HK1026203B - Arylsulfonylamino hydroxamic acid derivatives - Google Patents
Arylsulfonylamino hydroxamic acid derivatives Download PDFInfo
- Publication number
- HK1026203B HK1026203B HK00105541.3A HK00105541A HK1026203B HK 1026203 B HK1026203 B HK 1026203B HK 00105541 A HK00105541 A HK 00105541A HK 1026203 B HK1026203 B HK 1026203B
- Authority
- HK
- Hong Kong
- Prior art keywords
- radical
- aryl
- heteroaryl
- group
- alkyl
- Prior art date
Links
Description
The present invention relates to arylsulfonylamino hydroxamic acid derivatives which are inhibitors of matrix metalloprotease (msm) or Tumor Necrosis Factor (TNF) production and which are useful in the treatment of: arthritis, cancer, tissue ulceration, plaque degeneration, (heart valve) restenosis, periodontal disease, epidermolysis bullosa, scleritis, and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock, and other diseases involving TNF production. In addition, the compounds of the present invention may be used in combination with other standard non-steroidal anti-inflammatory drugs (NSAID' S) and analgesics for the treatment of arthritis, and also in combination with cytotoxic drugs (e.g., doxorubicin, daunorubicin, cisplatin, etoposide, taxol, taxane derivatives (taxotere) and alkaloids, vincristine) for the treatment of cancer.
The invention also relates to methods of using such compounds to treat the aforementioned disorders in mammals, particularly humans, and to pharmaceutical compositions useful in such methods.
There are many enzymes that can disrupt the structure of proteins, and they are structurally related to metalloproteinases. Matrix degrading metalloproteinases (e.g. gelatinases, stromelysins and collagenases) are involved in tissue matrix degradation (e.g. collagen collapse) and in many pathogenic conditions involving abnormal connective and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, and HIV-infection(s) ((J.Leuk.Biol.， 52(2)：244-248，1992)。
Tumor Necrosis Factor (TNF) is recognized to be involved in many infections and autoimmune diseases (w. fiers,FEBS Letters，1991， 285,199). Further, it has been shown that TNF is the major transmitter in inflammatory reactions of sepsis and septic shock (c.e. spooner et al,Clinical Immunology and Immunopathology，1992， 62 S11)。
the present invention relates to compounds of the formula or pharmaceutically acceptable salts thereof,wherein R is1And R2Each independently is (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl radical (C)1-C6) Alkyl (difluoromethylene), (C)1-C3) Alkyl (difluoromethylene (C)1-C3) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl, or R1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl; and is
Q is (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)1-C6) Alkoxy (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl group, (C)1-C6) Alkoxy (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl group, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl radical (C)1-C6) Alkyl radical (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)1-C6) Alkoxy (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)1-C6) Alkoxy (C)2-C9) Heteroaryloxy (C)6-C10) Aryl or (C)1-C6) Alkoxy (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, wherein each aryl group may be optionally substituted with 1-3 of the following groups, fluoro, chloro, bromo, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy or perfluoro (C)1-C3) Alkyl radical (C)6-C10) Aryloxy, trifluoromethoxy or difluoromethoxy.
Unless otherwise indicated, the term "alkyl" herein refers to a saturated single-bond hydrocarbon group having a straight, branched, or cyclic group or a mixture thereof.
The term "alkoxy" as used herein includes O-alkyl groups, wherein "alkyl" is as defined above.
Unless otherwise indicated, the term "aryl" herein includes organic radicals derived from aromatic hydrocarbons from which one hydrogen atom has been removed, such as phenyl or naphthyl, which may optionally be substituted with 1 to 3 of the following groups: fluorine, chlorine, bromine, perfluoro (C)1-C3) Alkyl, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy and (C)1-C6) An alkyl group.
Unless otherwise indicated, the term "heterocyclic aryl" herein includes organic groups derived from aromatic heterocyclic compounds from which one hydrogen atom has been removed, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl, which may be optionally substituted with 1-2 of the following groups: fluorine, chlorine, trifluoromethyl, (C)1-C6) Alkoxy group, (C)6-C10) Aryloxy, trifluoromethoxy, difluoromethoxy and (C)1-C6) An alkyl group.
Unless otherwise indicated, the term "acyl" herein includes groups having the general formula RCO, wherein R is alkyl, alkoxy, aryl, aralkyl or aralkoxy, and the terms "alkyl" and "aryl" are as defined above.
The term "acyloxy" as used herein includes O-acyl groups, wherein "acyl" is as defined above.
The compounds of formula I may have chiral centers and may therefore exist in different enantiomeric forms. The present invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl.
Other preferred compounds of formula I include those wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring.
Other preferred compounds of formula I include those wherein Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
Other preferred compounds of formula I include those wherein Q is (C)6-C10) Aryloxy radical (C)6-C10) And (4) an aryl group.
Other preferred compounds of formula I include those wherein R is1And R2Each independently is (C)1-C6) An alkyl group.
More preferred compounds of formula I include those wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl; and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
More preferred compounds of formula I include those wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring; and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
More preferred compounds of formula I include those wherein R is1And R2Each independently is (C)1-C6) Alkyl, and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
More preferred compounds of formula I include those wherein R is1And R2Each independently is (C)1-C6) An alkyl group; and Q is (C)6-C10) Aryloxy radical (C)6-C10) And (4) an aryl group.
