The invention relates to compounds of the formula 1:

The present invention relates to compounds that inhibit metalloproteinases, particularly matrix metalloproteinases and tumor necrosis factor-xcex1 convertase, and their pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs. The invention further relates to the uses of these compounds, salts and prodrugs for the therapeutic treatment of humans or animals.
Matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) are a family of enzymes, including, but not limited to, collagenases, gelatinases, matrilysin, and stromelysins, which are involved in the degradation and remodelling of connective tissues. These enzymes are found in a number of cell types that are found in or associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology.
Matrix metalloproteinases degrade the protein components of the extracellular matrix, i.e. the protein components found in the linings of joints, interstitial connective tissue, basement membranes, cartilage and the like. These proteins include collagen, proteoglycan, fibronectin and lamanin.
Collagen is the major structural protein of mammalian tissue, comprising one-third of the total protein in mammalian organisms, and is an essential component of many matrix tissues, including cartilage, bone, tendons and skin. Interstitial collagenases catalyze the initial (rate-limiting) cleavage of native collagen types I, II, III and X. These enzymes cleave collagen into two fragments which spontaneously denature at physiological temperature. Denaturation of collagen involves conversion of the rigidly coiled helix to a random coil referred to as gelatin. These gelatin (denatured collagen) fragments are then subject to further cleavage and degradation by less specific enzymes. The net result of collagenase cleavage is thus the loss of structural integrity in the matrix tissue (collagen collapse), an essentially irreversible process.
The gelatinases include two distinct yet highly related enzymes: a 72-kiloDalton (kDa) enzyme and a 92-kiloDalton enzyme. The former is released by fibroblasts while the latter is released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. Both enzymes degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectins (high molecular weight multifunctional glycoproteins found in soft connective tissue and basement membranes) and insoluble elastin (highly cross-linked hydrophobic proteins found in load bearing fibers of mammalian connective tissue).
Stromelysins (1 and 2) cleave a broad range of matrix substrates, including lamanin, fibronectins, proteoglycans and collagen types IV and IX (non-helical).
Matrilysin (putative metalloproteinase or PUMP) also degrades a wide variety of matrix substrates, including proteoglycans, gelatins, fibronectins, elastins and lamanin. Matrilysin has been found in mononuclear phagocytes, rat uterine explants and tumor cells.
In normal tissues, the activity of matrix metalloproteinases is tightly regulated. As a result, the breakdown of connective tissue mediated by these enzymes is generally in a dynamic equilibrium with synthesis of new matrix tissue.
In a number of pathological disease conditions, however, deregulation of matrix metalloproteinase activity leads to the uncontrolled breakdown of extracellular matrix. These disease conditions include arthritis (e.g., rheumatoid arthritis and osteoarthritis), periodontal disease, aberrant angiogenesis, tumor metastasis and invasion, tissue ulceration (e.g., corneal ulceration, gastric ulceration or epidermal ulceration), bone disease, HIV-infection and complications from diabetes.
Administration of matrix metalloproteinase inhibitors has been found to reduce the rate of connective tissue degradation, thereby leading to a favorable therapeutic effect. For example, in Cancer Res., vol. 53, p. 2087 (1993), a synthetic matrix metalloproteinase inhibitor was shown to have in vivo efficacy in a murine model for ovarian cancer with an apparent mode of action consistent with inhibition of matrix remodelling. The design and uses of MMP inhibitors are reviewed, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 5, 1287-1296 (1995); and Drug Discovery Today, 1, 16-26 (1996).
Matrix metalloproteinase inhibitors are also the subject of numerous patents and patent applications, including: U.S. Pat. No. 5,189,178; U.S. Pat. No. 5,183,900; U.S. Pat. No. 5,506,242; U.S. Pat. No. 5,552,419; U.S. Pat. No. 5,455,258; European Patent Application No. 0 438 223; European Patent Application No. 0 276 436; WIPO International Publication No. WO 92/21360; WIPO International Publication No. WO 92/06966; WIPO International Publication No. WO 92/09563; WIPO International Publication No. WO 96/00214; WIPO International Publication No. 95/35276; and WIPO International Publication No. WO 96/27583, the disclosures of each of which are incorporated herein by reference.
Tumor necrosis factor-xe2x88x9d (xe2x80x9cTNF-xcex1xe2x80x9d) is a cytokine which is produced as a 28-kDa precursor and released in an active 17-kDa form. This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration of TNF-xcex1 can cause cachexia and anorexia; accumulation of excess of TNF-xcex1 can be fatal.
TNF-xcex1 convertase is a metalloproteinase involved in the biosynthesis of TNF-xcex1. Inhibition of TNF-xcex1 convertase inhibits production of TNF-xcex1.
Since excessive TNF-xcex1 production has been noted in several disease conditions characterized by MMP-mediated tissue degradation, including multiple sclerosis, arthritis and cancer, compounds which inhibit both MMPs and TNF-xcex1 convertase are especially advantageous for the treatment or prophylaxis of disease conditions in which both mechanisms are involved. Although compounds that both inhibit MMPs activity and TNF-xcex1 production have been disclosed in WIPO International Publication Nos. WO 94/24140 and WO 94/02466, the disclosures of which are herein incorporated by reference, there is still a need for effective MMP and/or TNF-xcex1 convertase inhibiting agents.
Because of their beneficial therapeutic effects, there is a need for effective inhibitors of metalloproteinase activity. The present invention is therefore directed to certain compounds that inhibit metalloproteinases, such as MMPs and TNF-xcex1 convertase, their pharmaceutically acceptable prodrugs, salts and solvates, pharmaceutical compositions containing the same and methods of using the same, as well as to method and intermediates useful in their preparation. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description or may be learned from practice of the invention.
To achieve these and other advantages, the present invention provides a compound of formula 1:
wherein Z is O or S; V is a divalent radical which together with C* and N forms a ring having six ring atoms, where each of said ring atoms other than C* and N independently is unsubstituted or substituted by a suitable substituent, and at least one of said other ring atoms is a heteroatom selected from O, N and S, and the remainder are carbon atoms; and Ar is an aryl or heteroaryl group; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Preferred compounds of the formula 1 include those having the formula 1-a:
wherein
W, X and Y are each, independently of one another, CR1,R2, Cxe2x95x90O, S, Sxe2x95x90O, SO2, O, Nxe2x80x94R3, or N+(Oxe2x88x92)xe2x80x94R4, where
R1 and R2 are independently selected from H and a suitable organic moiety, or wherein R1 and R2 together form a cycloalkyl group or a heterocycloalkyl group,
R3 is hydrogen or a suitable organic moiety, and
R4 is an alkyl group,
with the proviso that at least one, but not all, of W, X, and Y are selected from CR1R2 and Cxe2x95x90O,
or a pharmaceutically acceptable prodrug, salt, or solvate thereof.
The invention is also directed to a method of inhibiting the activity of a metalloproteinase, such as an MMP or TNF-xcex1 convertase, by administering a compound of the formula 1 or 1-a, or a pharmaceutically acceptable prodrug, salt or solvate thereof. The invention is further directed to a pharmaceutical composition comprising an effective amount of a compound of the formula 1 or 1-a or a pharmaceutically acceptable prodrug, salt or solvate thereof.
The invention is still further directed to a method for making compounds of the formula 1 or 1-a involving one or more reactions as follows, wherein the variables in the formulas below are defined beginning at page 11:
(1) converting a compound of formula 2:
or a salt or solvate thereof, to a compound of formula 3:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 3;
(2) converting a compound of formula 3 above, or a salt or solvate thereof, to a compound of formula 4:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 4, or a salt or solvate thereof;
(3) converting a compound of formula 2 above, or a salt or solvate thereof, to a compound of formula 4 above, or a salt or solvate thereof, under conditions sufficient to form a compound of formula 4, or a salt or solvate thereof;
(4) converting a compound of formula 5:
or a salt or solvate thereof, to a compound of formula 6:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 6, or a salt or solvate thereof;
(5) converting a compound of formula 6 above, or a salt or solvate thereof, to a compound of formula 7:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 7, or a salt or solvate thereof;
(6) converting a compound of formula 11:
or a salt or solvate thereof, to a compound of formula 7 above, or a salt or solvate thereof, under conditions sufficient to form said compound of formula 7, or a salt or solvate thereof;
(7) converting a compound of formula 5 above, or a salt or solvate thereof, to a compound of formula 11 above, or a salt or solvate thereof, under conditions sufficient to form said compound of formula 11, or a salt or solvate thereof;
(8) reacting a compound of formula 7 above, or a salt or solvate thereof, or a compound of formula 11 above, or a salt or solvate thereof, with a compound of formula 4 above, or a salt of solvate thereof, under conditions sufficient to form a compound of formula 8:
or a salt or solvate thereof;
(9) converting a compound of formula 8 above, or a salt or solvate thereof, to a compound of formula 9:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 9, or a salt or solvate thereof;
(10) converting a compound of formula 4 above, or a salt or solvate thereof, to a compound of formula 9 above, or a salt or solvate thereof, under conditions sufficient to form a compound of formula 9, or a salt or solvate thereof;
(11) converting a compound of formula 7 above, or a salt or solvate thereof, to a compound of formula 9 above, or a salt or solvate thereof, under conditions sufficient to form a compound of formula 9, or a salt or solvate thereof;
(12) converting a compound of formula 9 above, or a salt or solvate thereof, to a compound of formula 10:
or a salt or solvate thereof, under conditions sufficient to form a compound of formula 10, or a salt or solvate thereof; and
(13) converting a compound of formula 7 above, or a salt or solvate thereof, to a compound of formula 10 above, or a salt or solvate thereof, under conditions sufficient to form a compound of formula 10, or a salt or solvate thereof.
