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Definitions

• the invention relates to a novel method of producing alpha-sulfonyl hydroxamic acid derivatives that can be important as matrix metalloproteinase (MMP) and TNF-alpha converting enzyme (TACE) inhibitors, phosphodiesterase inhibitors, renin inhibitors, antithrombotics, and 5-lipoxygenase inhibitors.
• MMP matrix metalloproteinase
• TACE TNF-alpha converting enzyme
• phosphodiesterase inhibitors phosphodiesterase inhibitors
• renin inhibitors renin inhibitors
• antithrombotics antithrombotics
• 5-lipoxygenase inhibitors 5-lipoxygenase inhibitors.
• Matrix metalloproteinases are a family of structurally related zinc-containing enzymes that mediate the breakdown of the extracellular matrix proteins. Members of this family, which include collagenases, stromelysins, and gelatinases are involved in the normal tissue remodeling process such as wound-healing, angiogenesis, and pregnancy. In these pathological processes, the MMP activity is tightly regulated by the endogenous tissue inhibitors of matrix metalloproteinases (TIMPS). In pathological conditions, this fine balance between MMP-TIMP can be disrupted leading to several disease states including rheumatoid and osteoarthritis, atherosclerosis, tumor growth, metastasis, and fibrosis. Therapeutic inhibition of MMPs is a promising approach for treatment of these diseases and therefore the MMPs are attractive targets for rational drug design.
• TIMPS matrix metalloproteinases
• TACE is also a new member of metalloproteinase family, which catalyses the formation of tumor necrosis factor-alpha precursor protein.
• TNF-alpha was selected as one of the early targets leading to the successiveful cloning and sequencing of human TNF-alpha in 1984 by Goeddel and collegues.
• TNF-alpha is a very powerful proinflammatory mediator produced by activated macrophages, blood monocytes. and mast cells.
• TNF-alpha is a proinflammatory cytokine that has a central role in rheumatoid arthritis, and Crohn * s disease. Animal models and association studies in humans have indicated a potential role for TNF in insulin resistance, multiple sclerosis, organ failure, pulmonary fibrosis, and HIV infection. Therefore, the inhibition of TNF-alpha has been the focus of drug discovery.
• the lipoxygenases are a family of enzymes, which c atalyze the oxygenation of arachidonic acid leading to the production of leukotrienes.
• Leukotrienes have been implicated as important mediators in asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, and inflammatory bowel disease. It is believed that inhibition of these enzymes will provide effective systematic treatment of these diseases. Renin inhibitors can be used to control or prevent high blood pressure and cardiac insufficiency.
• Alpha-sulfonyl hydroxamic acids of the general formula I have been disclosed as potent MMP and TACE inhibitors (Venkatesan, A.M.; Grosu, G.T.; Davis, J.M.; Baker, J.L.; Levin, J.I. PCT Int. Appl. WO 9942436; Barta, T.E.; Becker, D.P.; Boehm, T.L.; De Crescenzo, G.A.; Villamil, C.I. ; McDonald, J.J.; Freskos, J.N.; Getman, D.P. PCT Int. Appl.
• alpha-sulfonylhydroxamates in the above literature involves first, the alkylation of appropriately substituted mercaptan derivative with either substituted or unsubstituted alpha-bromoacetic acid ester to give alpha-thio ester followed by oxidation of sulfur to sulfone to provide alpha-sulfonyl ester.
• This alpha-sulfonyl ester is converted to the corresponding hydroxamic acid derivative via the carboxyhc acid.
• the enolate of the carbonyl compound is treated with the appropriately substituted disulfide to obtain the alpha-thio ester, which is then oxidized to the corresponding sulfone.
• the alpha-sulfonyl ester is converted to the hydroxamic acid derivative as mentioned above.
• the preparation of the thiol or the disulfide requires multiple steps that involve sulfonyl chloride, protected thiols, or disulfides as intermediates and the oxidation step to convert alpha-thio ester to alpha-sulfonyl ester. It is the object of this invention to provide a novel method for preparing alpha-sulfonyl hydroxamic acid derivatives, which provides the target molecules in a highly convergent and efficient manner.