Specific preferred compounds include the following:
3- [4- (4-fluorophenoxy) benzenesulfonylamino ] azetidine-3-carboxylic acid hydroxyamide;
4- [4- (4-fluorophenoxy) benzenesulfonylamino ] piperidine-4-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopropane-1-carboxylic acid hydroxyamide;
1- [4- (4-chlorophenoxy) benzenesulfonylamino ] cyclopropane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclobutane-1-carboxylic acid hydroxyamide;
1- [4- (4-chlorophenoxy) benzenesulfonylamino ] cyclobutane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclohexane-1-carboxylic acid hydroxyamide;
2- [4- (4-fluorophenoxy) benzenesulfonylamino ] -N-hydroxy-2-methylpropanamide;
2- [4- (4-chlorophenoxy) benzenesulfonylamino ] -N-hydroxy-2-methylpropanamide;
n-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide;
1- (5-pyridin-2-yl-thiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;
1- (4' -fluorobiphenyl-4-sulfonylamino) cyclopropane-1-carboxylic acid hydroxyamide;
1- (4' -fluorobiphenyl-4-sulfonylamino) cyclobutane-1-carboxylic acid hydroxyamide;
1- (4' -fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;
2- (4-methoxybenzenesulphonylamino) 1, 2-indane-2-carboxylic acid hydroxyamide; and
2- [4- (4-fluorophenoxy) benzenesulfonylamino ]1, 2-indane-2-carboxylic acid hydroxyamide.
The invention also relates to a pharmaceutical composition for (a) the treatment of the following diseases in synergy with cytotoxic antineoplastic agents: arthritis, cancer, tissue ulceration, plaque degeneration, (heart valve) restenosis, periodontal disease, epidermolysis bullosa, scleritis, combined with other standard NSAID' S and analgesics and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of Tumor Necrosis Factor (TNF), or (b) inhibiting the production of matrix metalloproteinase or Tumor Necrosis Factor (TNF) in mammals, including humans, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in such treatment.
The present invention relates to a method of inhibiting (a) Matrix Metalloprotease (MMP) or (b) Tumor Necrosis Factor (TNF) production in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to methods of treating the following diseases: arthritis, cancer, tissue ulceration, plaque degeneration, (heart valve) restenosis, periodontal disease, epidermolysis bullosa, scleritis, in combination with NSAID' S and analgesics, and in combination with cytotoxic antineoplastic agents and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of Tumor Necrosis Factor (TNF) in mammals, including humans, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in such treatment.
The following scheme will illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R in the schemes and subsequent discussion1，R2And Q is as defined above.
Preparation A
Route 1
In preparation A, reaction 1, an amino acid of formula III is treated with benzyl alcohol and an acid of formula HX, where X is preferably 4-tosylate, in an inert solvent (e.g., benzene or toluene, toluene being preferred) to provide the corresponding benzyl ester acid salt of formula V. Normally, the reaction is carried out at reflux temperature of the solvent used for 1 to 24 hours. The water formed during this reaction was collected using a Dean-Strar trap.
In preparation A reaction 2, V is reacted with sulfonic acid (QSO)2Reactive functional derivatives of OH (e.g. sulfonyl chlorides (QSO)2Cl)) in the presence of a base (e.g. sodium hydroxide or triethylamine) and a solvent (e.g. dichloromethane, tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water) to convert the compound of formula V to the corresponding compound of formula VI. The reaction mixture is stirred at about 0-50 deg.C (preferably at room temperature) for 10 minutes to 2 days, preferably about 60 minutes.
In preparative a reaction 3, the intermediate compound of formula VI is hydrogenolysed to give the intermediate of formula II. The reaction is carried out under hydrogen (preferably 3 atmospheres) in a solvent (e.g. ethanol) using a 10% Pd/C catalyst. The reaction mixture is stirred at room temperature for about 30 minutes to 24 hours, preferably 1.5 hours.
In scheme 1, reaction 1, III is reacted with QSO of formula2Reactive functional derivatives of OH sulfonic acids (wherein Q is as defined above) (e.g. sulfonyl chlorides (QSO)2Cl)) in the presence of a base (such as sodium hydroxide or triethylamine) and a polar solvent (such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water) to convert the compound of formula III to the corresponding compound of formula II. The reaction mixture is stirred at about 0-50 deg.C (preferably at room temperature) for 10 minutes to 2 days, preferably about 60 minutes.
In scheme 1, reaction 2, II is reacted with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxybenzotriazole in a polar solvent such as N, N-dimethylformamide, and after about 15 minutes to 1 hour (preferably about 30 minutes), hydroxylamine is added to the reaction mixture to convert the compound of formula II to the hydroxamic acid compound of formula I. Preferably, hydroxylamine is generated in situ from its salt form, for example from hydroxylamine hydrochloride, in the presence of a base, such as triethylamine. Alternatively, a protected derivative of hydroxylamine or a salt form thereof, wherein the hydroxyl group is protected with t-butyl, benzyl, allyl or 2-triethylsilyl ethyl ether, may be used in place of hydroxylamine or hydroxylamine hydrochloride. Removal of the hydroxy protecting group is carried out using the same conditions as hydrogenolysis of the benzyl protecting group (preferably 5% Pd/barium sulfate as catalyst) or by tert-butyl protecting group removal, i.e.treatment with a strong acid such as trifluoroacetic acid. Allyl protecting groups can be removed by treatment with tributyltin hydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride. 2-trimethylsilylether can be removed by reacting it with a strong acid such as trifluoroacetic acid or with a fluorine donor such as boron trifluoride etherate. The reaction of formula II with hydroxylamine, a hydroxylamine salt, a hydroxylamine protected derivative or a hydroxylamine protected derivative salt may be carried out in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate and a base (e.g. triethylamine) in an inert solvent (e.g. dichloromethane). The reaction mixture is stirred at 0-50 deg.C, preferably at room temperature, for 1 hour to 3 days, preferably 1 day. Preferably, the process for converting compound II to compound I is carried out by reacting II with O-benzylhydroxylamine hydrochloride in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate and triethylamine in dichloromethane. Carrying out hydrogenolysis under the condition of room temperature and 3 atmospheres of hydrogen and using 5 percent Pd/barium sulfate as a catalyst to remove O-benzyl protecting groups to obtain the compound shown in the formula I. The preferred solvent is methanol. The reaction time is about 1 to 5 hours (preferably 3.5 hours).
