KR20050019853A - Sulphonylpiperidine Derivatives Containing an Alkenyl or Alkynyl Moiety for Use as Matrix Metalloproteinase Inhibitors - Google Patents

Abstract

The present invention relates to at least one metalloproteinase, and in particular compounds of formula (1), wherein B is C _2-4 alkenyl or C _2-4 alkynyl, which may be optionally substituted, useful for the inhibition of TACE It is about.

<Formula (1)>

Description

Sulphonylpiperidine Derivatives Containing an Alkenyl or Alkynyl Moiety for Use as Matrix Metalloproteinase Inhibitors}, useful as matrix metalloproteinase inhibitors

Unless stated otherwise, the invention will be illustrated by the following non-limiting examples.

(i) the temperature is expressed in degrees Celsius (° C.); The run was carried out at room temperature or room temperature (ie, in the range of 18-25 ° C.).

(ii) the organic solvent is dried over anhydrous magnesium sulfate; The solvent evaporation process was carried out using a rotary evaporator at a bath temperature of up to 60 ° C. under reduced pressure (600-4000 Pascals; 4.5-30 mmHg).

(iii) unless otherwise stated, chromatography means flash chromatography on silica gel; Thin layer chromatography (TLC) was performed on silica gel plates; When a "Bond Elut" column is mentioned, it contains a column of 10 or 20 g of silica (contained in a 60 ml disposable syringe, supported by a porous disk) with a particle size of 40 μm (US Commercially available under the trade name " Mega Bond Elut SI " from Varian, Harbor City, California; If "Isolute ^™ SCX column" is mentioned, it is a column containing benzenesulfonic acid (not capped) (International, East Gladner, East Glasgow, Mingla, Duffin, Industrial Estate, First House) Sorbent technology limited (available from International Sorbent Technology Ltd.); When Flashmaster II is mentioned, it means UV driven automated chromatography units supplied by Jones.

(iv) In general, TLC was performed after the reaction procedure, and the reaction time is shown for illustrative purposes only.

(v) yields (if given) are for illustration only and do not necessarily indicate what can be obtained by advancing the method which has been carried out elaborately; If more material was needed, the manufacturing process was repeated.

(vi) ¹ H NMR data, if given, are expressed in delta values for major diagnostic protons (parts per million (ppm) for tetramethylsilane (TMS) as an internal standard, and unless otherwise stated, deuterium DMSO ( And measured at 300 MHz using CD ₃ SOCD ₃ ); Coupling constants (J) are expressed in Hz.

(vii) chemical symbols have their usual meanings; SI units and symbols are used.

(viii) Solvent ratio is shown by volume%.

(ix) mass spectra (MS) were performed using electron energy of 70 eV in chemical ionization (APCI) mode using direct exposure probes; If indicated, the ionization reaction was carried out by electrospray (ES); Given m / z values, generally only ions representing the source mass are recorded and unless otherwise stated the cited mass ions are positive mass ions-(M + H) ⁺ .

(x) LCMS characterization was performed using a pair of Gilson 306 pumps equipped with a Gilson 233 XL sample feeder and a Waters ZMD4000 mass spectrometer. The LC included a water symmetrical 4.6 × 50 column C18 with a particle size of 5 μm. Eluent A was water containing 0.05% formic acid, and Eluent B was acetonitrile containing 0.05% formic acid. Elution gradient was performed from 95% A to 95% B (6 minutes). If indicated, the ionization reaction was carried out by electrospray (ES); Given m / z values, generally only ions representing the source mass are recorded and unless otherwise stated the cited mass ions are positive mass ions-(M + H) ⁺ .

(xi) the following abbreviations were used:

DMSO dimethyl sulfoxide

DMF N-dimethylformamide

DCM dichloromethane

NMP N-methylpyrrolidinone

DIAD di-isopropylazodicarboxylate

LHMDS or LiHMDS lithium bis (trimethylsilyl) amide

MeOH Methanol

RT room temperature

TFA trifluoroacetic acid

EtOH Ethanol

EtOAc ethyl acetate

EDTA ethylenediaminetetraacetic acid

THF tetrahydrofuran

TBDMS tert-butyldimethylsilyl

DIPEA diisopropylethylamine

MTBE methyl tert-butyl ether

Example 1

(R / S) -1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl (hydroxy) formamide

(R / S)-[1-({[4- (4-but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidine-2 in THF (5.0 ml) To a stirred solution of -ylbutyl] hydroxylamine (170 mg, 0.43 mmol) was added a mixture of preformed acetic anhydride (200 μl, 2.1 mmol) and formic acid (0.75 ml). The mixture was stirred at RT for 23 h. After the solvent was removed by rotary evaporation, EtOAc (15 ml) was added followed by saturated sodium bicarbonate and the reaction mixture was stirred for 4 hours. The mixture was diluted with EtOAc (15 ml), washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated to give a colorless film. The aqueous layer was extracted again with DCM (3 × 10 ml), dried (Na ₂ SO ₄ ) and combined with the previous product. This residue was purified by chromatography (Flashmaster II, eluent 0 → 10% MeOH / DCM) to give a mixture. This mixture was dissolved again in MeOH (5 ml) and K ₂ CO ₃ was added. After 16 hours, the solution was concentrated, partitioned between DCM and brine, the organic layer was dried (Na ₂ CO ₃ ) and concentrated to give the title compound as a pure oil (84 mg, 46%).

Starting material (R / S)-[1-({[4- (4-but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl Hydroxylamines were prepared as follows:

i) To a solution of 4-hydroxypiperidine (20 g, 198 mmol) in 2M aqueous sodium hydroxide (350 ml) was added methanesulfonyl chloride (25 ml, 323 mmol) over 10 minutes. The solution was stirred for an additional 1 h at room temperature. The reaction mixture is poured into EtOAc (300 ml) and the organic phase is separated. The aqueous phase was extracted with EtOAc (2 × 300 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and filtered. The filtrate was treated with SCX-2 resin (20 g) for 15 minutes, then filtered and evaporated to afford 4-hydroxy-1- (methanesulfonyl) piperidine as a white solid (6.62 g, 19%).

ii) 4-hydroxy-1- (methanesulfonyl) piperidine (6.4 g, 35.7) in DMF (50 ml) in a suspension of sodium hydride (60% dispersion, 1.5 g, 37.5 mmol) in DMF (350 ml) mmol) was added. After 20 minutes at RT, 1-bromobut-2-yne (3.0 ml, 34.3 mmol) was added rapidly. After 4 hours, water (5 ml) was added at RT and the mixture was left for 16 hours. The solvent was concentrated and the resulting brown oil was partitioned between brine (200 ml) and EtOAc (200 ml). The aqueous phase was extracted with EtOAc (2 × 200 ml) and the organic layers combined. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give a brown oil, which was purified by chromatography (Flashmaster II, 70 g silica column, eluting with a 0 → 100% EtOAc / iso-hexane gradient). To give 4- (but-2-ynyloxy) -1-methanesulfonylpiperidine (1.8 g, 22% yield).

iii) To a stirred solution of 4- (but-2-ynyloxy) -1-methanesulfonylpiperidine (461 mg, 2 mmol) in THF (15 ml) LiHMDS (4.4 ml, 1.0 in THF) at -15 ° C. M solution, 4.4 mmol) was added. The solution was then stirred at this temperature for 30 minutes. Then a solution of ethyl 4- (pyrimidin-2-yl) butanoate (400 mg, 2.1 mmol) in THF (1 ml) was added dropwise. The reaction was slowly warmed to 5 ° C., then 20 minutes later, water (2 ml) was added. After partitioning the solution between brine (20 ml) and EtOAc (10 ml), the aqueous layer was extracted again with EtOAc (10 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 50% EtOAc in hexanes) purified 1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentane- 2-one was obtained as a yellow oil (286 mg, 38%).

iv) 1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentan-2-one (286 mg, 0.75 in EtOH (5 ml) sodium borohydride (15 mg) was added to the stirred solution of mmol) and the mixture was stirred at RT. After 25 minutes, the reaction mixture was concentrated and EtOAc (20 ml) was added. The organic layer was washed with brine (20 ml) and the aqueous fraction was extracted again with EtOAc (20 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and evaporated to (R / S) -1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidine-2- I) pentan-2-ol was obtained (286 mg, 100% yield).

v) (R / S) -1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentan-2- in DCM (5 ml) To a stirred solution of all (286 mg, 0.75 mmol) was added triethylamine (260 μl, 1.9 mmol) followed by methanesulfonyl chloride (65 μl, 0.83 mmol) and the mixture was stirred at RT. After 21 hours, the reaction mixture was poured into brine, diluted with DCM (20 ml) and partitioned. The organic layer was dried (Na ₂ SO ₄ ), evaporated and purified by chromatography (Flashmaster II, 10 g silica column, 0 → 100% hexanes / EtOAc) to give E-1-{[4- (but-2 -Inyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pent-1-ene was obtained (158 mg, 58% yield).

vi) E-1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pent-1-ene (158 mg) in THF (5 ml) , 0.43 mmol) was added hydroxylamine (50% solution in water, 450 μl) under argon and the mixture was stirred overnight. The mixture is poured into water (5 ml) and EtOAc (15 ml) and the partitioned organic layer is washed with brine (5 ml), dried (Na ₂ SO ₄ ) and concentrated to (R / S)-[1- ( Obtain {[4- (4-but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl] hydroxylamine (170 mg, 100%) It was used immediately at the last step.

Ethyl 4- (pyrimidin-2-yl) butanoate was prepared as follows:

<Ethyl 4- (pyrimidin-2-yl) butanoate>

2-bromopyrimidine (80 g, 500 mmol) was slurried in THF (400 ml). After forming the inert atmosphere by replacing the air atmosphere with nitrogen, the sludge was degassed by nitrogen purging. After charging bis (acetonitrile) palladium (II) chloride (2.5 mmol) and triphenylphosphine (7.5 mmol), 4-ethoxy-4-oxo-butylzinc bromide (0.5 M in THF, approximately 600 mmol) Was divided into 9 parts and charged. The mixture was stirred until the reaction was complete, at this point water was added and the solution was rotary evaporated to give an oil. DCM was added and the solution was washed with 1 M EDTA tetrasodium salt, water and brine. The DCM solution was then rotary evaporated to give an oil, at which time impurities precipitated out. This mixture was dissolved in THF, filtered to remove impurities, and then the solvent was removed on a rotary evaporator to give the desired ethyl 4- (pyrimidin-2-yl) butanoate as an orange oil (95.4 g, 492 mmol). .

Example 2

(R / S) -1-[({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl (hydroxy Formamide

4- (but-2-ynyloxymethyl) -1- (methanesulfonyl) piperidine (360 mg, 1.47 mmol) instead of 4- (but-2-ynyloxy) -1-methanesulfonylpiperidine Except that (R / S) -1-[({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonate according to the procedure described in Example 1 (synthesis method described below) Phonyl) methyl] -4-pyrimidin-2-ylbutyl (hydroxy) formamide (169 mg, 0.38 mmol) was obtained.