• X is hydrogen, alkyl of 1-6 carbon atoms, benzyl, hydroxyethyl, t-butyldimethylsilyl, trimethylsilyl or tetrahydropyranyl;
• R 3 is alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms having 1 to 3 double bonds, alkynyl of 2-18 carbon atoms having from 1 to3 triple bonds, cycloalkyl of 3-6 carbon atoms, 5-10 membered cycloheteroalkyl, aryl of 6 to 10 carbon atoms, 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O, and S; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl of R 3 may optionally be substituted on any atom capable of substitution with from 1 to 3 substituents selected from halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-6 carbon atoms having from 1 to 3 triple bonds, cycloalkyl of 3-6 carbon
• R 4 is hydrogen; aryl; aralkyl, heteroaryl; heteroaralkyl, alkyl of 1-6 carbon atoms; cycloalkyl of 3-6 carbon atoms; -C(O) R 5 , -CONR 5 R 6 or SO 2 R 5 ;
• R 5 and R 6 are each independently hydrogen, optionally substituted aryl; 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O and S; cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms or alkynyl of 2-18 carbon atoms; or R 5 and R 6 taken together with the nitrogen atom to which they are attached may form a 5-10 membered cycloheteroalkyl ring; and
• n 1 or 2; or pharmaceutical salts thereof,
• R 3 ' is as hereinabove defined for R 3 with the proviso that R 3 ' does not contain a group that can form an anion under basic conditions; with a carbonyl compound of the formula IV:
• R 3 ' is as hereinabove defined for R 3 with the proviso that R 3 ' does not contain a group that can form an anion under basic conditions; with an enol ether of formula VIII:
• R is cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-18 carbon atoms having from 1 to 3 triple bonds; or -SiR 8 R 9 R 10 ; and
• R 8 , R 9 , and R 10 are each, independently, aryl; 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O and S; cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-18 carbon atoms having from 1 to 3 triple bonds; or two of R 8 , R 9 , and R 10 taken together with the silicon atom to which they are attached form a heterocyclic ring of 5 or 6 members; in the presence of a Lewis acid or fluoride reagent in an ether organic solvent at temperatures ranging from about -78 °C to about room temperature ( eg up to about 15-30°C to produce an alpha-sulfonyl carbonyl compound of formula V:
• X is hydrogen, or alkyl of 1-6 carbon atoms
• R 3 is alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms having 1 to 3 double bonds, alkynyl of 2-18 carbon atoms having from 1 to3 triple bonds, cycloalkyl of 3-6 carbon atoms, 5-10 membered cycloheteroalkyl, aryl of 6 to 10 carbon atoms, 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O, and S; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl of R 3 may optionally be substituted on any atom capable of substitution with from 1 to 3 substituents selected from halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-6 carbon atoms having from 1 to 3 triple bonds, cycloalkyl of 3-6 carbon
• R 4 is hydrogen; aryl; aralkyl, heteroaryl; heteroaralkyl, alkyl of 1-6 carbon atoms; cycloalkyl of 3-6 carbon atoms; -C(O) n R 5 , -CONR 5 R 6 or SO 2 R 5 ;
• R 5 and R 6 are each independently hydrogen, optionally substituted aryl; 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O and S; cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms or alkynyl of 2-18 carbon atoms; or R 5 and R 6 taken together with the nitrogen atom to which they are attached may form a 5-10 membered cycloheteroalkyl ring; and
• n 1 or 2; or pharmaceutical salts thereof, comprising the steps of a) treating a compound of formula
• step b) hydrolyzing the compound of step b) to produce
• XONHY VII in the presence of coupling reagent and polar organic solvent at temperatures ranging from 0°C to about room temperature, eg up to about 15-30°C.
• ⁇ is hydrogen; aryl; aralkyl, heteroaryl; heteroaralkyl, alkyl of 1-6 carbon atoms; cycloalkyl of 3-6 carbon atoms; -C(O)trustR 5 , -CONR 5 R 6 or SO 2 R 5 ;
• R 5 and R 6 are each independently hydrogen, optionally substituted aryl; 4-8 membered heteroaryl having 1-3 heteroatoms selected from N, NR 4 , O and S; cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms or alkynyl of 2-18 carbon atoms; or R 5 and R 6 taken together with the nitrogen atom to which they are attached may form a 5-10 membered cycloheteroalkyl ring; and
• R p is methyl, n-butyl, 2-butynyl, or p-chlorophenyl; and n is 1 or 2; or pharmaceutical salts thereof, comprising the steps of : a) treating a compound of formula
• R Pain R 2 and R 3 ' are as previously defined and Z is H, OH, YNOX, OR 5 or NR 5 R 6 , comprising reacting a sulfonyl fluoride of the formula III
• R protest R, and R 3 ' are as previously defined and Z is H, OH, YNOX, OR 5 or NR 5 R 6 , comprising reacting a sulfonyl fluoride of the formula III
• Z is H, OH, YNOX, OR 5 or NR 5 R 6 , and R, and R 2 , are as hereinabove defined;
• R 7 is cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl: alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-18 carbon atoms having from 1 to 3 triple bonds; or -SiR 8 R,,R 10 ; and R 8 , R, and R 10 are each, independently, aryl; 4-8 membered heteroaryl having
• heteroatoms selected from N, NR 4 , O and S; cycloalkyl of 3-6 carbon atoms; 5-10 membered cycloheteroalkyl; alkyl of 1-18 carbon atoms; alkenyl of 2-18 carbon atoms having from 1 to 3 double bonds; alkynyl of 2-18 carbon atoms having from 1 to 3 triple bonds; or two of R 8 , R 9 , and R 1Q taken together with the silicon atom to which they are attached form a heterocyclic ring of 5 or 6 members; in the presence of a Lewis acid or fluoride reagent in an ether organic solvent at temperatures ranging from about -78 °C to about room temperature (eg up to from about 15°C to about 30°C) to produce an alpha-sulfonyl carbonyl compound of formula V.