In some cases it is preferred to react hydroxylamine, hydroxylamine salts, hydroxylamine protected derivatives or hydroxylamine protected derivative salts with an active ester of formula IV to give a compound of formula I as shown in scheme 1, reaction 3. The reaction is carried out in an inert solvent such as N, N-dimethylformamide at a temperature of about room temperature to about 80 deg.C, preferably about 50 deg.C, for a reaction time of about 1 hour to about 2 days. If a hydroxylamine-protected derivative or a salt of a hydroxylamine-protected derivative is used, the protecting group is removed as described above. Treatment of a compound of formula II with (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate (ester) and a base such as triethylamine in an inert solvent such as dichloromethane affords the active ester derivative of formula IV (scheme 1, reaction 4). The reaction mixture is stirred at about 0-50 c (preferably room temperature) for about 1 hour to 3 days, preferably 1 day.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts with bases, known as cationic salts, such as alkali and alkaline earth metal salts, for example sodium, lithium, potassium, calcium, magnesium and ammonium salts, such as ammonium, trimethylammonium, diethylammonium and tris (hydroxymethyl) -methylammonium salts.
Similarly, acid addition salts (e.g., mineral acids, organic carboxylic acids and organic sulfonic acids such as hydrochloric acid, methanesulfonic acid, maleic acid) may also form part of the structure with basic groups such as pyridyl.
The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as compounds of the invention) to inhibit the production of matrix metalloproteases or Tumor Necrosis Factor (TNF), and their effectiveness in treating diseases characterized by the production of matrix metalloproteases or tumor necrosis factor, can be seen in the following in vitro assay results.
Biological assay
Inhibition of human collagenase (MMP-1)
Human recombinant collagenase can be activated using trypsin in the following proportions: 10. mu.g trypsin per 100. mu.g collagenase. Trypsin and collagen were incubated for 10 minutes at room temperature. Then a 5-fold excess (50. mu.g/10. mu.g trypsin) of soybean trypsin inhibitor was added.
A10 mM stock solution of inhibitor was prepared in dimethylsulfoxide and then diluted as follows.
10mM→120μM→12μM→1.2μM→0.12μM
Each 25mL solution was added to the appropriate well of a 96-well microplate and each sample was prepared in triplicate. The final concentration of inhibitor after addition of enzyme and substrate was diluted 1: 4. Positive controls (with enzyme, no inhibitor) were established in D1-D6 wells, and blank controls (without enzyme, no inhibitor) were established in D7-D12 wells.
Collagenase was diluted to 400ng/mL and 25. mu.L of this solution was added to the appropriate well of the above microscope plate. The final concentration of collagenase in the assay was 100 ng/mL.
Preparation of 5mM substrate (DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH)2) The dimethylsulfoxide stock solution was then diluted to 20 μ M with assay buffer. The assay was started by adding 50. mu.L of substrate to each well of the microscope plate to give a final concentration of 10. mu.M.
Fluorescence readings (360nM excitation, 460nM emission) were taken at 0 min and every 20 min interval. The analysis was performed at room temperature, with a typical analysis time of 3 hours.
The results are then plotted for fluorescence of the collagenase with the blank and the samples versus time (taking the average of the three samples). The time points providing the better signal (blank) and the straight-line part on the curve (typically around 120 minutes) are selected to determine the IC50The value is obtained. Time zero was taken as a blank for each compound at each concentration and these values were subtracted from the data obtained at 120 minutes. Data for inhibitory concentration versus% control sample were plotted (inhibitor fluorescence value minus fluorescence value for the glue source enzyme alone x 100). The corresponding inhibitor concentration at which a signal value corresponding to 50% of the control sample is given is determined as IC50The value is obtained.
If reported IC50Values < 0.03. mu.M, inhibitors were assayed at concentrations of 0.3. mu.M, 0.03. mu.M and 0.003. mu.M.
Gelatinase inhibition (MMP-2)
DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMA) -NH is used under the same conditions as human collagenase inhibition (MMP-1)2Substrate (10. mu.M) the activity of gelatinase was analyzed.
72kD of gelatinase was activated with 1mMAPMA (mercury p-aminophenylacetate) at 4 ℃ and diluted to a final concentration of 100 mg/mL. The inhibitor for inhibiting human collagenase (MMP-1) was diluted to give final concentrations of 30. mu.M, 3. mu.M, 0.3. mu.M and 0.03. mu.M, 3 parts each.
Fluorescence readings (360nM excitation, 460nM emission) were taken at 0 min and every 20 min interval for 4 hours.
Inhibition of each human collagenase (MMP-1) was determined. If reported IC50Values < 0.03. mu.M, inhibitors were detected at final concentrations of 0.3. mu.M, 0.03. mu.M, 0.003. mu.M and 0.003. mu.M.
Inhibition of stromelysin activity (MMP-3)
Stromelysin activity inhibition is based on Weingarten and Feder (Weingarten, h. and Feder, j., spectrophometric Assay for vertebratecollagenese, anal.147437-440(1985)) by the modified spectrophotometric method described in (A-S). Thiopeptide ester (peptolide) substrate [ Ac-Pro-Leu-Gly-SCH [ CH ]2CH(CH3)2]CO-Leu-Gly-OC2H5]The hydrolysis of (a) produces thiol fragments which can be monitored in the presence of Ellman's reagent.
Human recombinant pro-stromelysin was activated with trypsin using a 10mg/mL trypsin stock solution at a ratio of 1 μ L of stromelysin per 26 μ g. Trypsin and stromelysin were incubated at 37 ℃ for 15 minutes, followed by 10 μ L of 10mg/mL soybean trypsin inhibitor at 37 ℃ for 10 minutes to stop trypsin activity.
The assay was performed with 96-well microscopy plates and in a total volume of 250. mu.L of assay buffer (200mM sodium chloride, 50mM MES and 10mM calcium chloride, pH 6.0). The activated stromelysin was diluted to 25. mu.g/mL with assay buffer. 1M stock solutions of Ellman's reagent (3-carboxy-4-nitrophenyldisulfide) were prepared in dimethylformamide and diluted with buffer to a concentration of 5mM to give a final concentration of 1mM at a loading of 50. mu.L per well.