The starting material 4- (but-2-ynyloxymethyl) -1- (methanesulfonyl) piperidine was prepared as follows:

i) Triethylamine (6 ml, 43.5 mmol) followed by methanesulfonyl chloride (3.0 ml, in a stirred solution of piperidin-4-ylmethanol (2 g, 17.4 mmol) dissolved in DCM (250 ml) 38.2 mmol) was added. After 2.5 h at RT, the reaction mixture is diluted with EtOAc (500 ml) and the organic layer is washed with 2M HCl (100 ml), NaHCO ₃ (100 ml), brine (100 ml), dried (Na ₂ SO ₄ Evaporation yielded 4- (methanesulfonyloxymethyl) -1-methanesulfonylpiperidine as an off-white solid (4.5 g, 96%).

ii) To a stirred solution of but-2-yn-1-ol (550 μl, 7.4 mmol) in DMF (25 ml) was added sodium hydride (300 mg, 8.1 mmol). After 90 minutes, a solution of DMF (30 ml) 4- (methanesulfonyloxymethyl) -1-methanesulfonylpiperidine (2.0 g, 7.4 mmol) was added. After stirring for 2 h at RT, water (5 ml) was added and the mixture was concentrated to give a brown oil. It was partitioned between EtOAc (100 ml) and brine (150 ml). The aqueous layer is extracted again with EtOAc (2 × 50 ml), the combined organic fractions are dried (Na ₂ SO ₄ ), evaporated and chromatographed (Flashmaster II, 50 g silica, 50 → 100% hexanes / EtOAc). Purification was carried out to give 4- (but-2-ynyloxymethyl) -1- (methanesulfonyl) piperidine (680 mg, 2.8 mmol, 37%).

Example 3

(R / S) -2-({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) -1-methylethyl (hydroxy) formamide

(R / S) -2-{[4- (but-2-ynyloxymethyl) piperidin-1-yl] sulfonyl} -1-methylethylhydroxylamine (112 mg, in THF (5.0 ml) 0.37 mmol) was added a mixture of acetic anhydride (200 μL, 2.1 mmol) and formic acid (0.75 ml) preformed. The mixture was stirred at rt overnight. After the solvent was removed by rotary evaporation, EtOAc (10 ml) was removed by saturated sodium bicarbonate and the reaction mixture was stirred for 2 hours. The mixture was washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated to give a pale yellow oil. This residue was purified by chromatography (Flashmaster II, eluent 0-60% EtOAc / DCM) to give (R / S) -2-({4-[(but-2-ynyloxy) methyl] piperidine -1-yl} sulfonyl) -1-methylethyl (hydroxy) formamide was obtained (75 mg, 0.22 mmol).

The starting material (R / S) -2-{[4- (but-2-ynyloxymethyl) piperidin-1-yl] sulfonyl} -1-methylethylhydroxyamine was prepared as follows:

i) Argon at −17 ° C. in a stirred solution of 4- (but-2-ynyloxymethyl) -1-methanesulfonylpiperidine (prepared above) (320 mg, 1.3 mmol) in THF (10 ml) Under LiHMDS (2.8 ml, 1.0 M solution in THF, 2.8 mmol) was added. The solution was then stirred at this temperature for 30 minutes. Then a solution of diethylchlorophosphate (190 μl, 1.31 mmol) was added and the reaction mixture was stirred at 0 ° C. for an additional 50 minutes. Acetaldehyde (100 μl, 1.8 mmol) was then added. After 15 hours, the reaction was quenched with saturated ammonium chloride (10 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (30 ml). The combined organic phases are combined, washed with brine (10 ml), dried (Na ₂ SO ₄ ), concentrated and purified by chromatography (Flashmaster II, 50 g silica, 50 → 100% hexanes / EtOAc) to E / Z- {1- [4- (4-but-2-ynyloxymethyl) piperidin-1-yl] sulfonyl} prop-1-ene was obtained as a yellow oil (100 mg, 0.37 mmol) . MS: 272.

ii) E / Z- {1- [4- (4-but-2-ynyloxymethyl) piperidin-1-yl] sulfonyl} prop-1-ene (100 mg, in THF (5 ml) 0.37 mmol) was added hydroxylamine (50% solution in water, 450 μl) under argon and the mixture was stirred over the weekend. The mixture is poured into water (5 ml) and EtOAc (15 ml) and the partitioned organic layer is washed with brine (5 ml), dried (Na ₂ SO ₄ ) and concentrated to (R / S) -2- [4 -(But-2-ynyloxymethyl) piperidin-1-yl] sulfonyl} -1-methylethylhydroxyamine was obtained (112 mg, 0.37 mmol). It was used immediately at the last step.

Example 4

2- (4-But-2-ynyloxymethylpiperidin-1-ylsulfonylmethyl) -4-methyl-pentanoic acid hydroxyamide

DMF (2 drops in a stirred solution of 2- (4-but-2-ynyloxymethylpiperidin-1-ylsulfonylmethyl) -4-methylpentanoic acid (350 mg, 0.97 mmol) in DCM (20 ml) ) And oxalyl chloride (0.1 ml, 1.16 mmol) were added. The reaction was stirred at RT for 1 h and then evaporated to dryness at RT to yield a yellow solid. The solid was dissolved again in DCM (6 ml) and added dropwise over 5 minutes to a solution of hydroxylamine (50% aqueous solution, 1.0 ml) in THF (15 ml). The resulting solution was stirred at RT for 1 h and then evaporated under reduced pressure. The crude product was purified by chromatography (Flashmaster II, 20 g silica bondlute, eluent 50% -80% EtOAc / isohexane) to give the product as a white solid (160 mg, 0.43 mmol).

The starting material 2- (4-but-2-ynyloxymethylpiperidin-1-ylsulfonylmethyl) -4-methyl-pentanoic acid was prepared as follows:

i) LiHMDS (1.0 M in THF, 2.2 ml in a solution of 4-but-2-ynyloxymethyl-1-methanesulfonylpiperidine (520 mg, 2.12 mmol) in THF (7 ml) cooled to -16 ° C. , 2.2 mmol) was added. The solution was stirred at -16 ° C for 10 minutes. To this solution was added dropwise a solution of 3-isobutyl-oxirane-2-one in THF at −16 ° C. (LiHMDS (1.0 M in THF, 2.3 ml, 2.3 mmol) was added 2-bromoy in THF (7 ml)). Prepared by addition to a solution of socaproic acid (431 mg, 2.2 mmol) at −16 ° C.). Stirring was continued at RT for 1 h. The reaction was quenched using ammonium chloride solution (saturated aqueous solution, 5 ml). 2M HCl (8 ml) and EtOAc (20 ml) were added. The organic phase was separated. The aqueous phase was extracted with EtOAc (20 ml). The combined organic phases were washed with brine (20 ml), dried (Na ₂ SO ₄ ), evaporated and purified by chromatography (Flashmaster II, 50 g, eluent 50 → 80% EtOAc / isohexane) to 2- (4-But-2-ynyloxymethylpiperidin-1-ylsulfonylmethyl) -4-methyl-pentanoic acid was obtained as a yellow oil (350 mg, 0.97 mmol).

Example 5

(R / S) -2-({4- [prop-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide

(R / S) -2-{[4- [prop-2-enyloxy] piperidin-1-yl] sulfonyl} -1-phenylethylhydroxylamine in DCM (1 ml) (described below) (0.75 mmol) was added a mixture of preformed formic acid (2 ml) and acetic anhydride (1 ml) and stirred overnight at RT. Then methanol (5 ml) was added followed by stirring for 30 minutes and the mixture was evaporated. The residue was dissolved again in methanol (2 ml) and left overnight at RT. After evaporation, the mixture was purified by Bondilut chromatography (10 g silica), eluting with a gradient of 5% methanol in DCM → DCM to give (R / S) -2- [prop-2-enyloxy] pi. Ferridin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide was obtained as a solid (0.16 mmol, 0.059 g). MS: 369.

The starting material (R / S) -2-{[4- [prop-2-enyloxy] piperidin-1-yl] sulfonyl} -1-fetylethylhydroxyamine was prepared as follows:

i) Triethylamine (8.0 g, 0.079 mol) of E-β-styrenesulfonyl chloride (12.0 g, 0.059 mol) and 4-hydroxypiperidine (8.0 g, 0.079 mol) in THF (100 ml) To the stirred solution was added at RT. After continued stirring overnight the reaction mixture was reduced to small volume and partitioned between EtOAc and aqueous 1 M HCl, saturated NaHCO ₃ and brine. The organic fractions were then dried (Na ₂ SO ₄ ) and evaporated to afford E- [4-hydroxypiperidin-1-ylsulfonyl] -2-phenylethene (12.75 g, 0.046 mol).

ii) E- [4-hydroxypiperidin-1-ylsulfonyl] -2-phenylethene (0.2 g, 0.75 mmol) was dissolved in DMF (3 ml) and added to allyl bromide (1.5 mmol). . After argon gas was introduced into the tube and covered, solid sodium hydride (0.1 g; contained in oil) was carefully added in three portions to the stirred reaction. Stirring was continued overnight. Water (5 ml) was added (initially added dropwise) and the resulting mixture was extracted with EtOAc (5 ml). The organic layer was separated and the aqueous layer was washed again with EtOAc (3 ml). The combined organic layers were evaporated, dissolved again in DCM (5 ml), loaded onto a 10 g silica bond column and eluted with a gradient of 2.5% MeOH in DCM → DCM to yield E- [4- [prop-2- Enyloxy] piperidin-1-ylsulfonyl] -2-phenylethene was obtained, which was used to carry out the next step reaction.

iii) E- [4- [prop-2-enyloxy] piperidin-1-ylsulfonyl] -2-phenylethene is dissolved in THF (1 ml) and argon is used to release the gas in the tube After addition, hydroxylamine in water (50% solution, 1 ml) was added and the mixture was stirred vigorously overnight. EtOAc (1 ml) was added and the aqueous layer was separated. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to (R / S) -2-{[4- [prop-2-enyloxy] piperidin-1-yl] sulfonyl} -1-phenylethylhydroxylamine was obtained, which was used to carry out the last step reaction.

Examples 6 and 7

The product shown below was obtained according to the method described in Example 5 except that an appropriate halide was used instead of aryl bromide.

Example number Structure and name Starting phenol MH + 6 (R / S) -2-({4- [but-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide 1-bromo-but-2-en 383 7 (R / S) -2-({4- [3-phenyl-prop-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide 1-bromo, 3-phenyl-prop-2-ene 439

The present invention relates to compounds useful in the inhibition of metalloproteinases, and in particular to pharmaceutical compositions comprising them, as well as their use.

The compounds of the present invention are inhibitors of one or more metalloproteinase enzymes and are particularly effective as inhibitors of TACE (TNFα converting enzyme). Metalloproteinases are a large family of proteinases (enzymes) whose numbers have increased significantly in recent years. As described in NM Hooper (1994) FEBS Letters 354 : 1-6, these enzymes have been classified into families and subfamily, taking into account their structure and function. Examples of metalloproteinases are matrix metalloproteinases (MMP), for example collagenase (MMP1, MMP8, MMP13), gelatinases (MMP2, MMP9), stromelysin (MMP3, MMP10, MMP11) ), Matylysine (MMP7), metalloelastine (MMP12), enamellysine (MMP19), MT-MMP (MMP14, MMP15, MMP16, MMP17); Leprolysine or adamalisine or MDC family, including secretases and sheddases such as TNF converting enzymes (ADAM10 and TACE); Astaxines, including enzymes such as procollagen processing proteinases (PCPs); And other metalloproteinases such as agrecanase, endothelin converting enzyme family and angiotensin converting enzyme family.

Metalloproteinases are believed to be important for the excess of physiological disease processes involved in tissue remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. This is based on the ability of metalloproteinases to cleave a wide range of matrix substrates such as collagen, proteoglycans and fibronectin. Metalloproteinases also include the processing (or secretion) of biologically important cell mediators such as tumor necrosis factor (TNF); And post-translational proteolytic processing (or shedding) of biologically important membrane proteins such as low-affinity IgE receptor CD23 (see NM Hooper et al., (1997) Biochem J. 321 : 265-279 for a more complete list). (shedding) is believed to be important.