In the above-described conversions and reactions, the following definitions apply:
D is N or Cxe2x80x94R,6, wherein R16 is an alkyl group, a cycloalkyl group,
a heterocycloalkyl group, an aryl group, or a heteroaryl group,
Z is O or S,
J is a halogen, 1,2,4-triazolyl, benzotriazolyl or imidazol-1-yl,
R1 and R2 are as defined above, and
Q is a cycloalkyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, or a group of formula
wherein A is C or Si, and R8, R9, and R10 are independently selected from H and any suitable organic moieity, or a salt or solvate thereof,
with the provisos that:
for conversion (1) above, when D is Cxe2x80x94R16, R16 is a heteroaryl group, and
for conversion (4) above, the compound, salt or solvate of formula 6 is not a diester and Q is not methyl, ethyl, isopropyl, n-butyl, xe2x80x94CH2-phenyl,
Additionally, the present invention is directed to compounds of formulas 3, 4, 6, 7, 8, and 9 above. For the compounds, salts and solvates of formula 3 above, when D is Cxe2x80x94R16, R16 is a heteroaryl group. Further, the compound, salt or solvate of formula 6 is not a diester. Additionally, for the compounds, salts, and solvates of formula 6, Q is not methyl, ethyl, isopropyl, n-butyl, xe2x80x94CH2-phenyl,
Preferred embodiments of the above-identified compounds, compositions, and methods are discussed in more detail below following the definitions.
As used in the present application, the following definitions apply, unless otherwise indicated:
An xe2x80x9calkyl groupxe2x80x9d is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i.e., containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
An xe2x80x9cO-alkyl groupxe2x80x9d or xe2x80x9calkoxy groupxe2x80x9d is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.
A xe2x80x9ccycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1. ]heptyl, bicyclo[2.2.1.]hept-2-en-5-yl, bicyclo[2.2.2]octyl, bicyclo[3.2.1.]nonyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl, and the like.
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
An xe2x80x9caryl groupxe2x80x9d is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.
An xe2x80x9cacyl groupxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94Rxe2x80x94 radical, wherein R is any suitable substituent as defined below.
A xe2x80x9csulfonyl groupxe2x80x9d is intended to mean a xe2x80x94S(O)(O)xe2x80x94Rxe2x80x94 radical, wherein R is any suitable substituent as defined below.
The term xe2x80x9csuitable substituentxe2x80x9d is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, groups of formula (A)
wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (B)
wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (C)
wherein Rb and Rc are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (D)
wherein Rd is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, or an acylamino group; and Re is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group, groups of formula (E)
wherein Rf is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (F)
wherein Rg and Rh are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (G)
wherein Ri is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (H), or formula (K), groups of formula (H)
wherein Rj is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula (A), formula (B), formula (C) or formula (D); and wherein Rk is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F), groups of formula (J)
wherein Rl is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula (C), and groups of formula (K)
wherein Rm and Rn are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.
The term xe2x80x9csuitable organic moietyxe2x80x9d is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and groups of formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), and (K), as defined above.
A xe2x80x9chydroxy groupxe2x80x9d is intended to mean the radical xe2x80x94OH.
An xe2x80x9coxo groupxe2x80x9d is intended to mean the divalent radical xe2x95x90O.
A xe2x80x9chalo groupxe2x80x9d or is intended to mean any of the radicals xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I.
A xe2x80x9ccyano groupxe2x80x9d is intended to mean the radical xe2x80x94Cxe2x89xa1N.
A xe2x80x9cnitro groupxe2x80x9d is intended to mean the radical xe2x80x94NO2.
A xe2x80x9ctrialkylsilyl groupxe2x80x9d is intended to mean the radical xe2x80x94SiRpRqRs, where Rp, Rq, and Rs are each independently an alkyl group.
A xe2x80x9ccarboxy groupxe2x80x9d is intended to mean a group of formula (B) wherein Rt is hydrogen.
A xe2x80x9calkoxycarbonyl groupxe2x80x9d is intended to mean a group of formula (B) wherein Rt is an alkyl group as defined above.
A xe2x80x9ccarbamoyl groupxe2x80x9d is intended to mean a group of formula (C) wherein Rt and Rt are both hydrogen.
An xe2x80x9camino groupxe2x80x9d is intended to mean the radical xe2x80x94NH2.
An xe2x80x9calkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NHRu, wherein Ru is an alkyl group as defined above.
A xe2x80x9cdialkylamino groupxe2x80x9d is intended to mean the radical xe2x80x94NRuRv, wherein Ru and Rv, which are the same or different, are each an alkyl group as defined above.
A xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis to a compound of the formula 1 or 1-a.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula 1 or 1-a.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula 1 or 1-a in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds may exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Additionally preferred is a compound of the formula 1-f:
wherein V is as defined above and Ar is a monocyclic aryl group or monocyclic heteroaryl group, or a pharmaceutically acceptable prodrug or a pharmaceutically acceptable salt thereof. More preferred is a compound having the formula 1-g
wherein W and X are independently selected from CH2, Cxe2x95x90O, S, Sxe2x95x90O, O, Nxe2x80x94R3, and N+(Oxe2x88x92)xe2x80x94R4, where R3 is a hydrogen atom or a suitable substituent, and R4 is a C1-C7 alkyl group, wherein the alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substituents, provided that when W is CH2 or Cxe2x95x90O, X is not CH2 or Cxe2x95x90O; and R1 and R2 are independently selected from a hydrogen atom, a C1-C7 alkyl group, a xe2x80x94C(O)OR17 group, or a xe2x80x94C(O)NR17R18 group, wherein R17 and R18 are independently selected from hydrogen and an alkyl group, and wherein the alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substituents, or R1 and R2 together form a monocyclic cycloalkyl group or a monocyclic heterocycloalkyl group; or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof.
Preferably, in the above formulas 1, 1-a, 1-f, and 1-g, Ar is a monocyclic aryl group or a monocyclic heteroaryl group. When Ar is a monocyclic aryl group, preferably it is unsubstituted or substituted at the meta position and/or the para position with a suitable substituent. Preferably, the substituent is a halogen atom, an aryl or heteroaryl group, an alkoxy group, or an alkyl group, wherein the alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substitutents. Even more preferably, Ar is an aryl group that is substituted at the para position with a halogen atom, an alkoxy group or a monocyclic heteroaryl group. Particularly preferred embodiments of the present invention include those where Ar is 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl 4-(imidazol-1-yl)phenyl or 4-(imidazol-2-yl)phenyl. Preferably when Ar is a monocyclic heteroaryl group, Ar is a pyrid4-yl group.
In formula 1-a, preferably Y is CR1R2, where R1 and R2 are independently selected from H and any suitable organic moiety. Preferably R1 and R2 are independently selected from H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, OR5, SR5, NR5R6, and C(O)R7, where
R5 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or C(O)NR13R14,
where R13 and R14 are independently selected from H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, or R13 and R14, together with the nitrogen atom to which they are attached form a heterocycloalkyl group,
R6 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, C(O)Oxe2x80x94R15, C(O)Sxe2x80x94R15 or SO2-R15,
wherein R15 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group,
R7 is OH, an alkyl group, a cycloalkyl group, a heterocyclolalkyl group, an aryl group, a heteroaryl group, an O-alkyl group, NR13R14, or Oxe2x80x94R15, wherein R13, R14, and R15 are independently as defined above,
or R1 and R2 together form a cycloalkyl group or a heterocycloalkyl group. More preferably R1 and R2 are each a methyl group.
