospray): 557.8 [M + H] ⁺ .

Example 24 3R-Cyclopentylmethyl-2S-[[dimethylsulfamoyl-methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical 29] C ₂₀ H ₃₈ N ₄ O ₄ S (430.6); MS (Electrospray): 431.6 [M + H] ⁺ , 453.6 [M + Na] ⁺

Example 25 2S-[(Butyl-methanesulfonyl-amino) -methyl] -3R-cyclopentylmethyl-N-
Hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical 30] C ₂₂ H ₄₁ N ₃ O ₄ S (443.7); MS (Electrospray): 444.7 [M + H] ⁺ , 466.7 [M + Na] ⁺ .

Example 26 3R-Cyclopentylmethyl-N-hydroxy-2S-[(isopropyl-methanesulfonyl)
-Amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical 31] C ₂₁ H ₃₉ N ₃ O ₄ S (429.6); MS (Electrospray): 430.6 [M + H] ⁺ , 452.6 [M + Na] ⁺ .

Example 27 2S-[(tert-Butyl-methanesulfonyl) -amino) -methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical 32] C ₂₂ H ₄₁ N ₃ O ₄ S (443.7); MS (Electrospray): 444.7 [M + H] ⁺ , 466.7 [M + Na] ⁺ .

Example 28 3R-Cyclopentylmethyl-N-hydroxy-2S-[(cyclopropyl-methanesulfonyl) -amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide

[Chemical 33] C ₂₁ H ₃₇ N ₃ O ₄ S (427.6); MS (Electrospray): 428.6 [M + H] ⁺ , 450.6 [M + Na] ⁺ .

Example 29 2S-[(Cyclopentyl-methanesulfonyl) -amino) -methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide

[Chemical 34] C ₂₃ H ₄₁ N ₃ O ₄ S (455.7); MS (Electrospray): 456.7 [M + H] ⁺ , 478.7 [M + Na] ⁺ .

Biological Example A The efficacy of compounds of the invention as inhibitors of human fibroblast collagenase can be measured by the method of Cawston and Barrett, which is incorporated herein by reference. Yes (Anal. Biochem., 99, 340-345, 1979). According to it, a 1 mM solution of the compound to be tested, or a dilution thereof, was added to collagen and human fibroblast collagenase (buffered with 25 mM Hepes, pH 7.5 5 mM CaCl ₂ , 0.05% Br).
ij35 and 0.02% NaN ₃ ) and incubated at 37 ° C. for 16 hours. Collagen is acetylated, and Cowston and Murphy (Murphy) are incorporated herein by reference.
¹⁴ C collagen was produced by the method of phy) (Methods in Enzymology, 80, 711, 19
81). Samples were centrifuged to obtain an undigested collagen precipitate, and then a portion of the radioactive supernatant was transferred for assay on a scintillation counter as a measure of hydrolysis. Collagenase activity in the presence of 1 mM of the test compound or its dilution was compared to the activity in the control without inhibitor and the results were compared to the concentration of inhibitor showing a 50% inhibitory effect on collagenase activity (IC ₅₀ ). As such, we report below. The compounds of the invention tested in this assay showed activity as inhibitors of human fibroblast collagenase.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/00 A61P 25/00 27/02 27/02 29/00 101 29/00 101 35/00 35 / 00 43/00 111 43/00 111 (72) Inventor Martin, Fiona, Mitchell England Oxksford Audex 45 Oerwei Coley, Watlington Road (no address) British Biotech Pharmaceuticals Limited (72) Inventor Miller, Andrew United Kingdom Otsk Sword Aud Oetts Cx 4 5 Erwei Coley, Watlington Road (no street number) British Biotech Pharmaceuticals Limited (72) Inventor Todd, Lid Chard, Simon United Kingdom Otsk Sword Oudtuks 4 5 Erwei Coley, Watlington Road (no address) British Biotech Pharmaceuticals Limited (72) Inventor Whittaker, Mark Otsk Suf Oetz Cox 4 5 Erwey Coley, Watlington Road (No address) British Biotech Pharmaceuticals Limited F-term (reference) 4C086 AA01 AA02 AA03 BC16 BC73 MA02 MA05 NA14 ZA01 ZA33 ZA67 ZA96 ZB11 ZB15 ZB26 ZC20 ZC61