Metalloproteinases are associated with a number of disease states. Inhibition of one or more metalloproteinase activity can be attributed to these disease states, for example various inflammatory and allergic diseases, such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially Inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema and dermatitis); Tumor metastasis or infiltration; Diseases associated with uncontrolled degradation of the extracellular matrix, such as osteoarthritis; Bone resorption diseases (eg, osteoporosis and Paget's disease); Diseases associated with abnormal angiogenesis; Enhanced collagen remodeling associated with diabetes, periodontal disease (eg, gingivitis), corneal ulcers, skin ulcers, postoperative conditions (eg colon anastomosis) and skin wound healing; Demyelinating diseases of the central and peripheral nervous systems (eg, multiple sclerosis); Alzheimer's disease; It can be very beneficial for the extracellular matrix remodeling observed in cardiovascular diseases such as restenosis and atherosclerosis.

Many metalloproteinase inhibitors are known; Different classes of compounds may have different degrees of efficacy and selectivity in inhibiting various metalloproteinases. We have found a group of compounds that are inhibitors of metalloproteinases and are particularly interesting in inhibiting TACE. Compounds of the present invention have beneficial efficacy and / or pharmacokinetic properties.

Isolated and cloned TACE (also known as ADAM17; RA Black et al. (1997) Nature 385: 729-733; ML Moss et al. (1997) Nature 385: 733-736) is a metal. It is a member of the admalisin family of proteins. TACE has been shown to play a role in cleaving pro-TNFα (ie, 26 kDa membrane binding protein) to release 17 kDa of biologically active soluble TNFα (Schlondorff et al. (2000) Biochem. J. 347: 131-138]. TACE mRNA is found in most tissues, but TNFα is produced primarily by activated monocytes, macrophages and T lymphocytes. TNFα is a broad range of pro-inflammatory biological processes, including induction of adhesion molecules and chemokines to promote cell trafficking, induction of matrix disrupting enzymes, activation of fibroblasts to produce prostaglandins, and activation of the immune system. Aggarwal et al (1996) Eur. Cytokine Netw. 7: 93-124. The clinical use of anti-TNF biologics has shown that TNFα plays an important role in a range of inflammatory diseases, including rheumatoid arthritis, Crohn's disease and psoriasis (Onrust et al (1998) Biodrugs 10 : 397-422] Jarvis et al (1999) Drugs 57: 945-964. TACE activity is also involved in the shedding of other membrane binding proteins including TGFα, p75 & p55 TNF receptors, L-selectin and amyloid precursor proteins (Black (2002) Int. J. Biochem. Cell Biol. 34: 1 -5]). The biology of TACE inhibition has been recently reviewed, where TACE plays a key role in TNFα production, and the efficacy of selective TACE inhibitors in the collagen-induced arthritis model of RA is the same as the strategy in directly neutralizing TNFα, Possibly showing greater efficacy (Newton et al (2001) Ann. Rheum. Dis. 60: iii25-iii32).

Thus, TACE inhibitors include, but are not limited to, inflammatory diseases including rheumatoid arthritis and psoriasis, autoimmune diseases, allergic / atopic diseases, transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury, and malignant tumors. Therefore, it can be expected to show efficacy in all diseases in which TNFα is associated.

Compounds that inhibit matrix metalloproteinases are already known in the art. WO 00/12477 discloses hydroxamic acid and carboxylic acid derivatives which are inhibitors of matrix metalloproteinases; WO 00/12478 discloses arylpiperazines which are useful for the inhibition of matrix metalloproteinases and are of particular interest with respect to the inhibition of MMP13 and MMP9; WO 01/87870 discloses hydroxamic acid derivatives that are inhibitors of matrix metalloproteinases, including ADAM or ADAM-TS enzymes.

Surprisingly, the inventors have discovered a series of sulfonyl piperidine compounds that have alkynyl or alkynyl substituents, which have metalloproteinase inhibitory activity and are especially inhibitors of TACE (ADAM17).

In one aspect of the invention, there is provided a compound of formula (1).

<Formula (1)>

(Wherein

Z is selected from -CONR ¹⁵ OH and -N (OH) CHO,

Wherein R ¹⁵ is hydrogen or C _1-3 alkyl;

R ¹ is hydrogen or C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl and heterocyclyl A group selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl (Optionally substituted by one or more R ¹⁷ ), aryl (optionally substituted by one or more R ¹⁷ ), heteroaryl (optionally substituted by one or more R ¹⁷ ), heterocycle Reel, C _1-4 alkoxycarbonyl, -OR ⁵ , -SR ² , -SOR ² , -SO ₂ R ² , -COR ² , -CO ₂ R ⁵ , -CONR ⁵ R ⁶ , -NR ¹⁶ COR ⁵ , Optionally substituted by one or more substituents independently selected from -SO ₂ NR ⁵ R ⁶ and -NR ¹⁶ SO ₂ R ² ,

Wherein R ¹⁶ is hydrogen or C _1-3 alkyl,

R ¹⁷ is selected from halo, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkoxy,

R ² is a group selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC _1-4 alkyl and heteroarylC _1-4 alkyl Wherein the group may be optionally substituted by one or more halo,

R ⁵ is hydrogen or C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC _1-4 alkyl and heteroarylC _1-4 A group selected from alkyl, said group may be optionally substituted by one or more halo,

R ⁶ is hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or

R ⁵ and R ⁶ together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring;

R ⁸ is hydrogen or a group selected from C _1-6 alkyl, C _3-7 cycloalkyl and heterocyclyl, said group being halo, nitro, cyano, trifluoromethyl, trifluoromethoxy and C _1- Optionally substituted by one or more substituents selected from ₄ alkyl; or

R ¹ and R ⁸ together form a carbocyclic or saturated heterocyclic 3- to 6-membered ring;

R ³ and R ⁴ are independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocyclyl, aryl or heteroaryl;

n is 0 or 1;

m is 0 or 1;

D is hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or fluoro;

X is-(CR ⁹ R ¹⁰ ) -Q- (CR ¹¹ R ¹² ) _u- ,

Where u is 0 or 1,

Q is O, S, SO or SO ₂ ,

R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl and C _3-6 cycloalkyl;

B is C _2-4 alkenyl or C _2-4 alkynyl, each of which is optionally C _1-4 alkyl, C _3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl (one or more halo, Nitro, cyano, trifluoromethyl, trifluoromethoxy, -CONHR ¹³ , -CONHR ¹³ R ¹⁴ , -SO ₂ R ¹³ , -SO ₂ NHR ¹³ , -SO ₂ NR ¹³ R ¹⁴ , -NHSO ₂ R ¹³ , May be optionally substituted by C _1-4 alkyl and C _1-4 alkoxy), and

Wherein R ¹³ and R ¹⁴ are independently hydrogen, C _1-4 alkyl or C _3-5 cycloalkyl, or

R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring.

Another aspect of the invention relates to a compound of formula (1) as defined above or a pharmaceutically acceptable salt thereof.

In the case of certain compounds of formula (1) as defined above, they may exist in optically active or racemic forms by one or more asymmetric carbon or sulfur atoms, and the present invention is in its definition metalloproteinase inhibitory activity, And in particular any of the above optically active forms or racemic forms having TACE inhibitory activity. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by cleavage of racemic forms. Likewise, the above mentioned activities can be assessed using standard experimental techniques mentioned below.

Thus, the compounds of formula (1) are provided as enantiomers, diastereomers, geometric isomers and atropisomers.

In the present invention, it is to be understood that the compound of formula (1) or a salt thereof may exhibit a tautomerism phenomenon, and the chemical formulas herein may represent only one possible tautomeric form. It is to be understood that the present invention includes any tautomeric form having metalloproteinase inhibitory activity, and in particular TACE inhibitory activity, and is not limited to any one tautomeric form used in the formula. The chemical formulas herein may represent only one possible tautomeric form, and it is to be understood that the present specification includes all possible tautomeric forms, not just the compounds of this type that may be represented schematically herein.

It is also to be understood that certain compounds of formula (1) and salts thereof may exist in solvated as well as unsolvated forms, for example hydrated forms. It is to be understood that the present invention encompasses all such solvated forms having metalloproteinase inhibitory activity, and in particular TACE inhibitory activity.

It is also to be understood that certain compounds of formula (1) may exhibit polymorphisms and that the present invention encompasses all of the above forms having metalloproteinase inhibitory activity and in particular TACE inhibitory activity.

The present invention relates to the compounds of formula (1) as well as to their salts as defined above. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the preparation of compounds of Formula (1) and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the invention include, for example, acid addition salts of compounds of formula (1) as defined above which are sufficiently basic to form said salts. Such acid addition salts include, but are not limited to, hydrochloride, hydrobromide, citrate and maleate salts, and salts formed by reaction with phosphoric acid and sulfuric acid. In addition, when the compound of formula (1) is sufficiently acidic, the salt is a base salt, for example an alkali metal salt (eg sodium salt or potassium salt), an alkaline earth metal salt (eg calcium salt or magnesium) Salts), or organic amine salts (eg, triethylamine or tris- (2-hydroxyethyl) amine).

Compounds of formula (1) may also be provided as hydrolyzable esters in vivo. In vivo hydrolyzable esters of compounds of formula (1) containing carboxyl or hydroxy groups are, for example, pharmaceutically acceptable esters that decompose in the human body or in the animal to produce the underlying acid or alcohol. The ester can be identified, for example, by intravenously administering the compound under test to a test animal and subsequently examining the body fluids of the test animal.

Pharmaceutically acceptable esters suitable for carboxy are C _1-6 alkoxymethyl esters such as methoxymethyl, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl ester, C _{3 -8} cycloalkoxycarbonyloxyC _1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolene-2-onylmethyl esters such as 5-methyl-1,3-dioxolene-2-onylmethyl; And C _1-6 alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group of the compounds of the present invention.

Pharmaceutically acceptable esters suitable for hydroxy are decomposed as a result of hydrolysis of inorganic esters such as phosphate esters (including phosphoramide acid cyclic esters) and α-acyloxyalkyl ethers, and esters in vivo And related compounds that provide hydroxy group (s). Examples of α-acyloxyalkyl ethers are acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Groups that form in vivo hydrolyzable esters for hydroxy include C _1-10 alkanoyls such as formyl, acetyl; Benzoyl; Phenylacetyl; Substituted benzoyl and phenylacetyl, C _1-10 alkoxycarbonyl (to provide alkyl carbonate esters), for example ethoxycarbonyl; Di- (C _1-4 ) alkylcarbamoyl and N- (di- (C _1-4 ) alkylaminoethyl) -N- (C _1-4 ) alkylcarbamoyl (to provide carbamate) ; Di- (C _1-4 ) alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, (C _1-4 ) alkylaminomethyl and di-((C _1-4 ) alkyl) aminomethyl, and 3 of the benzoyl ring from a ring nitrogen atom via a methylene linker. Or morpholino or piperazino bound to the 4-position. Other interesting in vivo hydrolyzable esters include, for example, R ^A C (O) O (C _1-6 ) alkyl-CO-, wherein R ^A is, for example, benzyloxy- (C _1-4 ) Alkyl, or phenyl). Suitable substituents on the phenyl group in the esters are, for example, 4- (C _1-4 ) piperazino- (C _1-4 ) alkyl, piperazino- (C _1-4 ) alkyl and morpholino- (C _1-4 ) alkyl.