In formulas 1-a and 1-g, preferably R3 is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, C(O)xe2x80x94NR13R14, C(O)xe2x80x94OR15, C(O)xe2x80x94SR15, SO2xe2x80x94R15, or C(O)xe2x80x94R13
where R13 and R14 are independently selected from H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, or R13 and R14, together with the nitrogen atom to which they are attached form a heterocycloalkyl group, and
R15 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
Preferably, when W is CH2 or Nxe2x80x94R3, X is S, Sxe2x95x90O, O, Nxe2x80x94R3, N+(O)xe2x80x94R4 or Cxe2x95x90O. More preferably, when W is CH2, X is O, Sxe2x95x90O or Nxe2x80x94R3, and R3 is a suitable substituent, preferably a hydrogen atom, an alkyl group, wherein said alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substituents, a C(O)xe2x80x94R17 group, a C(O)Oxe2x80x94R17 group, a C(O)NHxe2x80x94R17 group, a C(O)NR17R18 group, an SO2xe2x80x94R19 group, wherein R17 and R18 are each independently an alkyl group wherein said alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substituents, and wherein R19 is a monocyclic aryl group or an alkyl group as defined above. More preferably, R3 is a hydrogen atom, a C1-C7 alkyl group, or a SO2xe2x80x94R19 group, wherein R19 is an alkyl group. Most preferably, when W is CH2, X is O, S, Sxe2x95x900, Nxe2x80x94H, Nxe2x80x94(SO2CH3) or Nxe2x80x94(C1-C7 alkyl).
Alternatively, when W is Nxe2x80x94R3, X is preferably Cxe2x95x90O and R3 is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom.
Particularly preferred embodiments of the present invention include those compounds of the formula 1-a and 1-g where X is S, Sxe2x95x90O, O, Nxe2x80x94R3 or N+(Oxe2x88x92)xe2x80x94R4 and W is CH2; or X is S, O or Nxe2x80x94R3 and W is Cxe2x95x90O; or X is Cxe2x95x90O and W is Nxe2x80x94R3; or X is CH2 and W is O, S or Nxe2x80x94R3, where R3 is a C(O)xe2x80x94R17 group, where R17 is as defined above. According to these preferred embodiments of the present invention, R1 and R2 are preferably, independently of one another, a hydrogen atom or a methyl group, and Ar is preferably an aryl group which is unsubstituted or substituted in the para position with a suitable substituent, preferably a halogen atom, an alkoxy group or a heteroaryl group. More preferably, R1 and R2 are the same and Ar is an aryl group substituted in the para position with a fluorine atom, a chlorine atom, a methoxy group or an imidazolyl group.
Illustrative examples of compounds according to these preferred embodiments of the present invention include, but are not limited to, 3(S)-N-hydroxy-2,2-dimethyl-4-(4-(4-(imidazol-2-yl)phenoxy)benzenesulfonyl)-tetrahydro-2H-1,4-thiazine-3-carboxamide and 3(S)-N-hydroxy-2,2-dimethyl-4-(4-((pyrid-4-yl)oxy)benzenesulfonyl)-tetrahydro-2H-1,4-thiazine-3-carboxamide.
Other preferred embodiments of the present invention include those compounds where Y is Nxe2x80x94R3, where R3 is a C(O)xe2x80x94R17 group, a C(O)Oxe2x80x94R17 group, a C(O)NHxe2x80x94R17 group, a C(O)NR17R18 group, an SO2xe2x80x94R19 group, wherein R17 and R18 are each independently an alkyl group wherein said alkyl group is a straight or branched chain monovalent radical of carbon and hydrogen atoms having no unsaturation, which is optionally substituted by one or more suitable substituents, and wherein R19 is a monocyclic aryl group or an aryl group as defined above.
Also, according to the preferred embodiments of the present invention where X is Nxe2x80x94R3, R3 is a hydrogen atom, an alkyl group or an alkylsulfonyl group, more preferably a hydrogen atom, a methyl group or a methanesulfonyl group. Illustrative examples of compounds according to these preferred embodiments of the present invention include, but are not limited to, (R)-N-hydroxy-1-(4-(4-chlorophenoxy)benzenesulfonyl)-4-(methanesulfonyl)-piperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-fluorophenoxy)benzenesulfonyl)-4-(methanesulfonyl)-piperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-methoxyphenoxy)benzenesulfonyl)-4-(methanesulfonyl)-piperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-chlorophenoxy)benzene-sulfonyl)-4-methylpiperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-fluorophenoxy)-benzenesulfonyl)-4-methylpiperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-chlorophenoxy)benzenesulfonyl)-piperazine-2-carboxamide, (R)-N-hydroxy-1-(4-(4-fluorophenoxy)benzenesulfonyl)-piperazine-2-carboxamide, 3(S)-N-hydroxyl4-(4-(4-chlorophenoxy)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R)-3,3-dimethyl-N-hydroxy-1-(4-(4-chlorophenoxyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-dimethyl-N-hydroxy-1-(4-(4-fluorophenoxyl) benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-dimethyl-N-hydroxy-1-(4-(4-bromophenoxyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-1-(4-(4-(chlorophenoxybenzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R)-1-(4-(4-(fluorophenoxybenzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 3(S)-N-hydroxyl-4-(4-(4-chlorophenylsulfanyl)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 3(S)-N-hydroxyl-4-(4-(4-fluorophenylsulfanyl)benzenesulfonyl-2,2-dimethyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R)-3,3-dimethyl-N-hydroxy-1-(4-(4-fluorophenylsulfanyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-3,3-dimethyl-N-hydroxy-1-(4-(4-chlorophenylsulfanyl)benzenesulfonyl)-piperazine-2-carboxamide, 2(R)-1-(4-(4-(fluorophenylsulfanyl)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R)-1-(4-(4-(chlorophenylsulfanyl)benzenesulfonyl)-N-hydroxy-3,3,4-trimethylpiperazine-2-carboxamide, 2(R),3(S)-N-hydroxyl4-(4-(pyrid4-yl)oxy) benzenesulfonyl)-2-methyl-tetrahydro-2H-thiazine-3-carboxamide, 2(R),3(S)-N-hydroxyl-4-(4-(pyrid-4-yl)sulfanyl)benzenesulfonyl)-2-methyl-tetrahydro-2H-thiazine-3-carboxamide, and a compound of formula:
The inventive compounds may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.
Preferably, the hydroxamate-bearing carbon, i.e., the carbon atom designated with xe2x80x9c*xe2x80x9d in formulas 1-a and 1-g, is in the xe2x80x9cRxe2x80x9d configuration when X is CH2, Cxe2x95x90O, O, Nxe2x80x94R3, or N+(Oxe2x88x92)xe2x80x94R4 and in the xe2x80x9cSxe2x80x9d configuration when X is S or Sxe2x95x90O. It is understood by those skilled in the art that this difference in designating configuration is a consequence of the sequence rules of the Cahn-Ingold-Prelog system. When X is Sxe2x95x90O, the sulfur atom is also preferably in the xe2x80x9cRxe2x80x9d configuration in relation to the preferred xe2x80x9cSxe2x80x9d configuration at the hydroxamate-bearing carbon atom. Thus a preferred compound is a compound of the formula:
wherein X, W, Y, Z, and Ar are as defined above for formula 1-a. As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess (xe2x80x9ce.e.xe2x80x9d) or diastereomeric excess (xe2x80x9cd.e.xe2x80x9d)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.).
In the above described methods and intermediates, for conversions 1, 2, and 8-12 and for compounds 3, 4, 8, 9, and 10 preferably D is N. For conversions 2, 8, and 10 and for compound 4, preferably J is Cl. Particularly preferred intermediates of formula 4 useful in conversions 2, 8, and 10 are salts of formulas 4a and 4b:
For conversions 5 and 6 and 8-13 and for compounds 7, 8, and 9, when Q is a group of formula:
and A is C, preferably R8 is H, an alkyl group, an O-alkyl group, an S-alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, Cxe2x89xa1N, or C(O)R11, wherein R11 is an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group, or a heterocycloalkyl group, and R9 and R10 are independently selected from H, an alkyl group and an aryl group. For these same conversions and compounds, when A is Si, preferably R8, R9 and R10 are independently selected from an alkyl group, a cycloalkyl group, and an aryl group. More preferably, for these conversions and compounds Q is CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2xe2x80x94CHxe2x95x90CH2, CH2Cxe2x89xa1N, or a group of the formula:
wherein R12 is CH3 or CH(CH3)2.
For conversion 4 and for compound 6, preferred embodiments of the inventive methods and compounds are those such that when Q is an A(R8)(R9)(R10) group as shown above and A is C, preferably R8 is H, an alkyl group, an O-alkyl group, an S-alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, Cxe2x89xa1N, or C(O)R11, wherein R11 is an alkyl group, an aryl group, a cycloalkyl group, a heteroaryl group, or a heterocycloalkyl group, and R9 and R10 are independently selected from H, an alkyl group and an aryl group. For this same conversion and compound, when A is Si, preferably R8, R9 and R10 are independently selected from an alkyl group, a cycloalkyl group, and an aryl group. More preferably, for this conversion and compound, Q is CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2xe2x80x94CHxe2x95x90CH2, CH2Cxe2x89xa1N, or a group of the formula:
wherein R12 is CH3 or CH(CH3)2.