• a Lewis acid or fluoride reagent in an ether organic solvent at temperatures ranging from about -78 °C to about room temperature (eg up to from about 15°C
• compounds of Formula V may be converted to a hydroxamic acid derivative of Formula I in accordance with the steps of reacting the alpha-sulfonyl carbonyl compound of the formula V with an alkali metal hydroxide in the presence of water, and/or ether organic solvent or alcohol at temperatures ranging from about 0 °C to about 100°C to produce a carboxyhc acid of the formula VI:
• compounds of Formula V when Z is OH, compounds of Formula V may be converted to a hydroxamic acid derivative by reacting the alpha- sulfonyl carbonyl compound of formula V: with a hydroxylamine or hydroxylamine derivative of the formula VII:
• XONHY VII wherein X and Y are as hereinabove defined; in the presence of a coupling reagent and polar organic solvent at temperatures ranging from about 0°C to about room temperature (eg up to from about 15°C to about 30°C).
• sulfonyl fluoride compounds of Formula III can be prepared by reacting a sulfonyl chloride of formula II
• R 3 ' is as hereinabove defined for R 3 the proviso that R 3 ' does not contain a group that can form an anion under basic conditions, with a fluorinating agent in the presence of a polar organic solvent at room temperature (eg at about 15 °C to about 30°C) to produce a sulfonyl fluoride of formula III.
• a fluorinating agent in the presence of a polar organic solvent at room temperature (eg at about 15 °C to about 30°C) to produce a sulfonyl fluoride of formula III.
• Further chemical transformations can be carried out before or after each step for compounds of the formula I, V, and VI in cases where R ,, R 2 or R 3 of the product differs from R,, R, or R 3 ' of the starting compound.
• R 3 ' Groups which may form an anion under basic conditions of the invention and thus are excluded from the definition of R 3 ', include, but are not limited to -OH, -NH, -SH, -COCH, -SO 2 CH, -CHNO 2 , CHCN. Accordingly, during the sulfonylation of the carbonyl compound, such substituents at R 3 should be avoided or protected and released later by deprotection, as designated by R 3 '.
• Sulfonyl chloride compounds of the present invention are commercially available or can be prepared by those skilled in the art in accordance with procedures described in the literature such as Kende, A.S.; Medoza, J.S., J. Org. Chem., 1990, 55, 1125-1126.
• Preferred ether organic solvents of the present invention are those known to those skilled in the art including, but not limited to tetrahydrofuran, diethylether or dioxane.
• Bases used in methods of the present invention are those known to those skilled in the art, preferably metal hydride or amide bases, such as, but not limited to of lithiumdiisopropylamide, lithiumhexamethyldisilazide, and sodium hydride.
• Lewis acids and fluoride reagents used in methods of the present invention are known to those skilled in the art and include, but are not limited to borontribromide, tetrabutylammonium and sodium hydride.
• Polar organic solvents useful in methods of the present invention are known to those skilled in the art and include, but are not limited to acetonitrile, tetrahydrofuran and dimethylformamide.
• Alkali metal hydroxides used in preferred methods of the present invention are known to those skilled in the art and include, but are not limited to lithium hydroxide and sodium hydroxide.
• Alcohols used in some methods of the present invention are known to those skilled in the art and include, but are not limited to methanol and ethanol.
• Coupling reagents of the present invention are those known to those skilled in the art including, but not limited one or more of l-(3-dimethylaminopropyl)-3- ethylcarbodimide hydrochloride, N-hydroxybenzotriazole, N-methylmorpholine and oxalylchloride and triethylamine.
• the present invention further relates to low molecular weight, non-peptide inhbitors of matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) for the treatment of rheumatoid arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes and HIV infection.
• MMPs matrix metalloproteinases
• TACE TNF-alpha converting enzyme
• X is hydrogen and alkyl of 1-6 carbon atoms; and Y, R 3 and R are as previously defined, and pharmaceutical salts thereof. Particularly preferred is l-Benzyl-3-(4-methoxybenzenesulfonyl)piperidine- 3-carboxylic acid hydroxamide, or pharmaceutical salts thereof.
• Certain compounds prepared by the novel method of the present invention contain one or more asymmetric carbon atoms, giving rise to enantiomeric and diastereomeric forms of the compounds.
• certain compounds of this invention contain a carbon-carbon double bond, giving rise to cis- and trans- geometric isomers. It is to be understood that the invention encompasses the enantiomers, diastereomers, and geometrical isomers as well as mixtures thereof including racemic mixtures.
• Alkyl refers to branched and straight chain alkyl groups, preferably having from 1 to 18 carbon atoms, and more preferably from 1 to 6 carbon atoms.
• Exemplary alkyl groups include methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, n-heptyl, octyl and the like.
• Alkenyl refers to alkenyl groups, preferably having from 2-18 carbon atoms and more preferably from 2 to 6 carbon atoms, and having from 1 to 3 sites of alkenyl unsaturation (double bond).