Stock solutions of 10mM inhibitor were prepared in dimethyl sulfoxide and serially diluted with buffer to give final concentrations of 3. mu.M, 0.3. mu.M, 0.003. mu.M and 0.0003. mu.M when 50. mu.L of the solution was added to the appropriate wells. All conditions 3 samples were prepared.
Assay was started by diluting a 300mM peptide substrate in DMSO stock solution to 15mM with assay buffer, and adding 50. mu.L of this solution to each well to give a final concentration of 3mM substrate. The background contained peptide substrate and Ellman's reagent, but no enzyme. Product formation was monitored at 405nm with a Molecular Devices Uvmax plate reader.
IC was determined in the same manner as for collagenase50The value is obtained.
Inhibition of MMP-13
Human recombinant MMP-13 was activated with 2mM APMA (Mercury p-aminophenylacetate) for 1.5 hours at 37 ℃ and diluted to 400mg/ml with assay buffer (50mM Tris, pH7.5, 200mM sodium chloride, 50mM calcium chloride, 20. mu.M zinc chloride and 0.02% brij). 25. mu.l of the dilution was added to each well of a 96-well microplate. The enzyme was diluted to a final concentration of 100mg/ml in assay buffer by adding the inhibitor and substrate in a ratio of 1: 4 in assay buffer.
A10 mM inhibitor stock solution was prepared in dimethyl sulfoxide and diluted with buffer following the inhibitor dilution route for inhibition of human collagenase (MMP-1), and 25. mu.l of each concentration of solution was added to the microscope plate, 3 portions for each sample. The final concentrations in assay buffer were 30. mu.M, 3. mu.M, 0.3. mu.M and 0.03. mu.M.
Preparation of a substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NNA) -NH) for inhibiting human collagenase (MMP-1)2]And 50. mu.L of this solution was added to each well to give a final assay concentration of 10. mu.M. Fluorescence readings (360nM excitation, 450nM emission) were taken at time 0 and every 5 minutes for 1 hour.
The positive control contained enzyme and substrate but no inhibitor, and the blank contained only substrate.
IC was determined in the same manner as for human collagenase (MMP-1)50The value is obtained. If reported IC50Values < 0.03. mu.M, the inhibitors were further analyzed at final concentrations of 0.3. mu.M, 0.03. mu.M, 0.003. mu.M and 0.0003. mu.M.
Inhibition of TNF production
The following in vitro assays demonstrate the ability of the compounds or pharmaceutically acceptable salts thereof to inhibit TNF production and subsequently demonstrate their efficacy in treating disorders associated with TNF production:
human monocytes are separated from human anticoagulation by one-step Ficoll-hypaque (3, 5-diacetamido-2, 4, 6-triiodosodium benzoate) separation technique. (2) Mononuclear cells were washed three times with divalent cation solution in Hanks Balanced Salt Solution (HBSS) and resuspended in 2X 10 density containing 1% BSA6In HBSS per ml. Differentiation counts determined using an Abbott Cell Dyn 3500 analyzer indicated: in these preparations, single cells account for 17-24% of the total number of cells.
180. mu.L of the cell suspension was aliquoted to the flat bottom of a 96-well plate (Costar). Compound and LPS (final concentration 100ng/ml) were added to a final volume of 200. mu.L. All conditions were prepared in 3 parts. After 4 hours incubation in a humidified carbon dioxide incubator, the plates were removed, centrifuged (approximately 250 Xg, 10 minutes), the supernatant removed, and analyzed for TNFa using R & D ELISAKit.
For administration to mammals, including humans, various conventional routes of administration, including oral, parenteral and topical administration, may be employed in order to inhibit the production of matrix metalloproteases or Tumor Necrosis Factor (TNF). Usually the active ingredient is administered orally or parenterally in a dose of about 0.1 to 25mg/Kg of recipient body weight per day, preferably 0.3 to 5 mg/Kg. However, the dosage may be varied as necessary depending on the condition of the subject to be treated. In any case, the person responsible for administration will determine the appropriate dosage to administer, depending on the circumstances of the subject to whom it is administered.
The compounds of the present invention may be administered in a number of different dosage forms, typically having a concentration level of the therapeutically effective amount of the compound of the present invention of from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients (e.g., microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycerol) may be employed, along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. Solid compositions of a similar type are also used as fillers in gelatin capsules; in this case, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and dyes, and, if desired, emulsifying and suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. In the case of administration to animals, it is preferred to contain these substances in the animal feed or drinking water at a concentration of 5 to 5000ppm, preferably 25 to 500 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous), sterile injectable solutions of the active ingredient are usually prepared. Solutions of the therapeutic compounds of the present invention in sesame or peanut oil, or in aqueous propylene glycol, may be employed. The aqueous solution should be suitably adjusted and buffered, preferably to a pH greater than 8, if desired, by first rendering the liquid diluent isotonic. These aqueous solutions are suitable for intravenous administration. Oily solutions are suitable for administration by intra-articular, intramuscular and subcutaneous injection. The preparation of all these solutions can be conveniently accomplished under sterile conditions using methods well known to those skilled in the art. In animal administration, can be intramuscular and subcutaneous injection, dosage level in about 0.1-50 mg/Kg/day, preferably 0.2-10 mg/Kg/day, can be a single dose or up to 3 separate doses for administration.
The following examples will illustrate the invention without limiting the details of the invention.
Preparation A
4- (4-fluorophenoxy) benzenesulfonyl chloride
Chlorosulfonic acid (26ml, 0.392mole) was added dropwise to ice-cold 4-fluorophenoxybenzene (36.9g, 0.196mole) with mechanical stirring. After the addition was complete, the mixture was stirred at room temperature for 4 hours. It was poured into ice water. The product, 4- (4-fluorophenoxy) benzenesulfonyl chloride (18.6g, 33%), was collected by filtration and dried in air.