For conversions 3-13 and for intermediates 6, 7, 8, and 9, preferably R1 and R2 are each a methyl group.
Particularly preferred compounds of formula 8, useful in conversions 8 and 9, are those of formula 8a, where D is N, R1 and R2 are each a methyl group, and Z is O, and of formula 8b, where D is N, R1 and R2 are each a methyl group, and Z is S. For compounds 9 and 10, preferably D is N and R1 and R2 are each a methyl group.
The present invention is further directed to methods of inhibiting metalloproteinase activity, for example in mammalian tissue, by administering a compound of the formula 1, 1-a, 1-f or 1-g, or a pharmaceutically acceptable prodrug, salt or solvate thereof. The activity of the inventive compounds as inhibitors of metalloproteinase activity, such as the activity of MMPs (including stromelysins, collagenases, gelatinases and/or matrilysin) and/or TNF-xe2x88x9d convertase, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in Anal. Biochem., vol. 147, p. 437 (1985), Anal. Biochem., vol. 180, p. 110 (1989), FEBS, vol. 96, p. 263 (1992)and European Patent Application No. 0 606 046.
Administration of the compounds of the formula 1, 1-a, 1-f or 1-g, or their pharmaceutically acceptable prodrugs, salts or solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal and rectal. Preferably, the mode of administration is oral.
The inventive compounds of the formula 1, 1-a, 1-f or 1-g, or their pharmaceutically acceptable prodrugs, salts or solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan. Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. Preferably, the pharmaceutical form is a tablet or capsule for oral administration. The pharmaceutical composition may also include suitable excipients, diluents, vehicles and carriers as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural and/or rectal administration. Illustrative examples of such methods include those described in Remington""s Pharmaceutical Sciences, 18th edition (1990).
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of the formula 1, 1-a, 1-f or 1-g, or their pharmaceutically acceptable prodrugs, salts or solvates) and preferably is made up of one or more pharmaceutical dosage units. An exemplary dosage unit for a mammalian host contains an amount of from 0.1 milligram up to 500 milligrams of active compound per kilogram body weight of the host, preferably 0.1 to 200 milligrams, more preferably 50 milligrams or less, and even more preferably about 10 milligrams or less, per kilogram of the host weight. The selected dose may be administered to a mammal, for example, a human patient in need of treatment mediated by inhibition of metalloproteinase activity, by any known method of administrating the dose including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.
The amount of the inventive compounds, salts, solvates and/or prodrugs to be administered will vary based upon a number of factors, including the specific metalloproteinase to be inhibited, the degree of inhibition desired, the characteristics of the mammalian tissue in which inhibition is desired, the metabolic stability and activity of the particular inventive compound employed, and the mode of administration. One skilled in the art may readily determine a suitable dosage according to methods known to the art. Preferably, the amount of inventive compound of the formula 1, 1-a, 1-f or 1-g, or their pharmaceutically acceptable prodrugs, salts or solvates, administered is between 0.1 mg/kg body weight and 100 mg/kg body weight per day.
The inventive compounds, and the salts, solvates, and prodrugs thereof, may be prepared by employing the techniques available in the art using starting materials that are readily available. Exemplary methods of preparing the inventive compounds are described below. In the following schemes, unless otherwise indicated, W, X, Y, Z, Ar, R1 and R2 are as previously defined herein.
The inventive compounds of the formula 1-a preferably can be prepared by reacting a compound of the formula 12-a (where M is a hydroxy group) with hydroxylamine in the presence of a suitable peptide coupling reagent. Illustrative examples of suitable coupling agents include 1,1xe2x80x2-carbonyl-diimidazole, N-(dimethylaminopropyl)-Nxe2x80x2-ethyl carbodiimide (xe2x80x9cEDCxe2x80x9d), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or propanephosphonic anhydride in an inert polar solvent, such as dimethylformamide (xe2x80x9cDMFxe2x80x9d).
Alternatively, a compound of the formula 12-b (where M is a halogen such as chlorine) can be reacted with hydroxylamine in a suitable solvent mixture such as tert-butanol-tetrahydrofuran (xe2x80x9cTHFxe2x80x9d)-dichloromethane, preferably at 0 to 25xc2x0 C., to give hydroxamates of the formula 1-a.
Compounds of the formula 12-b are preferably prepared in a form that is directly useful for further reaction without isolation. For example, such compounds can be prepared by allowing compounds of the formula 12-a to react with a suitable halogenating agent, such as thionyl chloride or oxalyl chloride, preferably in the presence of a catalytic amount of dimethylformamide, and preferably in a suitable solvent such as dichloromethane at a temperature from 0xc2x0 C. to room temperature.
Alternatively, the coupling reactions described above can be carried out with compounds of the formula 12-a or 12-b and oxygen-protected compounds of hydroxylamine (i.e., where Pg is a suitable protecting group known to those skilled in the art, such as benzyl, t-butyl, t-butyidimethylsilyl, or t-butyldiphenylsilyl, and/or described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (1991), the disclosure of which is incorporated herein by reference) to give compounds of formula 13. Deprotection of compounds of the formula 13 provides compounds of formula 1-a. Suitable methods of deprotecting compounds of the formula 13 are known in the art, for example, as described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (1991).
Compounds of the formula 12-a can be prepared by alkaline hydrolysis of the corresponding ester 12-c (where M=OQ, and Q is a suitable protecting group such as methyl, ethyl, allyl, benzyl or t-butyl) using a suitable aqueous base, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, preferably in a homogeneous aqueous-organic solvent mixture at a temperature from 0xc2x0 C. to 25xc2x0 C. Alternatively, these compounds can also be prepared by acidic hydrolysis of the corresponding ester using a suitable aqueous acid, such as hydrochloric acid in aqueous dioxane, at a suitable temperature, preferably from 50xc2x0 C. to 100xc2x0 C. Other methods recognizable by those skilled in the art as suitable for converting esters to acids can also be employed, such as hydrogenolysis of benzyl esters using hydrogen and palladium on carbon, acid-promoted cleavage of t-butyl esters under anhydrous conditions, and palladium-catalyzed cleavage of allyl esters.
Compounds of the formula 1-c (i.e., 1-a, where W is CH2 and Y is CR1R2 and X is Nxe2x80x94R3) in which R3 is an alkyl group, can be prepared directly from compounds of the formula 1-b, for example by treatment with a suitable alkylating agent, such as an alkyl halide or alkyl sulfonate ester, in a suitable solvent at an appropriate temperature, such as THF at a temperature from 0xc2x0 C. to 50xc2x0 C.
Compounds of the formula 1-c where R3 is an alkylsulfonyl group or an arylsulfonyl group can also be prepared directly from compounds of the formula 1-b. For example, treatment compunds of formula 1-b with 2 equivalents of trimethylchlorosilane in the presence of an excess of a tertiary base, such as 4-methylmorpholine, in an aprotic solvent, such as dichloromethane, at 25xc2x0 C., followed by treatment with an alkylsulfonyl chloride or an arylsulfonyl chloride at a temperature from 0xc2x0 C. to 25xc2x0 C. leads to, after a conventional aqueous work-up, compounds of formula 1-c where R3 is alkylsulfonyl or arylsulfonyl. In a similar manner, compounds of formula 1-b can be reacted with the appropriate electrophilic carbonyl reagents to provide compounds of formula 1-c where R3 is COxe2x80x94R3xe2x80x2, where R3xe2x80x2 is any suitable organic moiety.
Compounds of formula 16 (i.e., 12-a where W and Y are CH2 and X is Nxe2x80x94R3) can be prepared according to the following scheme.
Preferably, commercially available racemic piperazine-2-carboxylic acid is allowed to react with a suitable electrophilic reagent R3xe2x80x94Lg, where Lg is any suitable leaving group, under conditions such that the reaction takes place predominantly at the N-4 position to give compounds of the formula 14. More preferably, the reaction takes place in aqueous-organic solvent, such as acetonitrile-water, at a temperature from xe2x88x9220xc2x0 C. to 25xc2x0 C., and in the presence of excess base such as triethylamine.
For the preparation of enantiomerically pure compounds of the formula 16, racemic piperazine-2-carboxylic acid can be first resolved according to known methods, such as those described in Helv. Chim. Acta, vol. 43, p. 888 (1960), and Helv. Chim. Acta, vol. 72, p. 1043 (1989), the disclosures of which are incorporated herein by reference.
Examples of suitable electrophilic reagents R3xe2x80x94Lg with suitable regioselectivity include BOC-ON, di-t-butyl dicarbonate, N-(benzyloxy-carboxy)succinimide, and acetic anhydride. The intermediate of the formula 14 is then preferably further reacted, without isolation, under the same conditions with a sulfonyl chloride of the formula 15 to give compounds of the formula 16.