• Alkynyl refers to alkynyl groups, preferably having from 2-18 carbon atoms and more preferably from 2 to 6 carbon atoms, and having from 1 to 3 sites of alkynyl unsaturation (triple bond).
• Cycloalkyl refers to cyclic alkyl groups of from 3 to 8 carbon atoms, and more preferably from 3-6 carbon atoms, including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
• Heteroaryl is a 5-10 membered mono- or bicyclic aromatic carbocyclic ring having from 1-3 heteroatoms selected from N, NR 4 , S and O within the ring.
• Such heteroaryl groups can have a single ring (e.g. pyridyl or furyl) or multiple condensed rings (e.g. benzothienyl), which condensed ring may or may not contain a heteroatom.
• Heteroaryl is preferably
• heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole.
• Heteroaryl groups of the present invention may have from 1 to 3 substituents, and more preferably may have one or two substituents.
• cycloheteroalkyl is a saturated or unsaturated group having a single ring or multiple condensed rings, from 2 to 10 carbon atoms and from 1 to 3 heteroatoms selected from S, N, O, or NR 4 within the ring, wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl.
• Preferred cycloheteroalkyl are
• K is O, N, S or NR 4 ; and R 4 is as hereinabove defined.
• the rings above shown as mono-radicals may also be illustrated as di-radicals eg when R, and R 2 together form a cycloheteroalkyl ring.
• Preferred cycloheteroalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. Cycloheteroalkyl groups of the present invention may optionally be mono-, di- or tri substituted.
• Aryl refers to an unsaturated, aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring (phenyl) or multiple condensed rings (naphthyl), which condensed rings may or may not be aromatic.
• Preferred aryls include phenyl and naphthyl.
• Aryl groups may optionally be mono-, di- or tri- substituted.
• Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties.
• Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted (carbons bonded to hydrogen or other carbons in the chain or ring) or may be mono- or poly-substituted.
• Halogen means bromine, chlorine, fluorine, and iodine.
• Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include, but are not limited to halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -OR 5 , -CN, -COR 5 perfluoroalkyl of 1-4 carbon atoms, -O-perfluoroalkyl of 1-4 carbon atoms, -CONR 5 R 6 ,-S(O) n R 5 , -OPO(OR 5 )OR 6 , -PO(OR 5 )R 6 , -OC(O)OR 5 , -OC(O)NR 5 R 6 , -C(O)NR 5 OR 6 , -COOR 5 , -SO 3 H, -NR 5 R
• a cycloheteroalkyl ring such as pyrrolidine, piperidine, morpholine, thiomorpholine, o
• Pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane- sulfonic, and similarly known acceptable acids.
• examples of Z are preferably OH or OR for example where R 5 is alkyl (preferably 1-6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl and pentyl).
• R is preferably an optionally substituted aryl group, e.g. a phenyl group, most preferably a 4-substituted phenyl group.
• the aryl group is preferably substituted by one or more -OR 5 groups, e.g. where R 5 is is alkyl (preferably 1-6 carbon atoms, eg methyl, ethyl, propyl, isopropyl, butyl or pentyl), alkynyl (preferably 2-7 carbon atoms) or optionally substituted aryl, eg where the substituents are selected from Cr C 6 -alkyl, -C ⁇ -alkoxy and halogen, such as chlorine.
• Ri and R 2 together with the carbon atoms to which they are attached preferably form a 5-10 membered heteroalkyl ring, eg having 1-3 heteroatoms selected from N, NR , O and S, most preferably a ring containing a single NR group, e.g. a six membered piperidine ring. They preferably form a 3,3 di-substituted, 4,4- di-substituted, 1,3,3 tri-substituted or 1,4,4-tri-substituted piperidine.
• R are hydrogen, alkyl of 1-6 carbon atoms, -COR5.
• -COOR 5 -SO 2 R 5 and optionally substituted benzyl (eg 4-chlorobenzyl, 4-methoxybenzyl or 4- (2-piperidin- 1 -yl-ethoxy )benzyl) .
• benzyl eg 4-chlorobenzyl, 4-methoxybenzyl or 4- (2-piperidin- 1 -yl-ethoxy )benzyl
• R 5 are an optionally substituted alkyl of 1-18 carbon atoms (such as methyl, trifluoromethyl), an optionally substituted alkenyl of 2-18 carbon atoms, an optionally substituted aryl (such as phenyl), an optionally substituted 4-8 membered heteroaryl (such as pyridyl, thienyl) or an optionally substituted 5-10 membered cycloheteroalkyl (such as pyrrolyl); preferably R 5 is methyl, ethyl, n-butyl, t-butyl, but-2-ynyl, 4-chlorophenyl, 4-methoxyphenyl, 1-pyrrolidinyl, 3, pyridinyl, 2- thienyl, 2,2,5-trimethyl-l,3-dioxan-5-yl or 2-hydroxy-l-(hydroxymethyl)-l -methyl- ethyl.
• R 5 is methyl, ethyl, n
• Typical optional substituents as used herein include C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, CrC ⁇ haloaikyl and halogen.
• the present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.