As used herein, the general term "alkyl" includes both straight and branched chain alkyl groups. However, references to unique alkyl groups such as "propyl" are limited to straight chains only, and references to unique branched alkyl groups such as tert-butyl are limited to branched chains. For example, "C _1-3 alkyl" includes methyl, ethyl, propyl and isopropyl, and examples of "C _1-4 alkyl" include examples of "C _1-3 alkyl", butyl and tert-butyl And examples of “C _1-6 alkyl” include examples of “C _1-4 alkyl”, and further pentyl, 2,3-dimethylpropyl, 3-methylbutyl and hexyl. Examples of "C _1-20 alkyl" include examples of "C _1-6 alkyl", and other straight and branched chain alkyl groups. Similar provisions apply to other general terms, for example "C _2-4 alkenyl" includes vinyl, allyl and 1-propenyl, and examples of "C _2-6 alkenyl" are "C _2-4 Alkenyl ", and additionally 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pen Tenyl and 4-hexenyl. Examples of “C _2-4 alkynyl” include ethynyl, 1-propynyl and 2-propynyl, and examples of “C _2-6 alkynyl” are examples and additions of “C _2-4 alkynyl” To 3-butynyl, 2-pentynyl and 1-methylpent-2-ynyl.

The term "C _3-6 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C _3-7 cycloalkyl" includes "C _3-6 cycloalkyl", and further cycloheptyl. The term "C _3-10 cycloalkyl" includes "C _3-7 cycloalkyl" and further cyclooctyl, cyclononyl and cyclodecyl.

"Heterocycloalkyl" is a monocyclic saturated 3- to 10-membered ring containing one or two heteroatoms selected from nitrogen, sulfur and oxygen, wherein the ring nitrogen or sulfur is N-oxide or S-jade Is oxidizable to seed (s).

"C _5-7 cycloalkenyl" is a monocyclic 5- to 7-membered ring containing 1 to 3 double bonds. Examples are cyclopentenyl and cyclohexenyl.

The term "halo" means fluoro, chloro, bromo and iodo.

Examples of "C _1-4 alkoxy" include methoxy, ethoxy, propoxy and isopropoxy. Examples of "C _1-6 alkoxy" include examples of "C _1-4 alkoxy" and further pentyloxy, 1-ethylpropoxy and hexyloxy. Examples of "C _1-4 alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl.

Examples of "aryl" are phenyl and naphthyl.

Examples of " _{arylC 1-4} alkyl" are benzyl, phenylethyl, naphthylmethyl and naphthylethyl.

"Heteroaryl" is a monocyclic or bicyclic aryl ring in which 1 to 4 ring atoms contain 5 to 10 ring atoms selected from nitrogen, sulfur or oxygen, wherein the ring nitrogen can be oxidized. Examples of heteroaryl are pyridyl, imidazolyl, quinolinyl, cynolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl and pyrazinyl. Preferably, heteroaryl is pyridyl, imidazolyl, quinolinyl, pyrimidinyl, thienyl, pyrazolyl, thiazolyl, oxazolyl and isoxazolyl.

Examples of "heteroarylC _1-4 alkyl" are pyridylmethyl, pyridylethyl, pyrimidinylethyl, pyrimidinylpropyl, quinolinylpropyl and oxazolylmethyl.

"Heterocyclyl" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 4 to 12 atoms, of which 1 to 4 ring atoms are carbon or nitrogen unless otherwise specified. May be linked via wherein a —CH ₂ — group may be optionally substituted by —C (O) —; Ring nitrogen or sulfur atoms may be optionally oxidized to form N-oxide or S-oxide (s); —NH in the ring may be optionally substituted by acetyl, formyl, methyl or mesyl. Examples and suitable meanings of the term “heterocyclyl” include piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl, homopiperazinyl, pipe Ferrazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,2 -Dimethyl-1,3-dioxolanyl and 3,4-dimethylenedioxybenzyl. Preferred meanings are 3,4-dihydro-2H-pyran-5-yl, tetrahydrofuran-2-yl, 2,2-dimethyl-1,3-dioxolan-2-yl and 3,4-dimethylenedi Oxybenzyl.

Heterocyclic rings are rings containing 1-3 ring atoms selected from nitrogen, oxygen and sulfur. "Heterocyclic 5- to 7-membered" rings are pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl, thiopyranyl and morpholinyl. "Heterocyclic 4- to 7-membered" rings include examples of "heterocyclic 5- to 7-membered" and further azetidinyl.

"Saturated heterocyclic 3- to 6-membered" rings include oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, pyrrolidinyl, tetrahydrofuranyl, Tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl and piperidinyl, and the ring nitrogen may be substituted by groups selected from formyl, acetyl and mesyl.

A "carbocyclic 3- to 6-membered" ring is a saturated, partially saturated or unsaturated ring containing 3 to 6 ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-3-enyl, cyclohexyl and cyclopent-2-enyl.

Where any substituent is selected from "one or more" groups or substituents, it is to be understood that the above definition includes all substituents selected from one specified group or substituents selected from two or more specified groups. Preferably "one or more" means "one to three", especially when the group or substituent is halo. "One or more" may also mean "one or two".

Compounds of the invention were named with the aid of computer software (ACD / name version 5.09).

Preferred meanings of Z, R ¹ , R ³ , R ⁴ , R ⁸ , n, m, D, X and B are as follows. This meaning can be used as appropriate in any definition, claim or embodiment defined above and below herein.

In one aspect of the invention there is provided a compound of formula (1), wherein Z is -CONR ¹⁵ OH. In another aspect, Z is -N (OH) CHO.

In one aspect of the invention, R ¹⁵ is hydrogen, methyl, ethyl or isopropyl. In another aspect, R ¹⁵ is hydrogen.

In one aspect of the invention, R ¹ is hydrogen or C _1-6 alkyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl and heterocyclyl A group selected from: halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl (optionally substituted by R ¹⁷ ), Aryl (optionally substituted by R ¹⁷ ), heteroaryl (optionally substituted by R ¹⁷ ), C _1-4 alkoxycarbonyl, -OR ⁵ , -SR ² , -SOR One independently selected from ² , -SO ₂ R ² , -COR ² , -CO ₂ R ⁵ , -CONR ⁵ R ⁶ , -NR ¹⁶ COR ⁵ , -SO ₂ NR ⁵ R ⁶ and -NR ¹⁶ SO ₂ R ² It may be optionally substituted by the above substituents. In other aspects, R ¹ is hydrogen, C _1-6 alkyl or aryl, and C _1-6 alkyl or aryl is C _1-4 alkyl, aryl (which may be optionally substituted by R ¹⁷ ) and heteroaryl (R ¹⁷ Optionally substituted by one or more substituents independently selected from. In a further aspect, R ¹ is aryl, C _1-6 alkyl, or C _1-6 alkyl substituted by aryl or heteroaryl. In other aspects, R ¹ is methyl, ethyl, propyl, isobutyl or phenyl, each of which may be optionally substituted by phenyl or pyrimidinyl. In yet other aspects, R ¹ is methyl, isobutyl, phenyl, 2-phenylethyl or 3-pyrimidin-2-ylpropyl. In a further aspect, R ¹ is methyl, phenyl, phenylethyl or pyrimidin-2-ylpropyl.

In one aspect of the invention, R ¹⁶ is hydrogen, methyl or ethyl. In other aspects, R ¹⁶ is methyl or ethyl. In another aspect, R ¹⁶ is hydrogen.

In one aspect of the invention, R ¹⁷ is halo or C _1-4 alkyl. In other aspects, R ¹⁷ is fluoro, chloro, bromo or methyl. In other aspects, R ¹⁷ is fluoro or methyl.

In one aspect of the invention, R ² is a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, which group may be optionally substituted by halo. In another aspect, R ² is a group selected from methyl, phenyl and benzyl, which group may be optionally substituted by chloro. In one aspect of the invention, R ² is methyl.

In one aspect of the invention, R ⁵ is hydrogen or a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, which group may be optionally substituted by halo. In another aspect, R ⁵ is hydrogen or a group selected from methyl, phenyl and benzyl, which group may be optionally substituted by chloro.

In one aspect of the invention, R ⁸ is hydrogen, methyl, ethyl, propyl or isopropyl. In another aspect, R ⁸ is hydrogen.

In one aspect of the invention, R ³ is hydrogen.

In one aspect of the invention, R ⁴ is hydrogen.

In one aspect of the invention n is zero. In another aspect n is 1.

In one aspect of the invention, m is zero. In another aspect, m is 1.

In one aspect of the invention, D is hydrogen, methyl or fluoro. In another aspect, D is hydrogen.

In one aspect of the invention, X is -CR ⁹ R ¹⁰ -Q- or -CR ⁹ R ¹⁰ -Q-CR ¹¹ R ^12- . In another aspect of the invention, X is - (CH ₂₎ -Q-, or _{- (CH 2) -Q- (CH} 2) - a. In a further aspect, X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - a.

In one aspect of the invention u is 1. In another aspect, u is zero.

In one aspect of the invention, Q is O.

In one aspect of the invention, R ⁹ is hydrogen.

In one aspect of the invention, R ¹⁰ is hydrogen.

In one aspect of the invention, R ¹¹ is hydrogen.

In one aspect of the invention, R ¹² is hydrogen.

In one aspect of the invention, B is C _2-4 alkenyl or C _2-4 alkynyl, each of which is optionally selected from C _1-4 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl, heterocycloalkyl It may be substituted independently. In another aspect, B is C _2-4 alkenyl or C _2-4 alkynyl, which may each be independently substituted by C _1-4 alkyl, C _3-6 cycloalkyl or heterocycloalkyl. In a further aspect, B is C _2-4 alkenyl or C _2-4 alkynyl, each of which may be optionally substituted independently by C _1-4 alkyl or aryl. In yet other aspects, B is vinyl or ethynyl, which can each be independently substituted by methyl, ethyl or phenyl. In another aspect, B is vinyl, ethynyl, prop-1-enyl, prop-1-ynyl, but-1-ynyl or 2-phenylvinyl. In a further aspect, B is vinyl, ethynyl, prop-1-enyl, prop-1-ynyl or but-1-ynyl.

Z is -N (OH) CHO;

R ¹ is hydrogen or a group selected from C _1-6 alkyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl and heterocyclyl, wherein Halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl (optionally substituted by R ¹⁷ ), aryl ( Optionally substituted by R ¹⁷ ), heteroaryl (optionally substituted by R ¹⁷ ), C _1-4 alkoxycarbonyl, -OR ⁵ , -SR ² , -SOR ² , -SO ₂ R ² , -COR ² , -CO ₂ R ⁵ , -CONR ⁵ R ⁶ , -NR ¹⁶ COR ⁵ , -SO ₂ NR ⁵ R ⁶ and -NR ¹⁶ SO ₂ R ² may be optionally substituted by one or more substituents independently selected from Can,

Wherein R ¹⁶ is hydrogen, methyl or phenyl,

R ¹⁷ is halo or C _1-4 alkyl,

R ² is a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, which group may be optionally substituted by halo,

R ⁵ is hydrogen or a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, said group may be optionally substituted by halo;

R ⁸ is hydrogen, methyl, ethyl, propyl or isopropyl;

R ³ is hydrogen, methyl, ethyl or phenyl;

R ⁴ is hydrogen, methyl, ethyl or phenyl;

n is 0;

m is 1;

D is hydrogen, methyl or fluoro;

X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - is;

B is C _2-4 alkenyl or C _2-4 alkynyl, each of which may be optionally substituted by C _1-4 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or heterocycloalkyl

Groups of compounds of formula (1) are preferred.

Also,

Z is -N (OH) CHO;

R ¹ is hydrogen or C _1-6 alkyl or aryl, C _1-6 alkyl or aryl is C _1-4 alkyl, aryl (which may be optionally substituted by R ¹⁷ ) and heteroaryl (optionally by R ¹⁷ ) May be optionally substituted by one or more substituents independently selected from

Wherein R ¹⁷ is halo or C _1-4 alkyl;

R ⁸ is hydrogen;

R ³ is hydrogen;

R ⁴ is hydrogen;

n is 0;

m is 1;

D is hydrogen, methyl or fluoro;

X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - is;

B is C _2-4 alkenyl or C _2-4 alkynyl, each of which may be optionally substituted independently by C _1-4 alkyl or aryl

Groups of compounds of formula (1) are preferred.