Preparation B
4- (3-Methylbutoxy) benzenesulfonic acid sodium salt
An aqueous solution (40mL) of 4-hydroxybenzenesulfonic acid (10.0g, 43.1mmole) and sodium hydroxide (3.3g, 83mole) was mixed with an isopropanol solution (60mL) of 1-iodo-3-methylbutane (11.3mL, 86.4mmole), and the resulting mixture was refluxed for 2 days. The isopropanol was distilled off under reduced pressure. Filtration and washing with isopropanol gave 10.0g (87%) of the title compound.
Preparation C
4- (3-Methylbutoxy) benzenesulfonyl chloride
A mixture of sodium 4- (3-methylbutoxy) benzenesulfonate (2.5g, 9.4mmole), thionyl chloride (10mL) and 5 drops of N, N-dimethylformamide was refluxed together for 5 hours. After cooling, the excess thionyl chloride was evaporated off and the residue was dissolved in ethyl acetate. The solution was cooled on an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was distilled off to give 2.4g (95%) of the title compound as an oil.
Preparation D
4- (2-Cyclopentylethoxy) benzenesulfonic acid sodium salt
An aqueous solution (15mL) of 4-hydroxybenzenesulfonic acid (65g, 282mmole) and sodium hydroxide (2.2g, 55mole) was mixed with an isopropanol solution (40mL) of 2- (bromoethyl) cyclopentane (15.0g, 84.7mmole), and the resulting mixture was heated under reflux for 2 days. The isopropanol was distilled off under reduced pressure. Filtration and washing with isopropanol gave 4.7g (57%) of the title compound.
Preparation E
4- (3-Methylbutoxy) benzenesulfonyl chloride
A mixture of sodium 4- (2-cyclopentylethoxy) benzenesulfonate (2.5g, 8.6mmole), thionyl chloride (15mL) and a few drops of N, N-dimethylformamide was refluxed together for 5 hours. After cooling, the excess thionyl chloride was evaporated off and the residue was dissolved in ethyl acetate. The solution was cooled on an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was distilled off to give 2.24g (90%) of the title compound as an oil.
Preparation F
4' -Fluorobiphenylsulfonyl chloride
Chlorosulfonic acid (8.7mL, 0.13mole) was added dropwise to 4-fluorobiphenyl (10.2g, 59mole) with stirring in an ice bath. Stirring was continued for 0.5 h under ice bath and then the mixture was poured into ice. The resulting white precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with water and brine, dried over magnesium sulfate, and concentrated to give a white solid. The desired product, 4 '-fluorobiphenyl sulfonyl chloride (4.3g, 27%) was separated from 4' -fluorobiphenyl sulfonic acid (unwanted by-product) by recrystallization from ethyl acetate, and the remaining material was recrystallized from hexane.
Preparation G
4- (4-fluorobenzyloxy) benzenesulphonic acid sodium salt
To a 1N aqueous solution (23mL) of sodium hydroxide in 4-hydroxybenzenesulfonic acid (513g, 221mmole) was added a solution of 4-fluorobenzyl bromide (33mL, 265mmole) in ethanol (20 mL). The resulting mixture was heated to reflux for 2 days. After cooling and standing, a white precipitate appeared. The precipitate was collected by filtration and washed with ethyl acetate and diethyl ether to give 4.95g (74%) of sodium 4- (4-fluorobenzyloxy) benzenesulfonate.
Preparation H
4- (4-fluorobenzyloxy) benzenesulfonyl chloride
To a slurry of sodium 4- (4-fluorobenzyloxy) benzenesulfonate (0.5g, 1.64mmole) in dichloromethane (5mL) was added phosphorus pentachloride (275mg, 1.31 mmole). The resulting mixture was refluxed together for 7 hours. After cooling in an ice bath, the reaction was quenched with water (15mL) and extracted with ethyl acetate. The organic phase was washed with brine. After drying over sodium sulfate, the solvent was evaporated to give 4- (4-fluorobenzyloxy) benzenesulfonyl chloride (130mg, 26%) as a white solid.
Preparation I
4- (4-chlorobenzyloxy) benzenesulfonyl chloride
Chlorobenzenesulfonic acid (9.7mL, 0.147mole) was added dropwise to 4-chlorophenoxybenzene (12.6mL, 73.4mmole) with stirring at room temperature. After the addition was complete, the resulting mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, dried in air and recrystallized from petroleum ether and ethyl acetate to give 4- (4-chlorobenzyloxy) benzenesulfonyl chloride (7.43g, 33%)
Example 1
1- (4-methoxybenzenesulphonylamino) cyclopentane-1-carboxylic acid hydroxyamide
(A) To a solution of 1-aminocyclopentane-1-carboxylic acid (6.0g, 46.5mmole) and triethylamine (14mL, 100mmole) in dioxane (90mL) and water (90mL) was added 4-methoxybenzenesulfonyl chloride (10.6g, 51.3 mmole). The mixture was stirred at room temperature for 4 hours, acidified with 1N hydrochloric acid solution and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate and concentrated to give a brown solid which was triturated with chloroform and 5.42g (39%) gave 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid as a white solid.
(B) To a solution of 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid (4.65g, 15.2mmole) and triethylamine (2.5mL, 17.9mmole) in dichloromethane (120mL) was added (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate (7.4g, 16.3 mmole). The mixture was stirred at room temperature for 2.5 days. The solvent was distilled off, and the residue was extracted with ethyl acetate. The solution was washed successively with 0.5N hydrochloric acid solution, water and brine. The solvent was concentrated after drying over magnesium sulfate to give 1- (4-methoxybenzenesulfonylamino) cyclopentane-carboxylic acid benzotriazol-1-yl ester as a yellow solid. This was dissolved in N, N-dimethylformamide (120mL), and diisopropylethylamine (5.3mL, 30mmole) and O-benzylhydroxylamine hydrochloride (3.2g, 20mmole) were added to the resulting solution. The mixture was heated on an oil bath at 50 ℃ for 20 hours. The solvent was evaporated and ethyl acetate was added. The mixture was filtered and a white solid was collected. The filtrate was washed successively with 0.5N hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. The solvent was evaporated and the resulting solid combined with the solid obtained by the previous filtration and triturated with ethyl acetate to give 2.92g (47%) of 1- (4-methoxybenzenesulphonylamino) cyclopentane-1-carboxylic acid benzyloxyamide as a white solid.