Alternatively, the intermediate of the formula 14 can be isolated and then allowed to react with trimethylsilyl chloride and a suitable tertiary amine base, such as triethylamine or 4-methylmorpholine. Without isolation, the resulting material is then reacted with a sulfonyl chloride 15 in a suitable solvent such as dichloromethane at 25xc2x0 C. to provide, after conventional acid workup, a compound of the formula 16.
The intermediate of the formula 14 can also be prepared by treating the copper (II) complex of piperazine-2-carboxylate, prepared according to the method described in U.S. Pat. No. 4,032,639, the disclosure of which is herein incorporated by reference, with R3xe2x80x94Lg, followed by decomplexation by acidification and ion-exchange chromatography using DOWEX 50 resin. With this procedure, a broad range of electrophilic reagents R3xe2x80x94Lg can be employed.
Compounds of formula 15 can be preferably prepared by treatment of the corresponding aryl/heteroaryl phenyl ether or aryl/heteroaryl phenyl thioether, which are commercially available or can be prepared by methods known to those skilled in the art, with an excess of chlorosulfonic acid in dichloromethane solution at a temperature from 0xc2x0 C. to 25xc2x0 C.
Alternatively, the aryl phenyl ether can be treated with between 0.9 and 1.2 molar equivalents of chlorosulfonic acid at xe2x88x9220xc2x0 C. to 25xc2x0 C. The resulting sulfonic acid, with or without isolation, can be subsequently converted to the sulfonyl chloride 15 with an excess of a chlorinating reagent, such as oxalyl chloride or thionyl chloride, in the presence of a catalytic amount of dimethylformamide (xe2x80x9cDMFxe2x80x9d) in a suitable solvent, such as dichloromethane, 1,2-dichloroethane, or acetonitrile, at 25xc2x0 C. to 80xc2x0 C.
Alternatively, compounds of the formula 16-a, where Pg is a suitable protecting group as described above, are first converted to the corresponding methyl esters 17 by conventional methods, such as treatment with trimethylsilyl diazomethane in a suitable solvent such as methanoldichloromethane at room temperature as shown in the following scheme.
Suitable protecting groups, Pg, for this type of reaction are recognizable to those skilled in the art and include, but are not limited to, t-butyl groups and benzyl groups. Removal of the protecting group by known methods provides compounds of formula 18-a where R3 is hydrogen, which can be further reacted with reagents having the formula R3xe2x80x94Lg, wherein Lg is any suitable leaving group, to give compounds of the formula 18-b where R3 is not hydrogen. Illustrative examples of suitable R3xe2x80x94Lg reagents include methanesulfonyl chloride, methyl iodide, methyl isocyanate, ethyl bromoacetate, dimethylcarbamoyl chloride, and methoxyacetic anhydride.
Compounds of formula 18 (i.e.,12-c where W is CH2, Y is CR1R2, and X is NR3) can be prepared as illustrated in the scheme below.
xcex2-Amino-xcex1-hydroxy esters of formula 19 and aziridines of formula 20 are allowed to react in inert solvent such as dichloroethane or preferably dioxane at elevated temperature, 60 to 100xc2x0 C., to give adducts 21. Derivization of the amine function of 21 to provide compounds of formula 22 can be effected by conventional methods known to those skilled in the art. Cyclization of compounds of formula 22 under Mitsunobu-type conditions (see J. Org. Chem. 1991, 56, 3900-3905, the disclosure of which is incorporated herein by reference) provides the piperazines 18.
Compounds of formula 19 where R1 is H and R2 is alkyl can be prepared according to literature methods known to those skilled in the art. Where R1 and R2 are both methyl, the amino alcohols 19 are available from a nitronate alkylation as described in Bull. Chem. Soc. Jpn. 1976, 49, 3181-3184, the disclosure of which is incorporated herein by reference.
The aziridines 20 can be prepared by treatment of sulfonyl chlorides of formula 15 with excess ethanolamine in THF at xe2x88x9220xc2x0 C. to 25xc2x0 C., followed by cyclization of the resulting xcex2-hydroxyethyl sulfonamides with DEAD and triphenylphosphine in THF. Compounds of formula 15 can be prepared as described above.
Compounds of formula 28 (i.e., 12-c where X is NH, W is Cxe2x95x90O, and Y is CR1R2) can be prepared according to the following scheme.
Treatment of compounds of formula 23 (prepared as described in Angew. Chem. Int. Ed. Engl. 1994, 33, 988-999, the disclosure of which is incorporated herein by reference) with sulfonyl chlorides of formula 15, as described above, give compounds of formula 24. Alkylation of compounds of formula 24 with ethyl bromoacetate proceeds in the presence of a suitable base, such as potessium carbonate, in a suitable solvent, such as DMF, at 25xc2x0 C. to 80xc2x0 C. for a period of 1 to 48 hours to provide compounds of formula 25. Oxidation of alkenes 25 to compounds of formula 26 proceeds under suitable oxidizing conditions, such as excess sodium periodate in the presence of catalytic ruthenium trichloride in acetonitrile:carbon tetrachloride:water (2:2:3) solvent at 25xc2x0 C. for 1 to 18 hours. Treatment of compounds of formula 26 with diphenylphosphoryl azide (xe2x80x9cDPPAxe2x80x9d) in the presence of a suitable base, such as triethylamine, in an inert solvent, such as benzene, at 70-100xc2x0 C. for 1-12 hours gives an intermediate isocyanate, which upon addition of a suitable alcohol, such as benzyl alcohol, provides compounds of formula 27, where Pg is a corresponding protecting such as benzyloxycarbonyl protecting group. Removal of the protecting group from compounds of formula 27 under conventional conditions leads to spontaneous lactamization to provide compounds of formula 28.
An alternative sequence making use of the intermediates of formula 24 is shown below.
Oxidation of compounds of formula 24 under the conditions described in the preceeding paragragh for the oxidation of compounds of formula 25 gives compounds of formula 29. Curtius rearrangement of acids 29, as described for the conversion of 26 to 27 above except in the absence of added alcohol, leads to formation of compounds of formula 30. Mild basic hydrolysis of compounds of formula 30 with, for example, 1 molar equivalent of lithium hydroxide in THF-water at 0xc2x0 C. for 0.5 to 18 hours leads to compounds of formula 31. Reaction of amines of formula 31 with excess ethylene oxide in alcoholic solvent at 25xc2x0 C. to 75xc2x0 C. for 1 to 18 hours provides compounds of formula 32, which upon treatment with DEAD and triphenylphosphine in THF at 25xc2x0 C. yields compounds of formula 18-c. It will be appreciated by those skilled in the art that utilization of enantiomerically-enriched compounds of formula 24, which are accessible utilizing the methods reported in the literature and known to those skilled in the art, will yield enantiomerically-enriched compounds of formula 28 and 18-c.
Alter natively, the intermediate compounds of formula 29 can be prepared in enantiomerically-enriched form according to the following scheme.
Treatment of compounds of formula 33, which are readily derived from D-aspartic acid by methods known to those skilled in the art, with trimethylsilyl chloride and triethylamine in dichloromethane at 25xc2x0 C. for approximately 1 hour provides the trimethylsilyl esters, which, without isolation, are further reacted with aryl sulfonyl chlorides of the formula 15 in the presence of additional base to provide, after conventional work-up, the corresponding sulfonamides of the formula 34. Treatment of a sulfonamide with approximately 3 molar equivalents of a strong base, such as lithium diisopropylamide (xe2x80x9cLDAxe2x80x9d), at a temperature between xe2x88x9278xc2x0 C. and 0xc2x0 C. in an inert solvent such as THF, followed with 1 equivalent of an appropriate lower alkyl halide of the formula R1xe2x80x94X, preferably at a temperature between 0xc2x0 C. and xe2x88x9278xc2x0 C., gives a mono-alkylated product of formula 35 where R2 is H. Without isolation, the reaction mixture is treated with an additional equivalent of base, and then allowed to react with a second alkyl halide of the formula R2xe2x80x94X, where R1 and R2 are preferably the same, but can be different, to give, after acidic work-up, a sulfonamide of the formula 35. Following esterification of the carboxylic acid function of 35, the protecting group Pg is removed to provide the acid 29.
Alternatively, compounds of the formula 18-c can be prepared according to the following scheme.
Arylsulfonyl chlorides of formula 15 can be converted to sulfonamides of formula 36 by reaction with monoprotected derivatives of ethylenediamine. Condensation of a sulfonamide 36 with an xcex1-keto ester of the formula 37 in the presence of an acid catalyst, such as p-toluenesulfonic acid, provides a compound of the formula 38. Conversion of a compound of the formula 38 to the corresponding compound of the formula 18-c is effected by cyclization in the presence of catalytic base, such as potassium carbonate, in a suitable solvent, such as DMF, followed by removal of the protecting group Pg.