• the present invention provides a pharmaceutical composition which comprises an effective amount of compound of this invention and a pharmaceutically acceptable carrier.
• compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients.
• a composition of the invention is in the form of a unit dose.
• Suitable unit dose forms include tablets, capsules, and powders in sachets or vials.
• Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention.
• the compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg per kg.
• Such composition may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
• compositions of the invention may be formulated with conventional excipients, such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner.
• excipients such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner.
• DETAILED DESCRIPTION OF THE INVENTION Several synthetic routes can be employed to prepare the compounds of formula I, using alpha-sulfonylation of the enolisable carbonyl compound as the key step in the process. Several preferred routes for the preparation of these compounds are described in schemes I-III. Although, each sequence is illustrated with a compound of formula I, wherein X and Y are hydrogen, R 3 is aryl.
• additional compounds of this invention can be prepared in the same manner using the appropriate starting materials and routes as would be appreciated by one skilled in the art and illustrated by the specific examples.
• the reagents and the solvents for the individual step are given for illustrative purposes only and may be replaced by other reagents and solvents known to those skilled in the art.
• step 1 sulfonyl chlo ⁇ de 1, wherein R p is methyl, n-butyl, 2- butynyl, or p-chlorophenyl, is treated with a potassium fluoride-calcium fluoride mixture (either commercially available or prepared according to the procedure by Ichihara) in acetonitrile at room temperature to obtain the sulfonyl fluoride 2
• step 2 the enolate prepared from the ester 3 (prepared by treating commercially available Boc-isonipecotic acid with methyl iodide/potassium carbonate ) and lithium dnsopropylamide (LDA) (prepared in situ using n-butyl lithium and dusopropylamine) is treated with compound 2 at -78°C-25°C to obtain the compound 4
• step 3 the protecting group, t-butoxycarbonyl, is cleaved with t ⁇ fluoroacetic acid in t ⁇ fluoroethanol to obtain the
• R 4 is introduced by treating compound 5 with R 4 L, wherein L is a leaving group such as but not limited to halogen, in the presence of other reagents such as triethylamine and the solvents known to those skilled in the art, to obtain compound 6
• step 5 the ester 6 is hydrolyzed with lithium hydroxide at 50 °C or sodium hydroxide for 15 hours to obtain acid 7
• step 6 compound 7 is treated with N-hydroxybenzot ⁇ azole, l-(3-d ⁇ methyl- am ⁇ nopropyl)-3-ethylcarbod ⁇ m ⁇ de hydrochloride, N-methylmorphohne, and aqueous hydroxylamine to obtain the desired hydroxamic acid 8
• step 3 ⁇ - j step 4 The target compounds can also be obtained by changing the order of transformations carried out for compound 4 as shown in the Scheme II.
• step 1 the compound 4 is treated with lithium hydroxide as in Scheme I, step 5, to obtain the N-protected carboxyhc acid 9.
• step 2 the acid 9 is treated with oxalyl chloride, triethylamine, and hydroxylamine hydrochloride in dimethylformamide to obtain N-protected hydroxamic acid 10, which is then deprotected with 4M hydrochloric acid in dioxane to give the salt 11 in step 3.
• step 4 is introduced selectively using the conditions in Scheme I, step 4 to obtain the hydroxamic acid 8.
• step 4 step 5
• the target compounds can be obtained by following the synthetic sequence of Scheme III.
• step 1 sulfonyl fluoride 2 is obtained by treating sulfonyl chloride 1 with either potassium fluoride or cesium fluoride in acetonitrile. Alternatively, this reaction is carried out in tetrahydrofuran and the resulting solution is used for the next step without isolation of the sulfonyl fluoride.
• R 4 as hereinabove defined is introduced early in the sequence by treating starting material such as ethyl isonipecotate R 4 L, wherein L is a leaving group such as but not limited to halogen, in the presence of appropriate reagents such as triethylamine with commercially available ethyl isonipecotate.
• starting material such as ethyl isonipecotate R 4 L, wherein L is a leaving group such as but not limited to halogen
• step 3 enolate prepared by reacting the compound 12 with lithium diisopropylamide or lithium hexamethyldisilazide, is treated with the fluoride 2 to obtain the compound 13.
• step 4 ester 13 is hydrolyzed with lithium hydroxide to give acid 14.
• step 3 and step 4 are carried out sequentially as a one-pot process without isolation of the ester 13.
• step 5 acid 14 is treated with oxalyl chloride, triethylamine, and hydroxylamine hydrochloride as in the Scheme II, step 2, to obtain the compound 8.
• oxalyl chloride, triethylamine, and hydroxylamine hydrochloride as in the Scheme II, step 2, to obtain the compound 8.
• Method B To a solution of the sulfonyl chloride (1 equiv) in acetonitrile was added potassium fluoride (2 equiv). The resulting suspension was stirred for 18 hours at 20-25 °C. The suspension was filtered and the solid was washed with diethylether. The mother liquor was concentrated in vacuo and resulting oil was seeded to give the product as a white crystalline solid.