Also,

Z is -CONR ¹⁵ OH;

R ¹ is hydrogen or a group selected from C _1-6 alkyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl and heterocyclyl, wherein Halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl (optionally substituted by R ¹⁷ ), aryl ( Optionally substituted by R ¹⁷ ), heteroaryl (optionally substituted by R ¹⁷ ), C _1-4 alkoxycarbonyl, -OR ⁵ , -SR ² , -SOR ² , -SO ₂ R ² , -COR ² , -CO ₂ R ⁵ , -CONR ⁵ R ⁶ , -NR ¹⁶ COR ⁵ , -SO ₂ NR ⁵ R ⁶ and -NR ¹⁶ SO ₂ R ² may be optionally substituted by one or more substituents independently selected from Can,

Wherein R ¹⁵ is hydrogen, methyl, ethyl or isopropyl,

R ¹⁶ is hydrogen, methyl or phenyl,

R ¹⁷ is halo or C _1-4 alkyl,

R ² is a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, which group may be optionally substituted by halo,

R ⁵ is hydrogen or a group selected from C _1-6 alkyl, aryl and arylC _1-4 alkyl, said group may be optionally substituted by halo;

R ⁸ is hydrogen, methyl, ethyl, propyl or isopropyl;

R ³ is hydrogen, methyl, ethyl or phenyl;

R ⁴ is hydrogen, methyl, ethyl or phenyl;

n is 0;

m is 1;

D is hydrogen, methyl or fluoro;

X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - is;

B is C _2-4 alkenyl or C _2-4 alkynyl, each of which may be optionally substituted independently by C _1-4 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or heterocycloalkyl sign

Groups of compounds of formula (1) are preferred.

Also,

Z is -CONR ¹⁵ OH;

R ¹ is hydrogen or C _1-6 alkyl or aryl, C _1-6 alkyl or aryl is C _1-4 alkyl, aryl (which may be optionally substituted by R ¹⁷ ) and heteroaryl (by R ¹⁷ Optionally substituted by one or more substituents independently selected from

Wherein R ₁₇ is halo or C _1-4 alkyl,

R ¹⁵ is hydrogen, methyl, ethyl or isopropyl;

R ⁸ is hydrogen;

R ³ is hydrogen;

R ⁴ is hydrogen;

n is 0;

m is 1;

D is hydrogen, methyl or fluoro;

X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - is;

B is C _2-4 alkenyl or C _2-4 alkynyl, each of which may be optionally substituted independently by C _1-4 alkyl or aryl

Groups of compounds of formula (1) are preferred.

Also,

Z is -CONR ¹⁵ OH or -N (OH) CHO,

Wherein R ¹⁵ is hydrogen;

R ¹ is methyl, ethyl, propyl, isobutyl or phenyl, each of which may be optionally substituted by phenyl or pyrimidinyl;

R ⁸ is hydrogen;

R ³ is hydrogen;

R ⁴ is hydrogen;

n is 0;

m is 1;

D is hydrogen;

X is - (CH ₂₎ -O- or _{- (CH 2) -O- (CH} 2) - is;

B is vinyl or ethynyl, each of which may be optionally substituted independently by methyl, ethyl or phenyl

Groups of compounds of formula (1) are preferred.

In another aspect of the invention, preferred compounds of the invention are compounds of any one of the following compounds:

(1-phenyl-2-{[4- (prop-2-ynyloxy) piperidin-1-yl] sulfonyl} ethyl) hydroxyformamide;

2-{[4- (allyloxy) piperidin-1-yl] sulfonyl} -1-phenylethyl (hydroxy) formamide;

2-({4- [but-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide;

2-{[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} -1-phenylethyl (hydroxy) formamide;

(2-{[4- (pent-2-ynyloxy) piperidin-1-yl] sulfonyl} -1-phenylethyl) hydroxyformamide;

1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -3-phenylpropyl (hydroxy) formamide;

2-{[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} -1-methylethyl (hydroxy) formamide;

1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl (hydroxy) formamide;

1-[({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl (hydroxy) formamide; And

2-({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) -1-methylethyl (hydroxy) formamide.

More preferred compounds of the invention are compounds of any one of the following compounds:

(R / S) -1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl (hydroxy) formamide ;

(R / S) -1-[({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) methyl] -4-pyrimidin-2-ylbutyl (hydroxy ) Formamide;

(R / S) -2-({4-[(but-2-ynyloxy) methyl] piperidin-1-yl} sulfonyl) -1-methylethyl (hydroxy) formamide;

2- (4-but-2-ynyloxymethylpiperidin-1-ylsulfonylmethyl) -4-methyl-pentanoic acid hydroxyamide;

(R / S) -2-({4- [prop-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide;

(R / S) -2-({4- [but-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide; And

(R / S) -2-({4- [3-phenyl-prop-2-enyloxy] piperidin-1-yl} sulfonyl) -1-phenylethyl (hydroxy) formamide.

In another aspect, the invention

a) converting the hydroxylamine of formula (2) to a compound of formula (1) as in Scheme 1 below; And later as needed,

i) converting the compound of formula (1) to another compound of formula (1);

ii) removing any protecting groups;

iii) forming a pharmaceutically acceptable salt or in vivo hydrolyzable ester

Provided is a process for preparing a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein Z is -N (OH) CHO.

A preformed mixture of acetic acid (8 equiv) and formic acid (excess) is added to the compound of formula (2) in tetrahydrofuran or dichloromethane, and the solution is Formylation may suitably be carried out by stirring for 15 hours in the temperature range of from C to room temperature, followed by stirring in methanol. Alternatively, trifluoroethylformate can be used as described in J. Chem. Med. Chem., 2002, 45, 219] can be used.

The method is

b) converting an alkene of formula (3) to a hydroxylamine of formula (2 '),

It may further comprise a process for the preparation of hydroxylamine of formula (2) represented by the compound of formula (2 '), wherein n is 0 and R ⁴ is hydrogen.

Suitable reagents for this conversion reaction are aqueous hydroxylamine in tetrahydrofuran under argon atmosphere.

The alkene of formula (3) wherein R ⁸ is hydrogen can be prepared by reacting a compound of formula (4 ') with a compound of formula (5) under Wadsworth-Emmons or Petererson reaction conditions. have.

The Wadsworth-Emons or Petersen reaction is -78 ℃ to 0 An anion of formula (4 ') is formed with 2 equivalents of lithium bis (trimethylsilyl) amide, sodium hydride or lithium diisopropylamide in tetrahydrofuran at a temperature of 1 ° C., which is equivalent to 1 equivalent of diethylchlorophosphate (Wazworth) Emons) or 1 equivalent of trimethylsilyl chloride (Peterson). After 1 hour aldehyde in tetrahydrofuran (1.1 equiv) was added to the resulting anions described above and reacted at room temperature over 15 hours.

Alkenes of formula (3) wherein R ⁸ is hydrogen may be prepared by reacting a compound of formula (4 ') with a compound of formula (6), as illustrated by Scheme 4 below;

Suitable bases include -78 to form anions ℃ to 0 Lithium bis (trimethylsilyl) amide, sodium hydride or lithium diisopropylamide in tetrahydrofuran at a temperature of &lt; RTI ID = 0.0 &gt; Suitable reducing agents for the reducing step are sodium borohydride in ethanol at room temperature, or borane-dimethylsulfide complex or borane-tetrahydrofuran complex in tetrahydrofuran. Suitable dehydrating agents for the dehydration step are methanesulfonyl chloride or tosyl chloride and triethylamine in dichloromethane at room temperature.

The present invention provides a process for preparing a compound of formula (6), wherein R ¹ is C _1-6 alkyl substituted with aryl or heteroaryl, wherein the aryl group and heteroaryl group may be optionally substituted by one or more R ¹⁷ . To provide. The procedure is outlined in the following scheme:

Wherein C is aryl or heteroaryl, each of which may be optionally substituted by one or more R ¹⁷ ; L is a suitable leaving group such as halo, tosyl, mesyl or triflate; Y is a group on which a zinc metal salt is formed, ie bromo or iodo; z is an integer from 1 to 6 such that () z represents C _1-6 alkylene. In this aspect of the invention, R ¹ is And thus the C _1-6 alkyl group represented by () z may be straight or branched. In another aspect of the invention, () z may represent C _1-20 alkyl. The reaction is carried out in an aprotic solvent such as tetrahydrofuran under an inert atmosphere (which ensures constant catalytic activity). Suitable catalysts include nickel based and palladium (0) based catalysts. Preferably, a catalyst based on palladium (0) is used. Catalysts based on palladium (0) can be produced from compounds based on palladium (II) when used with a promoter such as triphenylphosphine.

Specific examples of the compound of formula (6) include ethyl 4- (pyrimidin-2-yl) butanoate. This compound contains 2-bromopyrimidine 4-ethoxy-4-oxo-butyl under an inert atmosphere in an aprotic solvent in the presence of bis (acetonitrile) palladium (II) chloride (2.5 mmol) and triphenylphosphine. It is formed by reacting with zinc bromide. The stoichiometric amount of zinc salt produced as a by-product can be removed by washing the reaction mixture with an aqueous solution of ethylenediamine tetraacetic acid tetrasodium salt. Preferably, the aprotic solvent is tetrahydrofuran. Preferably, the inert atmosphere is a nitrogen atmosphere.

Alternatively, the method for preparing a hydroxylamine compound of formula (2) wherein n is 0 (denoted by the compound of formula (2 ^# )) is

c) i) reacting a compound of formula (4 ") (see Scheme 13 for its preparation) with R ¹ COOR, R ¹ COCl or activated R ¹ COOR, wherein R is a ketone of formula (7") _Obtaining C _1-20 alkyl, such as methyl, ethyl or arylC _1-4 alkyl, such as benzyl);

ii) reducing the ketone of formula (7 ") to obtain an alcohol of formula (8");

iii) converting the —OH group of the alcohol of formula (8 ″) to leaving groups (L) such as halides, mesylates, tosylate and the like (see compounds of formula (9 ″));

iv) replacing the leaving group with aqueous hydroxylamine to obtain a hydroxylamine of formula (2 ^# )

It may include.

Ketones of formula (7 ″) may be further prepared by the method shown in Scheme 6 below.

Tetrabutyl ammonium fluoride can remove the silyl groups present in the compound of formula (30). Suitable leaving groups (L) are halo, mesyl and tosyl. Suitable chlorinating agent is POCl ₃ . By reacting a compound of formula (33) with a suitable piperidine reagent, a compound of formula (7 '') is prepared in the final step.

Alternatively, the method for producing a hydroxylamine of the formula (2), represented by the compound of formula (2 ^** ), wherein n is 1 and both R ³ and R ⁴ are hydrogen,

d) i) reacting a compound of formula (4 ") with a compound of formula (10) (epoxide or equivalent) to obtain an alcohol of formula (8 ^** );

ii) converting the —OH group of the alcohol of formula (8 ^** ) to leaving groups such as halides, mesylates, tosylate and the like (see compounds of formula (9 ^** ));

iii) replacing the leaving group with aqueous hydroxylamine to obtain a hydroxylamine of formula (2 ^** )

It may further include.

Suitable base is -78 ℃ to 0 Lithium bis (trimethylsilyl) amide and lithium diisopropylamide at a temperature of &lt; RTI ID = 0.0 &gt; Suitable leaving groups (L) are chloro, bromo, iodo, methanesulfonyl and tosyl, which are methanesulfonyl chloride and pyridine (mesylate) in dichloromethane, tosyl chloride and pyridine (tosylate) in dichloromethane, tri Will be formed from alcohols by treatment with phenylphosphine and carbon tetrabromide (bromo); Chloro, bromo and iodo derivatives may also be prepared from mesylate or tosylate by addition of suitable halide sources such as tetrabutylammonium iodide or sodium iodide or lithium chloride in a solvent such as acetone.