Additionally, compounds of the formula 42 (i.e., 12-a where X is Nxe2x80x94R3, W is CH2, and Y is CR1R2 can be prepared according to the following scheme.
Treatment of diethyl aminomalonate, which is commercially available, with chloroacetonitrile or bromoacetonitrile in the presence of diisopropylethyl amine in ethyl alcohol provides diethyl (cyanomethyl)aminomalonate, which is further reacted with an arylsulfonyl chloride of the formula 15 to give a compound of the formula 39. Nitriles of the formula 39 are reduced to corresponding amine salts of the formula 40 by hydrogenation over a suitable metal catalyst, such as palladium or platinum, in the presence of acid in alcohol solution. Reaction of a amine salt of the formula 40 with an excess of a ketone R1xe2x80x94COxe2x80x94R2 gives a piperazine derivative of the formula 41. After protection of the amine function by conventional methods known to those skilled in the art, basic hydrolysis of the ethyl esters followed by decarboxylation under acid conditions provides a compound of the formula 42.
Compounds of the formula 44 (i.e., 12-a where where W is Nxe2x80x94H, X is Cxe2x95x90O, and Y is CH) can be prepared according to the following scheme.
Preferably, a warm aqueous solution of D-asparagine, which is commercially available, is treated with formalin to provide, after cooling to 0xc2x0 C., 6(R)-carboxy-tetrahydropyrimidin-4-one (43). Treatment of 6(R)-carboxy-tetrahydropyrimidin-4-one with trimethylsilylchloride in a suitable base, such as N-methylmorpholine or diisopropylethylamine, in a polar aprotic solvent, such as DMF, generates the corresponding trimethylsilyl ester. This ester can be treated, without isolation, with a sulfonyl chloride 15 in the presence of additional base for several hours at 25xc2x0 C. to provide, after aqueous work-up, a compound of the formula 44. Alternatively, the compound of the formula 44 can be prepared directly by treating a solution of 6(R)-carboxy-tetrahydropyrimidin4-one and a base, such as N-methyl-morpholine, in a suitable aqueous:organic mixed solvent, such as water:dioxane, with a sulfonyl chloride of the formula 15 at 25xc2x0 C. for several hours followed by aqueous acid work-up.
Compounds of formula 48 (i.e., compounds of formula 12-c where W and X are CH2 and Y is Nxe2x80x94R3) can be prepared according to the following scheme.
Slow addition of compounds of formula 15, as a solution in a inert solvent such as dichloromethane, to four molar equivalents of 1,3-diaminopropane in the same solvent at xe2x88x9220xc2x0 C. to 0xc2x0 C. provides the compounds of formula 45, which are readily isolated by a acid-base extraction sequence to remove small amounts of the bis-sulfonamide byproduct. Treatment of amines 45 with glyoxalate esters of formula 46, which are commercially-available or well-known in the literature, provides intermediates of formula 47, which can exist partially or substantially as the corresponding open-form imine tautomers. Reaction of compounds 47 with an appropriate electrophilic reagent R3xe2x80x94Lg then provides compounds of formula 48.
A method for preparing compounds of formula 54, where X is O or S, is shown in the scheme below.
The starting xcex2-hydroxy xcex1-amino esters 49 are either commercially available, for example serine, threonine, and allo-threonine esters, or can be prepared by methods described in the literature (see, for example, J. Org. Chem., 1996, 61, 2582-2583, the disclosure of which is incorporated herein by reference). Compounds of formula 49 are treated with an sulfonyl chloride having the formula 15 in the presence of a suitable tertiary amine base, such as N-methylmorpholine, in an aprotic solvent, such as DMF-dichloromethane, at 0xc2x0 C. to 25xc2x0 C. to provide the xcex2-hydroxy xcex1-sulfonylamino esters having the formula 50.
Treatment of compounds of the formula 50 with suitable dehydrating reagents, for instance triphenylphosphine and DEAD in THF solution at 25xc2x0 C., provide the sulfonylaziridines of formula 51. Treatment of aziridines of formula 51 with a thiol (X=S) or alcohol (X=O) of formula 52, where Lg is any suitable leaving group (or a precursor, such as hydroxyl, to such a leaving group) in the presence of a Lewis acid, such as boron trifluoride etherate, at 0xc2x0 C. to 25xc2x0 C., either without additional solvent or in a suitable inert solvent such as dichloromethane, yields compounds of formula 53. Subsequent treatment of the compounds having the formula 53 with a base such as potassium carbonate in an aprotic solvent such as DMF then provides compounds of formula 54. In the case where Lg is hydroxyl, cyclization of 53 to give 54 is effected with triphenylphosphine and DEAD in THF solution at 25xc2x0 C.
Alternatively, compounds of formula 54-a can be prepared from amino esters 49 by the sequence shown below.
Hydroxyethylation of amino esters 49 can be effected with ethylene oxide in alcholic solvent at 25xc2x0 C. to 70xc2x0 C. to provide compounds of formula 55, which can be converted to compounds of formula 56 by treatment with sulfonyl chlorides 15. Diol 56 can be cyclized with the Mitsunobu protocol (see Holladay, M. W.; Nadzan, A. M. J. Org. Chem. 1991, 56, 3900-3905), or in traditional Williamson-style via the tosylate 57 and base to give compound of formula 54-a.
Alternatively, compounds of the formula 54-c (i.e., 54-b where Q is tert-butyl, X is S and R1 and R2 are both hydrogen) can be prepared according to the following scheme.
Preferably, t-butyl 2,3-dibromopropionate (prepared according to the method described in J. Perkin Trans I, p. 1321 (1973), the dislosure of which is incorporated herein by reference) is treated with 2-mercaptoethylamine and triethylamine in a suitable solvent, such as a mixture of chloroform and benzene, to provide t-butyl tetrahydro-1,4-thiazine-3-carboxylate, which upon reaction with a compound of the formula 15 under suitable conditions, such as in the presence of triethylamine in dichloromethane solution at 25xc2x0 C., provides compounds of the formula 54-c.
As shown in the scheme below, oxidation of tetrahydrothiazines of formula 54-b to the corresponding sulfoxides of formula 54-d can be carried out under suitable oxidizing conditions, such as m-chloroperbenzoic acid in dichloromethane at xe2x88x9278xc2x0 C. to 0xc2x0 C. or sodium perborate in acetic acid at 25xc2x0 C. to 50xc2x0 C. It is to be understood that such oxidations can also be carried out at other intermediate stages in the synthesis of compounds of formula 1-a where X is Sxe2x95x90O, and also to directly convert compounds of formula 1-a where X is S to compounds of formula 1-a where X is Sxe2x95x90O.
Compounds of the formula 54-b can be prepared according to
the following scheme.
First, xcex2-mercapto-xcex1-amino acids of formula 58, such as D-penicillamine or D-cysteine, both of which are commercially available, are treated with 2-bromoethanol in the presence of a base, such as sodium hydroxide, to provide 2-hydroxyethyl sulfides of formula 59. Intermediates of formula 59 are then reacted directly with compounds of the formula 15 in the presence of a suitable base, such as sodium carbonate, in an appropriate solvent system, such as DMF/water to provide the N-sulfonyl derivatives 60. The acid function of compounds of formula 60 is then protected as a suitable ester group Q, for example, the t-butyl ester which is prepared by reaction of 60 with t-butyl bromide in the presence of a suitable base, such as potassium carbonate, and a suitable catalyst, such as benzyltriethylammonium chloride (xe2x80x9cBTEACxe2x80x9d) in dimethylacetamide at a temperature between 50xc2x0 C. and 60xc2x0 C. Cyclization of the compound of the formula 61 can be effected using triphenylphosphine and DEAD in a suitable solvent, such as THF, to yield a compound of the formula 54-b.
More preferably, compounds of the formula 1-d (e.g., 1-a where W is CH2, X is S, and Y is CR1R2) can be prepared according to the following scheme.
Treatment of compounds of formula 58 with a trialkylsilyl chloride, such as trimethylsilyl chloride, in the presence of a tertiary amine base, such as diisopropylethylamine, in an aprotic solvent, such as DMF, provides the corresponding trialkylsilyl ester, which upon reaction with 1,2-dichloroethane or 1,2-dibromoethane in the presence of DBU at 25xc2x0 C. gives the intermediate tetrahydrothiazine of the formula 7-b. Without isolation, this intermediate is further reacted with 9-fluorenylmethyl chloroformate (xe2x80x9cFMOC-Clxe2x80x9d) in the presence of additional base, such as N-methyl morpholine, to provide, after aqueous acidic workup, the free carboxylic acid of the formula 62. This acid can then be coupled to an O-protected hydroxylamine, for example where Pg is t-butyldiphenylsilyl, with conventional peptide coupling reagents, such as EDC, to give the protected hydroxamate of the formula 63. Removal of the FMOC protecting group with conventional methods, such as piperidine in DMF, followed by reaction with a sulfonyl chloride of the formula 15 in the presence of base, such as N-methyl morpholine, in a suitable solvent, such as dichloromethane, provides compounds of the formula 13-b. Removal of the protecting group Pg affords compounds of the formula 1-d.