• Method C To a solution of the sulfonyl chloride (1 equiv) in acetonitrile was added cesium fluoride (2 equiv). The resulting suspension was stirred for 18 hours at 20- 25°C. The suspension was filtered and the solid washed with diethylether. The mother liquor was concentrated in vacuo and resulting oil was seeded to produce the product as a white crystalline solid.
• Method D The solution of sulfonyl chloride (1 equiv) in tetrahydrofuran was mixed with potassium fluoride (2 equiv) and stirred for 30 hours at 20- °C. The suspension was filtered and the solid was washed with tetrahydrofuran. This solution was used for the next step without isolation.
• the organic layer was separated and washed successively with IN aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water.
• the organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to obtain the product.
• step 1 The general procedure for step 1 was followed using lithium diisopropylamide (70 mmol), product from Example 2 (15.5g, 64 mmol), and the product from Example 1 (70 mmol) to obtain 24.5g(85%) of the product as a white solid.
• IR 2978, 2242, 1740, 1697, 1594, 1418, 1301, 1002, 908cm "1 ; 'H NMR(300 MHz, CDCl 3 ): ⁇ 1.44(s, 9H), 1.87(m, 3H), 1.98(m, 2H).
• step 3 The general procedure for step 3 was followed using the product from Example 3 (15g, 33.2 mmol) in water (100 ml), methanol (50 ml), tetrahydrofuran
• step 4 The general procedure for step 4 was followed using dimethylformamide (3.53 ml, 46 mmol), oxalyl chloride (22.9 ml of a 2.0M solution in dichloromethane), the product from Example 4 (lOg, 22.9 mmol), hydroxylamine hydrochloride (16g, 229 mmol), and triethylamine (48 m, 344 mmol) to obtain the product as a white powder 6.3g (61%).
• step 1 The general procedure for step 1 was followed using lithium diisopropylamide (2.31 mmol), the product from Example 1 (510 mg, 2.1 mmol), and the product from Example 7 (600 mg, 2.2 mmol) to obtain 520 mg (49%) of the product as a solid.
• step 3 The general procedure for step 3 was followed using the product from Example 8 (450 mg, 0.88 mmol) and lithium hydroxide (32 mg, 1.32 mmol) in tetrahydrofuran (3 ml)/methanol (3 ml)/water (2 ml) at 55°C for 15 hours to obtain
• step 4 was followed using the product from
• Example 9 (350 mg, 0.71 mmol) in dimethylformamide (7 ml), hydroxybenzotriazol (114 mg, 0.85 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (190 mg, 0.99 mmol), N-methylmorpholine (117 uL, 1.06 mmol), and 50% aqueous hydroxylamine (217 uL, 3.55 mmol) to obtain 150 mg (41%) of the product.
• IR 3739, 3382, 2931, 1664, 1484, 1249, 1150 cm "1 .
• step 1 The general procedure for step 1 was followed using lithium diisopropyl- amide (28 mmol), product from Example 12 (5.3g, 28 mmol), and product from Example 13 (5.3g, 28 mmol) to obtain 7.2g (60%) of the product.
• step 3 The general procedure for step 3 was followed using the product from
• Example 16 (1.7g, 4.0 mmol), sodium hydroxide (ION, 3ml), methanol (10 ml) and tetrahydrofuran (10 ml) at 50°C for 2 hours to obtain 1.13 g (67%) of the product, mp
• the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of methylene chloride and added slowly to the hydroxylamine solution at O°C.
• the reaction mixture was stirred at room temperature for 24 hours and concentrated.
• the residue obtained was extracted with chloroform and washed well with water.
• the product obtained was purified by silica gel column chromatography; eluted with 2% methanohchloroform.
• the product was converted to the hydrochloride salt by dissolving in methanol (10 ml) at 5°C and adding saturated hydrogen chloride in methanol (5ml).
• step 3 The general procedure for step 3 was followed using the product from Example 21 (3.2g, 8.0 mmol) in tetrahydrofurammethanol (15:25 ml), and sodium hydroxide (15 ml) at 50°C for 2 hours to obtain 2.1 lg (71%) of the product as a white solid: mp 159.2°C.
• Example 25 3- ⁇ r4-(2-Butynyloxy)phenyll sulfonyl 1 - 1 -(4-chlorobenzyl)-3-piperidinecarboxylic acid
• step 3 The general procedure for step 3 was followed using the product from
• Example 24 (1.64g, 8.0 mmol) in tetrahydrofurammefhanol (15:50 ml) and sodium hydroxide (15 ml) at 50°C for 2 hours to obtain 1.1 lg (75%) of the product as a white solid, mp l l5.2°C.
• the reaction mixture was quenched with water and warmed to 20 - 25°C while stirring for 0.5 hour.
• the organic solvent was removed by distillation (50 mm Hg, 35°C) forming an oily layer on the bottom of the flask.
• Lithium hydroxide (15.5g, 370 mmol) and methanol (150 ml) were added and the reaction mixture was heated at reflux temperature overnight (70 °C).