(C) A solution of 1- (4-methoxybenzenesulfonylamino) cyclopentane-1-carboxylic acid benzyloxyamide (1.50mL, 3.71mmole) in methanol (200mL) was treated with 5% Pd/barium sulfate (0.75g) and hydrogenated in Parr shaker at 3 atmospheres for 3.5 hours. The mixture was passed through a 0.45 μm nylon filter and the filtrate was concentrated to give 1.13g (97%) of 1- (4-methoxybenzenesulphonylamino) cyclopentane-1-carboxylic acid hydroxyamide as a white solid. MS: 313 (M-1).
The title compounds in examples 2-8 were prepared in a similar manner to example 1 using the following reagents.
Example 2
1- (4-methoxybenzenesulphonylamino) cyclohexane-1-carboxylic acid hydroxyamide
1-aminocyclohexane-1-carboxylic acid; 4-methoxybenzenesulfonyl chloride. MS: 327 (M-1).
Example 31- [4- (4-fluorophenoxy) benzenesulfonylamino group]Cyclopentane-1-carboxylic acid hydroxyamide
1-aminocyclopentane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. MS: 393 (M-1). Elemental analysis (C)18H19FN2O5S.0.25H2O) theoretical value: c54.19, H4.93, N7.02. Measured value: c54.20, H5.13, N7.08
Example 4
1- [4- (4-fluorophenoxy) benzenesulfonylamino group]Cyclohexane-1-carboxylic acid hydroxyamides
1-aminocyclohexane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. And (4) recrystallizing with chloroform. MP: 174 ℃; MS: 393 (M-1).
Example 5
1- [4- (4-fluorophenoxy) benzenesulfonylamino group]Cyclopropane-1-carboxylic acid hydroxyamides
1-aminocyclopropane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. MP: 184 ℃; MS: 365 (M-1); elemental analysis (C)16H15FN2O5S) theoretical value: c52.45, H4.13, N7.65. Measured value: c52.20, H4.34, N7.44.
Example 6
1- (4' -fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide
1-aminocyclopentane-1-carboxylic acid; 4' -fluorobiphenyl sulfonyl chloride. And (4) recrystallizing with chloroform. MP: 159 ℃ C; MS: 377 (M-1).
Example 7
1- [4- (4-fluorophenoxy) benzenesulfonylamino group]Cyclobutane-1-carboxylic acid hydroxyamides
1-aminocyclobutane-1-carboxylic acid; 4- (fluorophenoxy) benzenesulfonyl chloride. MS: 379 (M-1).
Example 8
1- [4- (4-fluorophenoxy) benzenesulfonylamino group]Cyclopropane-1-carboxylic acid hydroxyamides
1-aminocyclopropane-1-carboxylic acid; 4- (4-fluorophenoxy) benzenesulfonyl chloride. MS: 379 (M-1).
Example 9
N-hydroxy-2- (4-methoxybenzenesulphonylamino) -2-methylpropanamide
(A) A solution of benzyl 2-amino-2-methylpropionate hydrochloride (12.0g, 52.2mmole) and 4-methoxybenzenesulfonyl (11.9g, 57.6mmole) in dioxane (100mL) and water (100mL) was cooled on an ice bath. Triethylamine (18.2mL, 0.13mole) was added. The ice bath was removed and the mixture was stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and water, the aqueous layer was separated, extracted twice with ethyl acetate, and the combined organic layers were washed successively with saturated aqueous sodium bicarbonate, 1N hydrochloric acid and brine. After drying over sodium sulfate, the solvent was evaporated to give a yellow oil (19.3g), a portion (10g) of which was purified by silica gel chromatography eluting with 3: 7 ethyl acetate/hexane to give, after recrystallization from ethyl acetate/hexane, 6.59g (67%) of benzyl 2- (4-methoxybenzenesulphonylamino) -2-methylpropionate as a white solid.
(B) A solution of benzyl 2- (4-methoxyphenylsulfonylamino) -2-methylpropionate (1.5g, 4.13mmole) in ethanol (80mL) was treated with 10% Pd/C (0.17g) and 3 atm hydrogen in a Parr shaker for 1.5 hours. The mixture was passed through a 0.45 μm nylon filter to remove the catalyst, and the filtrate was concentrated to give 1.09g (96%) of 2- (4-methoxyphenylsulfonylamino) -2-methylpropionic acid as a white solid.
(C) A solution of 2- (4-methoxyphenylsulfonylamino) -2-methylpropionic acid (1.08g, 3.95mmole) in dichloromethane (120mL) was cooled on an ice bath. Triethylamine (2.2mL, 15.8mmole), (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate (ester) salt (2.6g, 5.88mmole) and O-benzylhydroxylamine hydrochloride (0.95g, 5.95mmole) were added in this order. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated off, the residue was dissolved in ethyl acetate and water, and the solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to give an oil. This was purified by silica gel chromatography eluting with 1: 2 ethyl acetate/hexane to give 1.41g (95%) of the desired N-benzyloxy-2- (4-methoxybenzenesulphonylamino) -2-methylpropanamide as a white solid.
(D) A solution of N-benzyloxy-2- (4-methoxyphenylsulfonylamino) -2-methylpropanamide (1.40g, 3.70mmole) in methanol (80mL) was treated with 5% Pd/barium sulfate (0.75g) and 3 atmospheres of hydrogen in a Parr shaker for 1.5 hours. The mixture was passed through a 0.45 μm nylon filter, the catalyst was removed, and the filtrate was concentrated to give 1.06g (100%) of N-hydroxy-2- (4-methoxyphenylsulfonylamino) -2-methylpropanamide as a white solid. MP: 122-: 289(M + 1): elemental analysis (C)11H16N2O5S) theoretical value: c45.82, H5.59, N9.72; measured value: c45.88, H5.60, N9.69.