Particularly preferred compounds of this invention are compounds of formula 10. The preparation of compounds of formula 64-b described above can be applied to the synthesis of compounds of formula 10. More preferably, however, compounds of the formula 10 are prepared according to the process described below.
One aspect of the present invention is a process for the synthesis of certain matrix metalloprotease inhibitors, represented by the formula 10.
The reaction scheme can be summarized as involving the following steps:
The process comprises combining a suitably activated two-carbon piece with the amino acid 5 to form a tetrahydro-2H-1,4-thiazine derivative 11 or with a suitable ester 6 to form a tetrahydro-2H-1,4-thiazine derivative 7. A compound of formula 7 is treated with an activated sulfonic acid derivative 4 to give the corresponding sulfonamide 8. The ester functionality Q in compound 8 is deprotected to give compound 9, which is then activated by formation of an acid chloride or other suitable activating group. The activating group is displaced by hydroxylamine or a suitable salt or derivative of hydroxylamine to give the hydroxamic acid 10. The activated diarylether sulfonic acid derivative 4 can be prepared from the diaryl ether 2 by chlorosulfonation directly to the sulfonyl chloride or by a stepwise process of sulfonation to the sulfonic acid 3, followed by conversion to the sulfonyl chloride or other suitably activated sulfonic acid derivative.
A number of diarylethers 2 are commercially available. In cases where the diarylether is not commercially available, the first step of the process involves preparing the diarylether 2. In the case where D is nitrogen, compounds 2 can be made by combining either 4-chloropyridine hydrochloride or 1-(4-pyridyl)pyridinium chloride hydrochloride with phenol or thiophenol at or above 100xc2x0 C. either neat or in water, toluene, xylenes, or other suitable solvent.
In Step 2 of the process, the diaryl ether is treated with chlorosulfonic acid, sulfuric acid, sulfur trioxide, or other suitable sulfonating agent to give the sulfonic acid 3, which is used directly or isolated by water quench followed by solvent removal or extraction into a suitable water immiscible organic solvent. In some cases, a quaternary ammonium salt such as tetrabutylammonium bromide can be used to increase the solubility of the sulfonic acid 3 in organic solvents.
Step 3 of the process involves adding thionyl chloride, oxalyl chloride, chlorosulfonic acid, phosphorus pentachloride, or another suitable chlorinating reagent to the sulfonic acid 3 in acetonitrile, dichloromethane, 1,2-dichloroethane, or another suitable organic solvent. The resulting sulfonyl chloride 4 can be isolated by solvent removal or water quench followed by filtration or extraction. Alternatively, the sulfonic acid 3 can be converted to the sulfonyl fluoride with fluorosulfonic acid or sulfonyl bromide with thionyl bromide. If desired, the sulfonyl chloride, sulfonyl fluoride, and sulfonyl bromide compounds can be converted to the more stable triazolide or benzotriazolide derivatives by treatment with 1,2,4-triazole or benzotriazole respectively.
In Step 4, compound 5 is converted to a suitable silyl or carbon ester. In the cases where a silyl ester is utilized, trimethylsilyl chloride, tert-butyidimethylsilyl chloride, dimethylthexylsilyl chloride, triisopropylsilyl chloride, or another suitable silylating reagent is added to a mixture of compound 5 and 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, or other suitable tertiary amine base in N,N-dimethylformamide, acetonitrile, dichloroethane, or other suitable aprotic solvent. The resulting mixture of the silyl ester 6 can be used directly in Step 5, or the silyl ester can be isolated by aqueous work-up, extraction, and solvent removal.
In the cases where a carbon ester is utilized, a mixture of compound 5 and sulfuric acid, hydrogen chloride, p-toluenesulfonic acid, or another suitable organic or mineral acid in methanol, ethanol, isopropanol, 1-butanol, tert-butanol, allyl alcohol, or other suitable alcohol solvent is heated at reflux for 4 to 60 hours. The resulting ester is isolated as either the free base or amine salt by solvent removal and/or aqueous work-up, followed by formation by addition of an appropriate acid. Alternatively, the tert-butyl ester can be prepared by maintaining a mixture of compound 5 in liquid isobutylene, a suitable organic solvent such as 1,4-dioxane, and a suitable mineral acid or organic acid such as sulfuric acid, hydrogen chloride, or p-toluenesulfonic acid at reflux for 4 to 60 hours.
In Step 4A, compound 5 is mixed with 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, potassium hydroxide, or other suitable organic or inorganic base, and 1,2-dichloroethane, 1,2-dibromoethane, or other suitable activitated two carbon moiety in 1,2-dichloroethane, N,N-dimethylformamide, methanol, ethyl acetate, tetrahydrofuran, acetonitrile, water or other appropriate solvent. The resulting tetrahydro-2H-1,4-thiazine derivative 11 is isolated by precipitation, followed by filtration or by solvent removal. Alternatively, the carboxylic acid functionality of compound 5 can be protected in-situ by addition of trimethylsilyl chloride and 1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting silyl ester is treated with 1,2-dichloroethane, 1,2-dibromoethane, or another suitable activated two carbon moiety and 1,8-diazabicyclo[5.4.0]undec-7-ene or another suitable tertiary amine base in 1,2-dichloroethane, N,N-dimethylformamide, or other suitable aprotic solvent. The silyl ester is deprotected in-situ by addition of methanol, 2-propanol, or another alcoholic solvent and the resulting tetrahydro-2H-1,4-thiazine derivative 11 is isolated by precipitation and filtration.
In Step 5, the ester 6 is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, potassium hydroxide, or other suitable organic or inorganic base, and 1,2-dichloroethane, 1,2-dibromoethane, or other suitable activitated two carbon moiety in 1,2-dichloroethane, N,N-dimethylformamide, methanol, ethyl acetate, tetrahydrofuran, acetonitrile, or other appropriate solvent. The resulting tetrahydro-2H-1,4-thiazine derivative 7 is isolated by precipitation or aqueous work-up followed by extraction with an organic solvent and solvent removal.
In Step 5A, compound 11 is converted to a suitable silyl or carbon ester. In the cases where a silyl ester is utilized, trimethylsilyl chloride, tert-butyidimethylsilyl chloride, dimethylthexylsilyl chloride, triisopropylsilyl chloride, or another suitable silylating reagent is added to a mixture of compound 11 and 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, 4-methylmorpholine,pyridine, or other suitable tertiary amine base in N,N-dimethylformamide, acetonitrile, dichloroethane, or other suitable aprotic solvent. The resulting mixture of the silyl ester 7 can be used directly in Step 6, or the silyl ester can be isolated by aqueous work-up, extraction, and solvent removal.
In the cases where a carbon ester is utilized, a mixture of compound 11 and sulfuric acid, hydrogen chloride, p-toluenesulfonic acid, or another suitable organic or mineral acid in methanol, ethanol, isopropanol, 1-butanol, tert-butanol, allyl alcohol, or other suitable alcohol solvent is heated at reflux. The resulting ester is isolated as either the free base or amine salt by solvent removal and/or aqueous work-up, followed by extraction with an appropriate solvent, and finally solvent removal or salt formation by addition of an appropriate acid. Alternatively, the tert-butyl ester can be prepared by maintaining a mixture of compound 11 in 1,4-dioxane or other suitable solvent, liquid isobutylene, and sulfuric acid, hydrogen chloride, p-toluenesulfonic acid, or another suitable mineral acid or organic acid at reflux.
Alternatively, the tetrahydro-2H-1,4-thiazine derivative 11 can be left unprotected and used directly in Step 6. In this case, Step 5A is simply omitted.
In Step 6, the tetrahydro-2H-1,4-thiazine derivative 7 or 11 and the activated diarylether sulfonic acid derivative 4 are combined in dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, ethyl acetate, toluene, tert-butyl methyl ether, or another suitable solvent in the presence of 4-methylmorpholine, pyridine, triethylamine, diisopropylethylamine, potassium carbonate, or another suitable organic tertiary amine base or inorganic base. The resulting sulfonamide derivative 8 is isolated by aqueous work-up, extraction into an appropriate organic solvent, and solvent removal.
Step 7 involves the deprotection of the ester protecting group of compound 8 to give carboxylic acid 9. In the cases where a silyl ester is utilized, deprotection is accomplished by maintaining a mixture of the ester and methanol, ethanol, isopropanol, or another alcohol solvent at 20xc2x0 C. to reflux and isolating the product by filtration or solvent removal. Alternatively, silyl esters can be deprotected by treatment with mineral acid or acetic acid in either organic or aqueous solution or by treatment with fluoride ion in organic solution.