• the reaction mixture was clarified by filtration through filter paper to remove a small amount of gel-like insoluble material.
• the acid chloride suspension was added, over a 20 minute period, to a cooled solution of powdered hydroxylamine hydrochloride (175.0g, 2.51 mol) and triethylamine (330.9g, 3.27 mol) in acetonitrile (2.5 L), which had been stirring for 3-5 hours at room temperature.
• the reaction temperature should not exceed -8° C.
• the reaction mixture was concentrated to afford an off-white residue. To the residue ethyl acetate (2.0 L) and water (2.0 L) were added, and the mixture was stirred for 15-20 minutes.
• Example 35 The crude product from Example 35 (130.4g, 0.260 mol) was dissolved in ethyl acetate (350 ml) and conncentrated hydrochloric acid (31.3 ml, 0.313 mol) was added over a 20 minute period. Salts precipitated out of solution and the mixture was cooled in an ice bath at 2°C for 30 minutes. The mixture was filtered, washed with cold (0°C) ethyl acetate (50 ml x 2), dried in an oven for 18 hours to give the product 118.6g, (85%). This compound was recrystallized as follows:
• the white crystals were collected, washed with cold ethanol (100 ml x 2), dried in vacuo at 60°C with a nitrogen bleed for l ⁇ hours to give 89.23g, (75%) of the desired product as crystals, m.p. 233-235°C.
• step 4 The general procedure for step 4 was followed using product from Example 39 (180 mg, 0.48 mmol) in dimethylformamide (4 ml), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (127 mg, 0.66 mmol), N-methylmorpholine (0.078 ml, 0.71 mmol), and hydroxylamine (0.145 ml, 2.37 mmol) to obtain 100 mg (53%) of the product as a solid.
• step 3 The general procedure for step 3 was followed using product from Example 41 (300 mg, 0.66 mmol) in 4 ml of tetrahydrofuramwater (3:1), and lithium hydroxide (18 mg, 0.75 mmol) to obtain 250 mg(86%) of the acid.
• step 4 The general procedure for step 4 was followed using product from Example 42 (100 mg, 0.23 mmol) in dimethylformamide (2 ml), 1-hydroxybenzotriazole (36 mg, 0.27 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol), N-methylmorpholine (0.038 ml, 0.35 mmol) and hydroxylamine (0.083 ml, 1.15 mmol) to obtain 40 mg (38%) of the product as a solid.
• MS-ES m/z 457.2 (M+H) + .
• step 3 The general procedure for step 3 was followed using product from Example 44 (250 mg, 0.52 mmol) in 4 ml of tetrahydrofurammethanol (1 :1) and IN sodium hydroxide (1.03 ml, 1.03 mmol) to obtain 150 mg(62%) of the acid.
• step 4 The general procedure for step 4 was followed using product from Example 45 (90 mg, 0.19 mmol) in dimethylformamide (2 ml), 1-hydroxybenzotriazole (31 mg, 0.23 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol), N-methylmorpholine (0.031 ml, 0.28 mmol) and hydroxylamine (0.068 ml, 0.95 mmol) to obtain 70 mg (76%) of the product as a solid.
• HR - MS m/z Calculated for C 24 H 26 N 2 O.S 487.1534; Found 487.1531.
• step 3 The general procedure for step 3 was followed using product from Example 47 (400 mg, 0.89 mmol) in 4 ml of tetrahydrofuran: methanol; water (1: 1:0.5) and lithium hydroxide (48 mg, 2.0 mmol) to obtain 300 mg(78%) of the acid.
• step 4 The general procedure for step 4 was followed using product from Example 48 (255 mg, 0.23 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (96 mg, 0.71 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), N-methylmorpholine (0.099 ml, 0.84 mmol) and hydroxylamine (0.181 ml, 2.8 mmol) to obtain 150 mg (60%) of the product as a solid.
• Example 50 1 -Ethyl 4-methyl 4-(4-but-2-vnyloxybenzenesulfonyl)- 1 ,4-piperidinedicarboxylate
• step 3 The general procedure for step 3 was followed using product from Example 50 (400 mg, 0.95 mmol) in 8 ml of tetrahydrofuran: methanol: water (1:1:0.5) and lithium hydroxide (50 mg, 2.04 mmol) to obtain 340 mg(88%) of the acid.
• Example 52 Ethyl 4-(4-but-2-vnyloxybenzenesulfonyl)-4-F(hydroxyamino)carbonvH-l- piperidinecarboxylate
• step 4 The general procedure for step 4 was followed using product from Example 51 (225 mg, 0.55 mmol) in dimethylformamide (5 ml), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), N-methylmorpholine (0.091 ml, 0.86 mmol) and hydroxylamine (0.168 ml, 2.75 mmol) to obtain 150 mg (64%) of the product as a solid.
• HR - MS m/z Calculated for C 19 H 24 N 2 O 7 S 425.1377; Found 425.1375.