The title compounds in examples 10-12 were prepared in a similar manner to example 9 using the following reagents.
Example 10
2- [4- (4-fluorophenoxy) benzenesulfonylamino group]-N-hydroxy-2-methylpropionamide
2-amino-2-methylpropanoic acid benzyl ester hydrochloride; 4- (4-fluorophenoxy) benzenesulfonyl chloride. MP: 133-: 369(M + 1): elemental analysis (C)16H17FN2O5S) theoretical value: c52.17, H4.65, N7.60; measured value: c52.21, H4.83, N7.80.
Example 11
N-hydroxy-2-methyl-2- [4- (3-methylbutoxy) benzenesulfonylamino]Propanamides
2-amino-2-methylpropanoic acid benzyl ester hydrochloride; 4- (3-methylbutoxy) benzenesulfonyl chloride. Ethyl acetate/hexane was recrystallized. MP: 126.5-128 ℃, MS: 343 (M-1): elemental analysis (C)15H24N2O5S) theoretical value: c52.31, H7.02, N8.13; measured value: c52.30, H7.07, N8.16.
Example 12
2- [4- (2-Cyclopentylethoxy) benzenesulfonylamino group]-N-hydroxy-2-methyl-propionamide
2-amino-2-methylpropanoic acid benzyl ester hydrochloride; 4- (2-cyclopentylethoxy) benzenesulfonyl chloride. Ethyl acetate/hexane was recrystallized. MP: 126 ℃ and 127 ℃, MS: 369 (M-1): elemental analysis (C)17H26N2O5S) theoretical value: c55.12, H7.07, N7.56; measured value: c55.46, H7.09, N7.38.
Example 13
N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -propionamide
(A) To a solution of 2-amino-2-methylpropionic acid (2.0g, 19.4mmole) in 1N sodium hydroxide (45mL) was added 5-pyridin-2-ylthiophene-2-sulfonyl chloride (8.41g, 32.4 mmole). The resulting mixture was stirred at room temperature for 16 hours. Then, 1N sodium hydroxide solution (45mL) was added thereto, and the mixture was extracted with diethyl ether. The organic layer was discarded, and the aqueous layer was acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine. After drying over sodium sulfate, concentration yielded 2.18g (34%) 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionic acid as a white solid.
(B) To a solution of 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionic acid (1.60g, 4.91mmole) in dichloromethane (160mL) was added triethylamine (2.3mL, 16.5mmole), (benzotriazol-1-yloxy) tris (dimethylamino) -phosphonium hexafluorophosphate (2.4g, 5.41mmole) and O- (2-trimethylsilylethyl) hydroxylamine hydrochloride (0.92g, 5.41 mmole). The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was extracted with ethyl acetate and water. The solution was washed successively with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate, the solvent was evaporated to give a white foam. This was purified by silica gel chromatography eluting with 3: 2 ethyl acetate/hexanes to give 220mg (10%) of the desired 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -N-2- (trimethylsilylethoxy) propionamide as a white solid.
(C) 2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -N-2- (trimethylsilylethoxy) propionamide (80mg, 0.18mmole) was dissolved in trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 16 hours. Trifluoroacetic acid was evaporated under reduced pressure and dissolved with methanol to give N-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) -propionamide (60mg, 97%) as a yellow oil which was recrystallized from ethanol. MP: 165-166 ℃. MS: 342(M + 1).
The title compounds in examples 14-15 can be prepared by a similar method to that in example 13 using the following reagents.
Example 14
1- (5-pyridin-2-yl-thiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide
1-aminocyclopentane-1-carboxylic acid; 5-pyridin-2-ylthiophene-2-sulfonyl chloride. MS: 368(M + 1).
Example 15
1- [4- (4-chlorophenoxy) benzenesulfonylamino group]Cyclopropane-1-carboxylic acid hydroxyamides
1-aminocyclopropane-1-carboxylic acid; 4- (4-chlorophenoxy) benzenesulfonyl chloride. MS: 381 (M-1).
Claims (14)
1. A compound of the formula or a pharmaceutically acceptable salt thereof,
wherein R is1And R2Each independently is (C)1-C6) Alkyl, trifluoromethyl (C)1-C6) Alkyl radical (C)1-C6) Alkyl (difluoromethylene), (C)1-C3) Alkyl (difluoromethylene (C)1-C3) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl radical，(C6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl, or R1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl; and is
Q is (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)1-C6) Alkoxy (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl group, (C)1-C6) Alkoxy (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl group, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl radical (C)1-C6) Alkyl radical (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)2-C9) Heteroaryloxy (C)6-C10) Aryl radical, (C)1-C6) Alkyl radical (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)1-C6) Alkoxy (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)1-C6) Alkoxy (C)2-C9) Heteroaryloxy (C)6-C10) Aryl or (C)1-C6) Alkoxy (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, wherein each aryl group may optionally be substituted by fluorine, chlorine, bromine, (C)1-C6) Alkyl radical (C)1-C6) Alkoxy or perfluoro (C)1-C3) Alkyl substitution.
2. The compound of claim 1, wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl.
3. The compound of claim 2, wherein R1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring.
4. The compound of claim 1 wherein Q is (C)1-C6) Alkyl radical (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
5. The compound of claim 4 wherein Q is (C)6-C10) Aryloxy radical (C)6-C10) And (4) an aryl group.
6. The compound of claim 1, wherein R is1And R2Each independently is (C)1-C6) An alkyl group.
7. The compound of claim 1, wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring or a group of the formulaWherein n and m are each independently 1 or 2 and X is CF2S, O or NR3Wherein R is3Is hydrogen, (C)1-C6) Alkyl radical (C)6-C10) Aryl radical, (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)1-C6) Alkyl radical (C)2-C9) Heteroaryl (C)1-C6) Alkyl radical (C)1-C6) Alkylsulfonyl group (C)6-C10) Arylsulfonyl or acyl; and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
8. The compound of claim 1, wherein R is1And R2Together form (C)3-C6) Cycloalkyl or benzo-fused (C)3-C6) A cycloalkyl ring; and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Hetero compoundAryloxy radical (C)6-C10) And (4) an aryl group.