In addition, a method for producing a hydroxylamine of the general formula (2) represented by the compound of formula (2 ^) wherein n is 1 and R ⁸ is hydrogen,

e) i) reacting the compound of formula (4 ") with a compound of formula (11) to obtain an ester of formula (12 ^);

ii) converting the ester of formula (12 ^) to an alcohol of formula (13 ^);

iii) substituting the -OH group with aqueous hydroxylamine to obtain a hydroxylamine of formula (2 ^)

It may further include.

The —COOR group of formula (12 ^) may be a C _1-20 alkyl such as methyl, ethyl or arylC _1-4 alkyl such as benzyl and B is a protecting group such as trimethylsilyl or tert butyl dimethylsilyl Ester. Bayer-Villiger reaction conditions, such as peracids in dichloromethane, such as m-CPBA (methane-chloroperbenzoic acid), are suitable for converting ester groups to alcohol groups. After the Bayer-Billiger reaction, the protecting group wherein B is of formula (12 ^) will have to be removed and replaced with the B group as defined for formula (1) described herein. It may be appropriate to convert the alcohol group to leaving groups such as bromo, iodo, mesyl and tosyl and then to aqueous hydroxylamine.

In another aspect, the invention

a) converting an acid of formula (14) to a compound of formula (1) as in Scheme 9 below; And later as needed,

i) converting the compound of formula (1) to another compound of formula (1);

ii) removing any protecting groups;

iii) forming a pharmaceutically acceptable salt or in vivo hydrolyzable ester

Provided is a process for preparing a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein Z is -CONR ¹⁵ OH.

The acid of formula (14) may be suitably activated by converting it to an acid halide (such as an acid chloride) or to an activated ester using a carbonyldiimidazole, carbodiimide or pentafluorophenyl ester. have. Alternatively, when the acid of formula (14) is an ester such as methyl or ethyl ester, it can be converted directly to the compound of formula (1) by reaction with NHR ¹⁵ OH.

In addition, the present invention

b) reacting a compound of formula (4 ") with an alkene of formula (11) to give an ester of formula (12 ^), wherein the acid of formula (14 '), wherein the acid of formula (14') Hydrolysis to acid of formula (14)

It provides a method of producing an acid of the formula (14), including.

Suitable bases which can deprotonate the compound of formula (4 ") are subsequently used in solvents such as dimethylsulfide, ether, copper salts in tetrahydrofuran, such as copper bromide-dimethylsulfide complex, copper iodide. Butyllithium, lithium diisopropylamide, and lithium bis (trimethylsilyl) amide, which are added at a temperature of from C to room temperature.

Alternatively, the process for preparing the acid of formula (14)

c) formula (4 ") of the compound to react with a compound of formula (15) of an acid (wherein the formula (14 ^** of the formula (14 ^**)) and the acid is n is 0, and R ³ is hydrogen, R Obtaining an acid of formula (14) wherein ⁴ is hydrogen.

Suitable bases for deprotonating the compound of formula (4 ") include -78 ℃ to 0 Lithium bis (trimethylsilyl) amide, lithium diisopropylamide and sodium hydride in solvents such as tetrahydrofuran and ether at temperatures of &lt; RTI ID = 0.0 &gt;

In another aspect, the invention provides a compound of formula (1) wherein Z is -CONR ¹⁵ OH, R ⁸ is hydrogen, and n is 0, comprising the steps outlined in Scheme 12, or a pharmaceutically acceptable Methods of preparing salts or in vivo hydrolysable esters are provided.

The scheme of Scheme 12 is

a) thiol of formula (22) is substituted with acrylate of formula (23) ℃ 70 Reacting at a temperature of &lt; 0 &gt; C to give thioethers of formula (24);

b) 0 Oxidizing the thioether of formula (24) to sulfonyl chloride of formula (25) by bubbling chlorine gas onto a solution of thioether in acetic acid at a temperature from &lt; RTI ID = 0.0 &gt;

c) sulfonyl chloride of formula (25) is treated with piperidine of formula (26) and standard sulfonamide conditions (eg, 0 ℃ 50 Reaction under triethylamine in dichloromethane at a temperature of &lt; 0 &gt; C to give a compound of formula (27);

d) removing the protecting group to obtain a compound of formula (1).

The protecting group (PG) can be 2,4-dimethoxybenzyl, which can be removed by treatment with a weak acid (see Tetrahedron Letters, 1998, 39 (43), 7865). The scheme of Scheme 12 is

i) converting the compound of formula (1) to another compound of formula (1);

ii) removing any other protecting groups;

iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.

In another aspect, the invention

a) reacting a compound of formula (16) with a compound of formula (17), wherein Q is O or S, in the presence of a base to deprotonate the compound of formula (17) Obtaining;

b) removing the protecting group (PG) from the compound of formula (18) to obtain a compound of formula (19);

c) reacting the compound of formula (19) with a suitable reagent to obtain a compound of formula (4), wherein X is-(CR ⁹ R ¹⁰ ) -Q- (CR ¹¹ R ¹² ) _u ; And

d) if necessary, oxidizing Q, where Q is S

It provides a method of preparing a compound of formula (4), formula (4 ') and formula (4 ") comprising a.

When R ⁴ is hydrogen, a compound of formula (4 ′) is prepared; when R ³ and R ⁴ are both hydrogen, a compound of formula (4 ″) is prepared;

In addition, the compounds of formula (4), formula (4 ') and formula (4 ")

a) reacting a compound of formula (20), wherein Q is O or S, with a compound of formula (21) in the presence of a base to obtain a compound of formula (18);

b) removing the protecting group (PG) from the compound of formula (18) to obtain a compound of formula (19);

c) reacting the compound of formula (19) with a suitable reagent to obtain a compound of formula (4), wherein X is-(CR ⁹ R ¹⁰ ) -Q- (CR ¹¹ R ¹² ) _u ; And

d) if necessary, oxidizing Q, where Q is S

It may also be prepared by a method comprising a.

Compounds of formula (4 ') are prepared when R ⁴ is hydrogen, and compounds of formula (4 ") are prepared when both R ³ and R ⁴ are hydrogen.

In both Schemes 13 and 14, L is a suitable leaving group such as halo (chloro, bromo, iodo), mesyl or tosyl; Suitable bases for deprotonating the compounds of formula (17) and formula (20) include sodium hydride, lithium diisopropylamide, butyllithium and lithium bis (trimethylsilyl) amide; Suitable reaction conditions for a) are -78 under argon. ℃ 70 Temperatures in the range of ° C and aprotic solvents such as tetrahydrofuran; Suitable protecting groups (PG) include Boc (t-butoxycarbonyl) groups, CBz (carbonyloxybenzyl) groups and mesyl or another alkylsulfonyl. When PG is alkylsulfonyl, the reaction of the compounds of the formulas (16) and (17), and (20) and (21) directly prepares the compound of formula (4). The compound of formula (18) can be converted to the compound of formula (19) by treatment with acid (Boc) boron trifluoride diethyl ether in dichloromethane in the presence of dimethylsulfite (CBz). The compound of formula (19) can be converted to the compound of formula (4) by treatment with alkylsulfonyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane.

Compounds of formula (1) can be prepared by directly removing the protecting groups on the zinc bond groups. The protecting group (PG) can be 2,4-dimethoxybenzyl, which can be removed by treatment with a weak acid (see Tetrahedron Letters, 1998, 39 (43), 7865). Properly protected hydroxylamine at the beginning of the synthesis can be used to obtain the required protected hydroxylsamic acid or reverse hydroxylxamate.

As discussed herein, since metalloproteinases, and especially compounds that inhibit TACE, are of great importance, it is evident that any intermediates (and manufacturing processes) associated with the preparation of the compounds of the invention will have commercial value. .

One of the metalloproteinases and TACE inhibitors disclosed herein is (R / S) -1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl)- 4-pyrimidin-2-ylbutyl (hydroxy) formamide is:

This compound

a) reacting 4-hydroxypiperidine with methanesulfonyl chloride in the presence of a base to yield 4-hydroxy-1- (methanesulfonyl) piperidine;

b) A solution of 4-hydroxy-1- (methanesulfonyl) piperidine is added to sodium hydride, followed by addition of 1-bromobut-2-yne to 4- (but-2-ynyloxy)- Obtaining 1-methanesulfonylpiperidine;

c) Lithium bis (trimethylsilyl) amide is added to a solution of 4- (but-2-ynyloxy) -1-methanesulfonylpiperidine followed by ethyl 4- (pyrimidin-2-yl) butanoate To obtain 1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentan-2-one;

d) reducing 1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentan-2-one with a reagent such as sodium borohydride ( Obtaining R / S) -1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentan-2-ol;

e) (R / S) -1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pentane-2 using methanesulfonyl chloride Dehydrating -ol to yield E-1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pent-1-ene;

f) A solution of E-1-{[4- (but-2-ynyloxy) piperidinyl] sulfonyl} -5- (pyrimidin-2-yl) pent-1-ene is reacted with hydroxylamine (R / S)-[1-({[4- (4-but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidin-2-ylbutyl] hydroxyl Obtaining an amine; And

g) A mixture of acetic anhydride and formic acid was added to (R / S)-[1-({[4- (4-but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyridine (R / S) -1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl)-by addition to a solution of midin-2-ylbutyl] hydroxyamine Obtaining 4-pyrimidin-2-ylbutyl (hydroxy) formamide

It may be prepared by a method comprising a.

Thus, a further embodiment of the invention is (R / S) -1-({[4- (but-2-ynyloxy) piperidin-1-yl] sulfonyl} methyl) -4-pyrimidine-2 -Ethyl 4- (pyrimidin-2-yl) butanoate, which is an intermediate used for the synthesis of monobutyl (hydroxy) formamide, is provided (see step c) of the process).

Also provided is a process for the preparation of ethyl 4- (pyrimidin-2-yl) butanoate. This method utilizes a Negishi coupling reaction. The Negisch coupling reaction involves a reaction in which an organozinc reagent is cross-coupled with an aryl halide to form a carbon-carbon bond (Baba S., Negishi E., J. Am. Chem. Soc., 1976 , 98, 6729-6731 and Negishi E., King A., Okukado N., J Org, Chem., 1977, 42, 1821-1823).

The Negisch coupling reaction is advantageous in several ways over other coupling methods using organometallic reagents other than organozinc reagents. First, it couples the sp ³ center directly to the aryl group. Second, organozinc reagents can be readily prepared from the corresponding organohalides, and finally the mild properties of organozinc reagents indicate that sensitive functional groups such as esters, ketones, nitriles and halides can be resistant. For more details on the Negisch coupling reaction and cross coupling reaction catalyzed by other transition metals, see Yamamoto Y., Negishi E., J. Organomet. Chem., 1999, 576, 1-317 and references cited therein, and Tsuji J., Palladium reagents and Catalysts, Wiley, New York (1995) and references cited therein.

The process of the present invention comprises 2-halopyrimidine, 2-tosylpyrimidine, 2-pyrimidinyl triflate or 2-pyrimidinyl mesylate in the presence of a catalyst 4-ethoxy-4-oxo-butylzinc bromide Or reacting with 4-ethoxy-4-oxo-butylzinc iodide.

Wherein X is halo, triflate or mesylate, and Y is bromide or iodide.

The method may further comprise removing zinc salt byproducts by washing the resulting crude product with an aqueous solution of ethylenediamine tetraacetic acid tetrasodium salt. This step removes more than 99.9% of zinc salt by-products.