Claims (5)

[Claims] 1. 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-
Amino] -methyl] -5-methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 3R-cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]- 4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino) -methyl)]-4-morpholin-4-yl-4-oxo -Butylamide, 3R-Cyclopentylmethyl-N-hydroxy-2S-[[(4-benzenesulfonyl) -methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 3R-Cyclopentylmethyl- N-hydroxy-2S-[[(4-benzenesulfonyl) -methyl-amino] -methyl] -4-morpholin-4-yl-4-oxo-butyramide, 2S-[(methanesulfonyl-methyl-amino) -methyl ] -5-Methyl-3R- (morpholine-4
-Carbonyl) -hexanoic acid hydroxyamide, 2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -5-methyl-3
R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide, 3R-cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -N-hydroxy-4-oxo-4 -Morpholin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[ethyl- (4-methoxy-benzenesulfonyl) -amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4-oxo -Butylamide, 3R-Cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl
) -Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[(5-dimethylamino-naphthalene-1-sulfonyl)
) -Methyl-amino] -methyl] -N-hydroxy-4-morpholin-4-yl-4-oxo-butyramide, 2S-[[(5-dimethylaminonaphthalene-1-sulfonyl) -ethyl-amino] -methyl ]-
5-Methyl-3R- (morpholine-4-carbonyl) -hexanoic acid hydroxyamide, 2S-[[(5-Dimethylaminonaphthalene-1-sulfonyl) -methyl-amino] -methyl]-
5-Methyl-3R- (piperidine-1-carbonyl) -hexanoic acid hydroxyamide, 3R-Cyclopentylmethyl-2S-[(ethanesulfonyl-methyl-amino) -methyl] -N
-Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (propane-2-sulfonyl) -amino] -methyl] -4-oxo- 4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (octane-1-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl -Butylamide, 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methyl-trifluoromethanesulfonyl-amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 2S-[[4-chloro- Benzenesulfonyl) -methyl-amino] methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- ( Quinoline-8-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl-butyla Amido, 3R-cyclopentylmethyl-N-hydroxy-2S-[[methyl- (naphthalene-1-sulfonyl) -amino] -methyl] -4-oxo-4-piperidin-1-yl-butylamide, 3R-cyclopentylmethyl- N-hydroxy-2S-[[isoquinoline-5-sulfonyl)-
Methyl-amino] -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[6-dimethylamino-naphthalene-1-sulfonyl)
-Methyl-amino] -methyl] -N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentylmethyl-2S-[[dimethylsulfamoyl-methyl-amino] -methyl] -N -Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 2S-[(butyl-methanesulfonyl-amino) -methyl] -3R-cyclopentylmethyl-N
-Hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-Cyclopentylmethyl-N-hydroxy-2S-[(isopropyl-methanesulfonyl) -amino] -methyl] -4-oxo-4-piperidine- 1-yl-butyramide, 2S-[(tert-butyl-methanesulfonyl) -amino) -methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, 3R-cyclopentyl Methyl-N-hydroxy-2S-[(cyclopropyl-methanesulfonyl) -amino) -methyl] -4-oxo-4-piperidin-1-yl-butyramide, 2S-[(Cyclopentyl-methanesulfonyl) -amino)- Methyl] -3R-cyclopentylmethyl-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide, a compound which is a member of the group consisting of, and pharmaceutically acceptable salts, hydrates and solvents thereof Japanese food. 2. A compound according to claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, together with a pharmaceutically or veterinarily acceptable additive or carrier.
A pharmaceutical or veterinary composition comprising a hydrate or a solvate. 3. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs. 4. A method for treating a disease or condition mediated by MMPs, which comprises administering an effective amount of the compound according to claim 1 to a mammal. 5. The use according to claim 3 or the use according to claim 4, wherein the disease or condition is rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulcer, cancer or nervous system inflammatory disease. The method described.