9. The compound of claim 1, wherein R is1And R2Each independently is (C)1-C6) Alkyl, and Q is (C)6-C10) Aryl radical, (C)6-C10) Aryl radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)6-C10) Aryl radical, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl group, (C)2-C9) Heteroaryl (C)6-C10) Aryl or (C)2-C9) Heteroaryloxy (C)6-C10) And (4) an aryl group.
10. The compound of claim 1, wherein R is1And R2Each independently is (C)1-C6) An alkyl group; and Q is (C)6-C10) Aryloxy radical (C)6-C10) And (4) an aryl group.
11. The compound of claim 1, wherein said compound is selected from the group consisting of:
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopropane-1-carboxylic acid hydroxyamide;
1- [4- (4-chlorophenoxy) benzenesulfonylamino ] cyclopropane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclobutane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentane-1-carboxylic acid hydroxyamide;
1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclohexane-1-carboxylic acid hydroxyamide;
2- [4- (4-phenoxy) benzenesulfonylamino) -N-hydroxy-2-methylpropanamide;
2- [4- (4-fluorophenoxy) benzenesulfonylamino ] -N-hydroxy-2-methylpropanamide;
n-hydroxy-2-methyl-2- (5-pyridin-2-ylthiophene-2-sulfonylamino) propionamide;
1- (5-pyridin-2-yl-thiophene-2-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;
n-hydroxy-2-methyl-2- [4- (3-methylbutoxy) benzenesulfonylamino ] -propionamide;
1- (4' -fluorobiphenyl-4-sulfonylamino) cyclopentane-1-carboxylic acid hydroxyamide;
2- [4- (2-cyclopentylethoxy) benzenesulfonylamino ] -N-hydroxy-2-methyl-propionamide.
12. A pharmaceutical composition for use in (a) treating arthritis, cancer, tissue ulceration, plaque degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, AIDS, sepsis, septic shock, or (b) inhibiting the production of matrix metalloproteinases or tumor necrosis factor in a mammal, including a human, in combination with NASID and an analgesic or in combination with a cytotoxic anticancer agent, comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
13. The use of a compound of formula I in the manufacture of a medicament for inhibiting (a) matrix metalloprotease in a mammal, including a human, or (b) tumor necrosis factor production.
14. The use of a compound of claim 1 in combination with an NSAID and an analgesic and in combination with a cytotoxic antineoplastic agent in the manufacture of a medicament for the treatment of: arthritis, cancer, tissue ulceration, plaque degeneration, restenosis, periodontal disease, epidermolysis bullosa, scleritis, AIDS, sepsis, septic shock.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3685797P | 1997-02-03 | 1997-02-03 | |
| US60/036,857 | 1997-02-03 | ||
| PCT/IB1998/000023 WO1998033768A1 (en) | 1997-02-03 | 1998-01-12 | Arylsulfonylamino hydroxamic acid derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1026203A1 HK1026203A1 (en) | 2000-12-08 |
| HK1026203B true HK1026203B (en) | 2003-12-24 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1113862C (en) | Arylsulfonylamino hydroxamic acid derivs | |
| JP3710489B2 (en) | Arylsulfonylhydroxamic acid derivatives | |
| CN1225639A (en) | Phosphinate-Based Matrix Metalloproteinase Inhibitors | |
| CN1296481A (en) | (4-arylsulfonylamino)-tetrahydropyran-4-carboxylic acid hydroxamides | |
| JP3448275B2 (en) | Aryloxyarylsulfonylaminohydroxamic acid derivatives | |
| CN1304930A (en) | Arylsulfurylisooximino acid derivative | |
| CN1077885C (en) | Biphenylsulfonamide matrix metalloproteinase inhibitors | |
| KR20000068248A (en) | Arylsulfonylamino Hydroxamic Acid Derivatives | |
| CN1274288A (en) | Peptide-containing & alpha, -ketoamide cysteine and serine protease inhibitors | |
| CN1072667C (en) | Mercaptoalkylpeptidyl compounds having an imidazole substituent and their use as inhibitors of matrix metalluproteinass (MMP) and/or tumour necrosis factor (TNF) | |
| CN1171780A (en) | Hydroxamic acid-containing inhibitors of matrix metalloproteases | |
| EA003585B1 (en) | alpha-HYDROXY, -AMINO AND -FLUORO DERIVATIVES OF beta-SULPHONYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASES INHIBITORS | |
| CN1289322A (en) | Hydroxamic and carboxylic acid derivatives | |
| CN1212835C (en) | Hydroxamate-containing cysteine and serine protease inhibitors | |
| US20020006920A1 (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| HK1026203B (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| CN1288135C (en) | Certain 1-(D-cyclopropylglycyl)-4-(piperidin-4-yl)piperazine compounds as inhibitors of serine protease factor XA | |
| HK1018940A (en) | Phosphinate based inhibitors of matrix metalloproteases | |
| CZ267699A3 (en) | Derivatives of arylsulfonylaminohydroxamic acid, pharmaceutical preparation, inhibition method of matrix metalloproteinases or production of tumor necrosis factor and treatment method | |
| HK1034245A (en) | (4-arylsulfonylamino)- tetrahydropyran-4-carboxylic acid hydroxamides | |
| HK1029575B (en) | Aryloxyarylsulfonylamino hydroxamic acid derivatives | |
| MXPA99007143A (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| CN87107599A (en) | 4-Hydroxy-4-(substituted alkenyl)cyclohexanecarboxylic acid | |
| HK1025314A (en) | New hydroxamic acid compounds, a process for their preparation and pharmaceutical compositions containing them | |
| HK1016996A (en) | Thio-substituted peptides as inhibitors for metalloproteinases and thf liberation |