The reaction is preferably carried out under an inert atmosphere which ensures constant catalytic activity. In addition, the reaction is preferably carried out in an aprotic solvent. Preferably, the aprotic solvent is tetrahydrofuran, diethyl ether or dimethoxyethylglycol dimethyl ether, more preferably the solvent is tetrahydrofuran. Preferably, the inert atmosphere is a nitrogen atmosphere.

Suitable catalysts for use in this process include nickel based and palladium (0) based catalysts. However, it is preferable to use a catalyst based on palladium (0). Preferably, the catalyst based on palladium (0) is produced by the action of a promoter such as triphenylphosphine on the compound based on palladium (II). More preferably, the catalyst is produced from bis (acetonitrile) palladium (II) dichloride and triphenylphosphine.

A further aspect of the present invention relates to the use of a pro catalyst in the Negisch coupling reaction comprising bis (acetonitrile) palladium (II) dichloride and triphenylphosphine.

2-halopyrimidine, 2-tosylpyrimidine, 2-pyrimidinyl triflate and 2-pyrimidinyl mesylate are readily available or can be readily derived by those skilled in the art.

4-ethoxy-4-oxo-butylzinc bromide is readily available and is known, for example, liche metals known to use a method of reducing zinc (II) cyanide to lithium and naphthalene for their reagent preparation. It is available from Rike Metals Inc. (WO 93/15086). Alternatively, 4-ethoxy-4-oxo-butylzinc bromide is prepared from DMPU (1,3-dimethyl-3, using diethylzinc and manganese (II) / copper (I) catalyst system from 4-bromobutyrate. 4,5,6-tetrahydro-2 (1H) -pyrimidinone), see I. Klement, P Knochel, Tetrahedron Lett., 1994, 35, 1177; the text herein Deemed to be incorporated by reference). 4-Ethoxy-4-oxo-butylzinc iodide can also be prepared as above, but can also be prepared using a zinc / copper coupling activation reaction with chlorotrimethylsilane / 1,2-dibromoethane (see [ P. Knochel, MCP Yeh, SC Berk, J. Talbert; J. Org. Chem., 1988, 53, 2392] or by using sonication methods (E. Erdik, Tetrahedron, 1987, 43, 2203). ) Can be prepared.

Some of the various ring substituents present in the compounds of the present invention may be introduced by standard aromatic substitution reactions, or may be produced by conventional functional group modification reactions before or immediately after performing the above-mentioned methods, which It will be understood that it is included in the method aspect. The reaction and the modification reaction include, for example, a substituent introduction reaction by an aromatic substitution reaction, a substituent reduction reaction, a substituent alkylation reaction, and a substituent oxidation reaction. Reagents and reaction conditions used in such procedures are known in the chemical art. Specific examples of the aromatic substitution reaction include nitro group introduction reaction using concentrated nitric acid; Acyl group introduction reaction using acyl halides and Lewis acids (eg, aluminum trichloride) and the like under Friedel Craft conditions; Alkyl group introduction reaction using an alkyl halide and Lewis acid (eg, aluminum trichloride) under Friedel Craft conditions; And halogen group introduction reactions. Specific examples of reforming reactions include the reaction of reducing a nitro group to an amino group, for example by catalytic hydrogenation with a nickel catalyst or by heating with iron in the presence of hydrochloric acid: and oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl There is a reaction.

It will also be appreciated that in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups present in the compound. If a protective reaction is necessary or desirable, and suitable methods of protection are known to those skilled in the art. Conventional protecting groups can be used according to standard practice (see, eg, T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, when the reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups include, for example, acyl groups (eg, alkanoyl groups such as acetyl), alkoxycarbonyl groups (eg, methoxycarbonyl groups, ethoxycarbonyl groups or t-butoxycarbonyl groups), Arylmethoxycarbonyl groups (eg benzyloxycarbonyl), or aroyl groups (eg benzoyl). The deprotection conditions for the protecting group should depend on the protecting group selected. Thus, for example, acyl groups or alkoxycarbonyl groups or aroyl groups such as alkanoyl groups can be removed by hydrolysis with a suitable base such as, for example, alkali metal hydroxides (eg lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as t-butoxycarbonyl groups may be removed by treatment with a suitable acid such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups For example, by hydrogenation on a catalyst such as palladium on carbon or by treatment with Lewis acid (eg, boron tris (trifluoroacetate)). Other protecting groups suitable for primary amino groups are, for example, phthaloyl groups which can be removed by treatment with alkylamines (eg dimethylaminopropylamine) or hydrazine.

Suitable protecting groups for the hydroxy group are, for example, acyl groups (eg alkanoyl groups such as acetyl), aroyl groups (eg benzoyl) or arylmethyl groups (eg benzyl). The deprotection conditions for the protecting group should depend on the protecting group selected. Thus, for example, acyl groups such as alkanoyl groups, or aroyl groups can be removed by hydrolysis with a suitable base such as, for example, alkali metal hydroxides (eg lithium hydroxide or sodium hydroxide). Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation, for example on a catalyst such as palladium on carbon.

Suitable protecting groups for the carboxyl groups include, for example, esterification groups [eg, methyl groups or ethyl groups (which can be removed by hydrolysis with bases such as, for example, sodium hydroxide), tert-butyl groups (for example , An acid (for example, an organic acid such as trifluoroacetic acid), or a benzyl group (which can be removed by hydrogenation on a catalyst such as palladium on carbon).

The protecting group can be removed at any convenient stage of the synthetic reaction using conventional techniques known in the chemical art.

As mentioned above, the compounds defined in the present invention have metalloproteinase inhibitory activity, and in particular TACE inhibitory activity. Such properties can be assessed using, for example, the procedures listed below.

Isolated Enzyme Assay

Matrix metalloproteinases including MMP13

Recombinant human proMMP13 has been described in V. Knauper et al., (1996) The Biochemical Journal 271: 1544-1550 (1996). Purified enzymes can be used to monitor inhibitor activity using the following: Purified proMMP13 is activated using 1 mM amino phenyl mercuric acid (APMA) at 21 ° C. for 20 hours; Activated MMP13 (11.25 ng per assay) was added to 0.1 M Tris-HCl containing assay buffer (0.1 M NaCl, 20 mM CaCl ₂ , 0.02 mM ZnCl and 0.05% (w / v) Brij 35, with or without inhibitor). , 7-methoxycoumarin-4-yl-acetyl.Pro.Leu.Gly.Leu.N-3- (2,4-dinitrophenyl) -L-2,3-diamino Incubate at 35 ° C. for 4-5 hours with propionyl.Ala.Arg.NH ₂ . Activity is determined by measuring fluorescence at λ _excitation 328 nm and λ _emission 393 nm. % Inhibition is calculated as follows:% inhibition = [fluorescence _{inhibitor present} -fluorescence _background ] / [fluorescence _{inhibitor absence} -fluorescence _background ].

See, eg, C. Graham Knight et al., (1992) FEBS Lett. 296 (3): 263-266, similar protocols can be used for other proMMPs expressed and purified using substrate and buffer conditions that are optimal for a particular MMP.

Adamacins, including TNF convertases

The ability of compounds to inhibit proTNFα convertase enzyme (TACE) can be assessed using enzymatic assays that are partially purified and isolated, as described in KM Mohler et al., (1994) Nature 370: 218-. 220, obtained from a membrane of THP-1. The activity of the purified enzyme and its inhibition was determined in substrate in assay buffer (50 mM Tris-HCl, pH 7.4 containing 0.1% (w / v) Triton X-100 and 2 mM CaCl ₂ ) in the presence or absence of the test compound. Phosphorus 4 ', 5'-dimethoxy-fluoresinyl Ser.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser.Arg.Cys (4- (3-succinimide-1 -Yl) -fluorescein) -NH ₂ to determine by incubating the partially purified enzyme at 26 ° C. for 4 hours. The amount of inhibition is determined as in the case of MMP13 except that λ _excitation 485 nm and λ _emission 538 nm are used. Substrates were synthesized as follows. The peptide portion of the substrate is at least four or five times Fmoc-amino acid and O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) as coupling agent. Assembled onto Fmoc-NH-Rink-MBHA-polystyrene resin either manually or on an automated peptide synthesizer by standard methods, including use in fold excess. Ser ¹ and Pro ² were double-coupled. The following side chain protection methods were used: Ser ¹ (But), Gln ⁵ (trityl), Arg ^8,12 (Pmc or Pbf), Ser ^9,10,11 (trityl), Cys ¹³ (trityl). After assembly, the N-terminal Fmoc-protecting group was removed by treatment with Fmoc-peptidyl-resin with DMF. The amino-peptidyl-resin thus obtained is 1.5 to 2 equivalents of 4 ', 5'-dimethoxy-fluorescein-4 (5) -carboxylic acid at 70 ° C. for 1.5 to 2 hours (di- in DMF Acylated by treatment with isopropylcarbodiimide and preactivated with 1-hydroxybenzotriazole (Khanna & Ullman, (1980) Anal Biochem. 108: 156-161). The dimethoxyfluoresinyl-peptide was then treated with trifluoroacetic acid containing 5% water and triethylsilane each to simultaneously perform deprotection and cleavage from the resin. Dimethoxyfluoresceinyl-peptide was isolated via evaporation, softening with diethyl ether and filtration. The isolated peptide was reacted with 4- (N-maleimido) -fluorescein in DMF containing diisopropylethylamine, the product was purified by RP-HPLC and finally isolated by freeze drying from aqueous acetic acid solution. . The product was characterized by MALDI-TOF MS and amino acid analysis.

The compounds of the present invention were shown to be active against TACE at 0.1 nM to 50 μM, in particular 10 μM of compound 1 and compound 3 showing 72% inhibitory activity.

Natural substrate

The activity of the compounds of the invention as aggrecan degradation inhibitors is described, for example, in E.C. Arner et al., (1998) Osteoarthritis and Cartilage 6: 214-228; It can be analyzed using methods based on the disclosure of ((1999) Journal of Biological Chemistry, 274 (10), 6594-6601) and the antibodies described above. The efficacy of compounds acting as inhibitors to collagenase is described in T. Cawston and A. Barrett (1979) Anal. Biochem. 99: 340-345.

Inhibition of metalloproteinase activity in cell / tissue-based activity

Test as an agent that inhibits membrane sheddase, such as TNF convertase

The ability of compounds of the invention to inhibit cellular processing of TNFα production is essentially described in K.M. Mohler et al., (1994) Nature 370: 218-220, can be evaluated by detecting TNF released in THP-1 cells using ELISA. In a similar manner, N. M. Hooper et al., (1997) Biochem. Processing or shedding of other membrane molecules, such as those described in J. 321: 265-279), can be tested using appropriate cell lines and suitable antibodies to detect shed proteins.

Tests as Agents to Inhibit Cell-Based Infiltration

The ability of the compounds of the present invention to inhibit cell migration in invasion assays is described in A. Albini et al., (1987) Cancer Research 47: 3239-3245.

Tests as Agents to Inhibit Whole Blood TNF Shadase Activity

The ability of the compounds of the invention to inhibit TNFα production is assessed by human whole blood assays that stimulate the release of TNFα using LPS. 160 μl of heparinized (10 units / mL) human blood obtained from volunteers were added to the plate and with 20 μl (doubled) of test compound in medium (RPMI1640 + bicarbonate, penicillin, streptomycin, glutamine and 1% DMSO). After 30 min incubation at 37 ° C. in a humidified (5% CO ₂ /95% air) incubator, 20 μl of LPS (E. coli 0111: B4; final concentration 10 μg / mL) is added. Each assay includes a control of pure blood incubated alone or with LPS (6 wells per plate). The plates are then incubated at 37 ° C. (humidity incubator) for 6 hours, centrifuged (2000 rpm for 10 minutes; 4 ° C.), plasma collected (50-100 μl), and 96-well plates at −70 ° C. After storage in TNFα concentrations are analyzed by ELISA.