• step 3 The general procedure for step 3 was followed using product from Example 53 (225 mg, 0.47 mmol) in 5 ml of tetrahydrofuran: methanol; water (1: 1 :0.5) and lithium hydroxide (24 mg, 0.98 mmol) to obtain 175 mg (80%) of the acid.
• step 4 The general procedure for step 4 was followed using product from Example
• step 3 The general procedure for step 3 was followed using product from Example 56 (430 mg, 0.94 mmol) in 8 ml of tetrahydrofuran: methanol (1:1) and IN sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 235 mg(57%) of the acid.
• HR - MS m/z Calculated for C 22 H 22 N 2 O 6 S 443.1271; Found 443.1270.
• Example 58 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1 -(3-pyridinylcarbonyl)- 4- piperidinecarboxamide
• step 4 The general procedure for step 4 was fo llowed using product from Example
• step 3 The general procedure for step 3 was followed using product from Example
• step 4 The general procedure for step 4 was followed using product from Example 60 (335 mg, 0.75 mmol) in dimethylformamide (7 ml), 1-hydroxybenzotriazole (121 mg, 0.90 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol) and hydroxylamine (0.229 ml, 3.75 mmol) to obtain 216 mg (62%) of the product as a solid.
• step 3 The general procedure for step 3 was followed using product from Example
• step 4 The general procedure for step 4 was followed using product from Example
• step 4 The general procedure for step 4 was followed using product from Example 37 (500 mg, 1.29 mmol) in dimethylformamide (10 ml), (2,2,5-trimethyl-l,3-dioxan- 5-yl)carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (346 mg, 1.81 mmol) and N-methylmorpholine (0.212 ml, 1.94 mmol) to obtain 385 mg (59%) of the product as a solid.
• step 3 The general procedure for step 3 was followed using product from Example
• step 4 The general procedure for step 4 was followed using product from Example 66 (280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.68 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol) and hydroxylamine (0.174 ml, 2.85 mmol) to obtain 180 mg (62%) of the product as a solid.
• HR - MS m/z Calculated for C 24 H 32 N 2 O 8 S 531.1771; Found 531.1768.
• the subject compounds of the present invention may be tested for biological activity according to the following procedures.
• the assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu-Gly(2 mercapto-4 methyl-pentanoyl)-Leu-Gly-OEt), Bachem Bioscience) by the enzyme, gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)).
• DTNB (5,5'-dithio-bis(2-nitro-benzoic acid)
• the thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl 2 ) before use.
• substrate buffer 50 mM HEPES pH 7.5, 5 mM CaCl 2
• the stock of human neutrophil gelatinase B is diluted with assay buffer (50 mM HEPES pH 7.5, 5 mM CaCl 2 , 0.02% Brij) to a final concentration of 0.15 nM.
• the assay buffer, enzyme, DTNB/substrate (500 ⁇ M final concentration) and vehicle or inhibitor are added to a 96 well plate (total reaction volume of 200 ⁇ l) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
• the increase in OD 405 is plotted and the slope of the line is calculated which represents the reaction rate.
• the assay is based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly- Cys(Me)-His-Ala-Lys(NMa)-NH2), Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which is quantitated on the fluorometer. Dnp quenches the NMa fluorescence in the intact substrate.
• HCBC assay buffer 50 mM HEPES, pH 7.0, 5 mM Ca +2
• the reaction is read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.
• the linearity of the reaction rate is confirmed (r 2 >0.85).
• the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test.
• Dose-response relationships can be generated using multiple doses of drug and IC 50 values with 95% CI are estimated using linear regression (IPRED, HTB) .
• the reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate.
• the linearity of the reaction rate is confirmed (r 2 >0.85).
• the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug- treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC 50 values with 95% CI are estimated using linear regression.
• Example 18 The compound of Example 18 was found to inhibit MMPs and TACE as follows: TACE inhibition (atlOuM) : 54%; MMP1 (1C50): 1.3uM;
• compounds of the present invention are useful inhibitors of MMPs and TACE.
• compositions of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
• the pharmaceutical carrier may be solid or liquid.
• Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable pharmaceutical additives such as a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
• Oral administration may be either liquid or solid composition form.
• the compounds of this invention may be administered rectally in the form of a conventional suppository.
• the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
• the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
• the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
• the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
• Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
• the dosage to be used in the treatment of a specific patient suffering from a disease or condition in which MMPs and TACE are involved must be subjectively determined by the attending physician.
• Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
• the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

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• 2001
  • 2001-01-25 AU AU2001233034A patent/AU2001233034A1/en not_active Abandoned
  • 2001-01-25 CN CN01804199A patent/CN1400968A/zh active Pending
  • 2001-01-25 WO PCT/US2001/002669 patent/WO2001055112A1/en not_active Application Discontinuation
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  • 2001-01-25 JP JP2001555054A patent/JP2003520852A/ja active Pending
  • 2001-01-25 EP EP01905121A patent/EP1252143A1/en not_active Withdrawn
  • 2001-01-25 MX MXPA02007291A patent/MXPA02007291A/es unknown
  • 2001-01-25 CA CA002398561A patent/CA2398561A1/en not_active Abandoned
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