Test as an agent to inhibit cartilage degradation in vitro

The ability of the compounds of the invention to inhibit degradation of the aggrecan or collagen component of cartilage is essentially described in K.M. Bottomley et al., (1997) Biochem J. 323: 483-488.

In vivo evaluation

Test as anti-TNF formulation

The ability of the compounds of the invention as TNFα inhibitors in vivo is evaluated in rats. In short, routes suitable for the group consisting of female Wistar Alderley Park (AP) rats (90-100 g), such as the oral (po), intraperitoneal (ip) and subcutaneous (sc) routes Compound (5 rats) or drug vehicle (5 rats), followed by lipopolysaccharide (LSP) (30 μg per rat, intravenously) after 1 hour. After 60 minutes of LPS administration, the rat is anesthetized and a peripheral blood sample is taken through the posterior vena cava. Blood is coagulated for 2 hours at room temperature to obtain a serum sample. It is stored at -20 ° C for TNFα ELISA and the compound concentration is analyzed.

For each compound / dose the data analysis is calculated via dedicated software:

Test as an antiarthritis

The activity of the compounds as anti-arthritis agents is described in D.E. Trentham et al., (1977) J. Exp. Med. 146: 857] in collagen-induced arthritis (CIA). In this model, acid soluble native type II collagen causes multiple arthritis in rats when administered in Freund's incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.

Pharmaceutical composition

In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as defined above with respect to a pharmaceutically acceptable diluent or carrier. do.

The composition can be administered orally, e.g. in tablets or capsules, parenteral injection (including intravenous, subcutaneous, intramuscular, endovascular or infusion) as sterile solutions, suspensions or emulsions, topically as ointments or creams, Or in a form suitable for rectal administration with suppositories. The composition may also be in a form suitable for inhalation.

In general, the compositions can be prepared by conventional methods using conventional excipients.

Pharmaceutical compositions of the invention will typically be administered to a human so that the daily dose is between 0.5 and 75 mg / kg body weight (preferably between 0.5 and 30 mg / kg body weight). Such daily dosages may be administered in divided doses as needed and the exact amount and route of administration of the compound administered will depend on the principles known in the art to the weight, age and sex of the patient to be treated, and the particular disease to be treated. Or depends on the state.

Typically, unit dosage forms will contain about 1 mg to 500 mg of a compound of the present invention.

Thus, in a further aspect of the invention, a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, for use in a method of therapeutic treatment of a warm blooded animal such as a human Is provided.

Furthermore, a compound of formula (1) as defined above, or a pharmaceutical composition thereof, for use in a method of treating a disease condition mediated by one or more metalloproteinase enzymes, and in particular a disease condition mediated by TNFα. Acceptable salts or in vivo hydrolyzable esters are provided.

Also defined above for use in methods of treating inflammatory diseases, autoimmune diseases, allergic / atopic diseases, transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury, and malignant cancers in warm-blooded animals such as humans. Compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is provided. In particular, there is provided a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, for use in a method of treating rheumatoid arthritis, Crohn's disease and psoriasis, in particular rheumatoid arthritis do. Provided is a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, for use in a method of treating a breathing disorder, eg asthma or COPD.

In a further aspect of the invention there is provided a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a medicament.

Furthermore, a compound of formula (1) as defined above, or a pharmaceutically acceptable thereof, for use as a medicament for the treatment of disease symptoms mediated by one or more metalloproteinase enzymes, and in particular disease symptoms mediated by TNFα. Salts or in vivo hydrolysable esters are provided.

Also defined above for use as a medicament for the treatment of inflammatory diseases, autoimmune diseases, allergic / atopic diseases, transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury and malignant cancer in warm-blooded animals such as humans. Compounds of formula (1), or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, are provided. In particular a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a medicament for the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, in particular rheumatoid arthritis, is provided. Also provided is a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, for use as a medicament for the treatment of respiratory disorders such as asthma or COPD.

In another aspect of the invention, a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, is applied to at least one metalloproteinase enzyme in a warm blooded animal such as a human Use is provided in the manufacture of a medicament for the treatment of disease symptoms mediated by, and in particular disease symptoms mediated by TNFα.

In addition, inflammatory diseases, autoimmune diseases, allergic / atopic diseases, transplant rejection in warm-blooded animals, such as humans, of the compounds of formula (1), or pharmaceutically acceptable salts thereof or hydrolyzable esters thereof, as defined above A use is provided in the manufacture of a medicament for the treatment of response, graft-versus-host disease, cardiovascular disease, reperfusion injury, and malignant cancer. In particular, the use of a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or hydrolyzable ester thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, in particular rheumatoid arthritis Is provided. Use of a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or hydrolyzable ester thereof, in the manufacture of a medicament for the treatment of respiratory disorders such as asthma or COPD is provided.

In a further aspect of the invention, a metalloproteinase inhibitory effect in an animal comprising administering an effective amount of a compound of formula (1) to a warm blooded animal such as a human being in need of a metalloproteinase inhibitory effect A method of representing is provided.

In a further aspect of the invention there is also provided a method of exhibiting a TACE inhibitory effect in an animal comprising administering an effective amount of a compound of formula (1) to a warm blooded animal such as a human being in need of a TACE inhibitory effect. .

In addition, in a further aspect of the invention, an effective amount of a compound of formula (1) may be used to treat autoimmune diseases, allergic / atopic diseases, transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury, and malignant cancer. There is provided a method of treating the disease in an animal comprising administering to a warm blooded animal such as a human.

In addition, a method of treating said disease in said animal comprising administering an effective amount of a compound of formula (1) to a warm blooded animal, such as a human, in need of treatment of rheumatoid arthritis, Crohn's disease and psoriasis, in particular rheumatoid arthritis Is provided. Also provided is a method of treating said disease in said animal comprising administering an effective amount of a compound of formula (1) to a warm blooded animal, such as a human, in need of treatment of a breathing disorder, eg asthma or COPD.

Compounds of formula (1) and their pharmaceutically acceptable salts, in addition to their use in therapeutic medicine, are part of the process for the discovery of novel therapeutic agents and include cell cycle activity inhibitors in experimental animals such as cats, dogs, rabbits, monkeys, rats, and mice. It is useful as a pharmacological tool in the development and standardization of in vitro and in vivo test systems for evaluating the effects of.

In the other pharmaceutical compositions, processes, methods, uses and pharmaceutical preparation features, other preferred embodiments of the compounds of the invention described herein also apply.

Claims (14)

A compound of formula (1), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. <Formula (1)> (Wherein Z is selected from -CONR ¹⁵ OH and -N (OH) CHO, Wherein R ¹⁵ is hydrogen or C _1-3 alkyl; R ¹ is hydrogen or C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, heteroaryl and heterocyclyl A group selected from halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl (Optionally substituted by one or more R ¹⁷ ), aryl (optionally substituted by one or more R ¹⁷ ), heteroaryl (optionally substituted by one or more R ¹⁷ ), heterocycle Reel, C _1-4 alkoxycarbonyl, -OR ⁵ , -SR ² , -SOR ² , -SO ₂ R ² , -COR ² , -CO ₂ R ⁵ , -CONR ⁵ R ⁶ , -NR ¹⁶ COR ⁵ , Optionally substituted by one or more substituents independently selected from -SO ₂ NR ⁵ R ⁶ and -NR ¹⁶ SO ₂ R ² , Wherein R ¹⁶ is hydrogen or C _1-3 alkyl, R ¹⁷ is selected from halo, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkoxy, R ² is a group selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC _1-4 alkyl and heteroarylC _1-4 alkyl Wherein the group may be optionally substituted by one or more halo, R ⁵ is hydrogen or C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylC _1-4 alkyl and heteroarylC _1-4 A group selected from alkyl, said group may be optionally substituted by one or more halo, R ⁶ is hydrogen, C _1-6 alkyl or C _3-6 cycloalkyl, or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring; R ⁸ is hydrogen or a group selected from C _1-6 alkyl, C _3-7 cycloalkyl and heterocyclyl, said group being halo, nitro, cyano, trifluoromethyl, trifluoromethoxy and C _1- Optionally substituted by one or more substituents selected from ₄ alkyl; or R ¹ and R ⁸ together form a carbocyclic or saturated heterocyclic 3- to 6-membered ring; R ³ and R ⁴ are independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _5-7 cycloalkenyl, heterocyclyl, aryl or heteroaryl; n is 0 or 1; m is 0 or 1; D is hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or fluoro; X is-(CR ⁹ R ¹⁰ ) -Q- (CR ¹¹ R ¹² ) _u- , Where u is 0 or 1, Q is O, S, SO or SO ₂ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are independently selected from hydrogen, C _1-4 alkyl and C _3-6 cycloalkyl; B is C _2-4 alkenyl or C _2-4 alkynyl, each of which is optionally C _1-4 alkyl, C _3-6 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl (one or more halo, Nitro, cyano, trifluoromethyl, trifluoromethoxy, -CONHR ¹³ , -CONHR ¹³ R ¹⁴ , -SO ₂ R ¹³ , -SO ₂ NHR ¹³ , -SO ₂ NR ¹³ R ¹⁴ , -NHSO ₂ R ¹³ , May be optionally substituted by C _1-4 alkyl and C _1-4 alkoxy), and Wherein R ¹³ and R ¹⁴ are independently hydrogen, C _1-4 alkyl or C _3-5 cycloalkyl, or R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a heterocyclic 4- to 7-membered ring). The compound of claim 1, wherein X is — (CH ₂ ) —O— or — (CH ₂ ) —O— (CH ₂ ) —. 3. The compound of claim 1, wherein B is C _2-4 alkenyl or C _2-4 alkynyl, each of which is optionally C _1-4 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or heterocyclo A compound that can be independently substituted by alkyl. 4. The compound of claim 1, wherein R ¹ is hydrogen, C _1-6 alkyl or aryl, wherein C _1-6 alkyl or aryl is optionally substituted by C _1-4 alkyl, aryl (R ¹⁷ . Optionally substituted by one or more substituents independently selected from heteroaryl (which may be optionally substituted by R ¹⁷ ), wherein R ¹⁷ is halo or C _1-4 alkyl Phosphorus compounds. The compound according to any one of claims 1 to 4 for use as a medicament. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of disease symptoms mediated by one or more metalloproteinase enzymes. Use of the compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of disease symptoms mediated by TNFα. Administering an effective amount of a compound according to claim 1 to a warm blooded animal, such as a human, in need of treatment of autoimmune disease, allergic / atopic disease, transplant rejection, graft-versus-host disease, cardiovascular disease, reperfusion injury and malignant cancer Comprising; treating said disease in said animal. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier. If Z is -N (OH) CHO, a) converting the hydroxylamine of formula (2) to the compound of formula (1) ; or If Z is -CONR ¹⁵ OH, b) converting an acid of formula (14) to a compound of formula (1) ; And Afterwards, as needed i) converting the compound of formula (1) into another compound of formula (1); ii) removing any protecting groups; iii) A process for preparing a compound according to claim 1 comprising forming a pharmaceutically acceptable salt or hydrolyzable ester in vivo. Ethyl 4- (pyrimidin-2-yl) butanoate of formula 2-halopyrimidine, 2-tosylpyrimidine, 2-pyrimidinyl triflate or 2-pyrimidinyl mesylate in the presence of a catalyst 4-ethoxy-4-oxo-butylzinc bromide or 4-ethoxy- Reacting with 4-oxo-butylzinc iodide. Wherein X is halo, triflate or mesylate, and Y is bromide or iodide. 12. The process of claim 11 wherein the catalyst is produced from bis (acetonitrile) palladium (II) dichloride and triphenylphosphine. Use of a bis (acetonitrile) palladium (II) dichloride and triphenylphosphine in the Negishi coupling reaction.