In the cases where a carbon ester is utilized, the ester can by removed by heating a mixture of compound 8 and hydrogen chloride, sulfuric acid, or other mineral in water, dioxane or another suitable organic solvent at reflux. Alternatively, the ester can be removed by treatment with sodium hydroxide, lithium hydroxide, potassium hydroxide, or another suitable inorganic base in water or a combination of water and methanol, tetrahydrofuran, or another suitable organic solvent. In the case where Q is allyl, the ester can be removed by treatment with N-methylaniline, morpholine, or another suitable secondary amine and tetrakis(triphenylphosphine)palladium(0) or another suitable palladium(0 ) catalyst in ethyl acetate, acetonitrile, or another suitable organic solvent. In the case where Q is benzyl, the ester can be removed by catalytic hydrogenation.
The final step of the process is a two-step procedure involving in-situ activation of the carboxyl functionality of compound 9 and subsequent displacement with hydroxylamine or a suitable salt or derivative of hydroxylamine. The activation is accomplished by reaction of compound 9 with oxalyl chloride or thionyl chloride with or without N,N-dimethylformamide present as catalyst in dichloromethane, acetonitrile, or other suitable solvent to give the corresponding acid chloride. Alternatively, the carboxyl can be activated by addition of methanesulfonyl chloride, isobutylchloroformate or various other chloroformate reagents, 1,3-dicyclohexylcarbodiimide or other carbodiimide reagents. The activated compound is added to hydroxylamine or a suitable salt or derivative of hydroxylamine and an appropriate organic or inorganic base, if necessary, in water, tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl alcohol, dichloromethane, or other suitable solvent or solvent combinations. The resulting hydroxamic acid 10 can be isolated by solvent removal or by dissolution in aqueous hydroxide, adjusting the pH to 5 to 10 range, and collecting the precipitate by filtration.
A preferred compound is 3(S)-N-hydroxy-4-(4-((pyrid-4-yl)oxy)benzenesulfonyl)-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxamide, illustrated by the structural formula:
A preferred carboxylic acid protecting group, Q, is dimethylthexylsilyl, where A is silicon, R8 and R9 are both CH3, and R10 is (CH3)2CHC(CH3)2, illustrated by the following structural formula:
Other compounds of the formula 1 may be prepared by methods known to those skilled in the art in a manner analagous to the general procedures described above. Specific examples of methods used to prepare the inventive compounds are described below along with illustrative preferred embodiments of the inventive compounds of the formula 1, 1-a, 1-f or 1-g, or their pharmaceutically acceptable prodrugs, salts or solvates.

Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof

Abstract: wherein: Z is O or S; V is a divalent radical which together with C* and N forms a ring having six ring atoms, where each of said ring atoms other than C* and N independently is unsubstituted or substituted by a suitable substituent, and at least one of said other ring atoms is a heteroatom selected from O, N and S, and the remainder are carbon atoms; and Ar is an aryl or heteroaryl group; and pharmaceutically acceptable prodrugs, salts and solvates thereof.

Abstract: The invention further relates to pharmaceutically acceptable prodrugs, salts and solvates of these compounds. The invention also relates to methods of inhibiting the activity of metalloproteinases by administering a compound of the formula I or a prodrug, salt of solvate thereof. The invention further relates to pharmaceutical compositions comprising an effective amount of these compounds, prodrugs, salts, and solvates. The invention still further relates to methods and intermediates useful for preparing these compounds, prodrugs, salts, and solvates.


A dental restoration cementing device for cementing a dental restoration is disclosed having a closable axial passage to a base having a hollow interior which is open into an occlusal direction. The device includes a preferably elastic body portion dimensioned to tightly fit into the hollow interior of the base via the passage of the dental restoration. The device further includes a hollow cementing portion extending from the body portion. The cementing portion has a lateral opening which is located outside the base when the body portion is fitted into the hollow interior of the base such that a pathway is formed from the interior of the cementing portion through the lateral opening into a gap between the dental restoration and the base. The dental restoration cementing device allows for precisely, quickly and cost efficiently cementing the dental restoration to the base.

For dental restoration, often damaged or lost teeth are replaced by artificial teeth which comprise dental restorations such as bridges, crowns or the like. Thereby, the dental restorations are placed either on remainders of original teeth or on implants set as artificial roots into jaw bones. Known restorations usually are made of materials which meet specific requirements such as biocompatibility, robustness, longevity and the like. For example, in non-exposed sections of the mouth metal dental restorations, e.g. made of gold or zirconium, are often used. In sections of the mouth which are visible, usually other materials are preferred which optically better suit to the appearance of natural teeth. For example, ceramic materials, composite materials, fiber-reinforced composites or acrylic glasses (Polymethylmethacrylate—PMMA) are commonly used.
As mentioned, the materials of crows are typically chosen in consideration of the requirements for being used as teeth such aesthetic requirements, mechanical conditions and the like. However, for being directly placed on implants which are typically made of titanium or on remainders of original teeth these materials are often not suitable. Therefore, usually an intermediate structure is provided between the dental restoration and the implant or remainder. Widespread intermediate structures are bases which are cemented to the crowns. For example, for being connected to titanium implants often crowns are cemented to titanium bases which are then placed on and connected to the implant.
Typically, restorations are cemented on bases outside the mouth by a dental technician or dentist. Thereby, specific adhesives are used as cements wherein many cements are mixed of plural components before being applied. The cemented bases and restorations are then connected to the implants or remainders in the mouth wherein the bases contact the implants or remainders. Often, the dental restoration together with the base is fixed to the implant by means of a screw axially projecting through the dental restoration and the base into the implant.
For cementing a dental restoration on a base, often a model is used. For that purpose, at least a portion of the mouth in which an implant is set for mounting the dental restoration is modelled by a dental technician or a dentist using known modelling techniques. However, even though such model based cementing allows for precisely cementing the restoration to the base and for providing sophisticated cemented restoration-base-structures it is comparably cumbersome. For example, such techniques require the models to be generated. For that purpose, patients have to separately see the dental technician or dentist after setting the implant. Thereafter, the dental technician or dentist builds the model and cements the crown to the base. Then, the cemented crown and base are mounted to the implant in a separate step. Thus, such cementing is comparably time consuming, causes a comparably large effort and is comparably expensive.
For making the cementing process faster and cheaper many dentists do manually cement the dental restoration to the base. Thereby, often the base which typically has a hollow interior is closed by an elastic plug such that no cement can enter the interior of the base. The elastic plug typically is adapted to the geometry of the base in order to allow a safe closing. However, considering that dental restorations and particularly bases usually are comparably small such manual cementing often provides results of reduced quality. For, example often the cement is not regularly or uniformly distributed between the crown and the base such that the connection is not consistently strong. Also, often the crown can manually not be precisely positioned or oriented such that a reduced comfort and a reduced usability may result.
Therefore, there is a need for a system or device allowing for a precise, fast and cost efficient cementing of a dental restoration to a base.

Cementing a dental restoration to a base


A laundry treatment apparatus includes a drawer. The laundry treatment apparatus further includes a cabinet that has an entrance opening and that is configured to receive the drawer through the entrance opening. The laundry treatment apparatus further includes a drum that is located inside the drawer and that is configured to receive laundry. The laundry treatment apparatus further includes a drum drive unit that is located inside the drawer and that is configured to rotate the drum. The laundry treatment apparatus further includes a fastening mechanism that is configured to reciprocate in a first direction that is either up and down or left and right with respect to a front of the drawer. The laundry treatment apparatus further includes a transfer member that is configured to reciprocate in a second direction that is either up and down or left and right with respect to the front of the drawer.

Generally, a laundry treatment apparatus is a generic term for an apparatus that washes laundry (e.g. objects to be washed or objects to be dried), an apparatus that dries laundry, and an apparatus that may perform both washing and drying of laundry.
In the case of a front loading type laundry treatment apparatus (referred to as a drum washing machine) configured to introduce laundry through the front side of the apparatus, a laundry opening is formed at a height lower than the waist of a user, which requires the user to bend his/her body when introducing or retrieving laundry into or from the laundry treatment apparatus.

Laundry treatment apparatus with drawer locking unit


A role and entitlements mining system uses network intelligence to facilitate role definition. The system records traffic on a network. The traffic is analyzed to identify the user and application involved. The matched data is then provided to an analytics engine, which analyzes that data to attempt to derive an initial set of one or more roles and the application entitlements for each role. Each role derived by the analytics engine identifies one or more users who are identified as belonging to the role, as well as one or more application entitlements. Preferably, one or more directory services are then interrogated for known group and user relationships to detect whether the roles identified by the analytics engine can be modified or enriched. Evaluation of the known group and user relationships provides a way to identify a more granular set of role definitions. A role-based access control policy is then generated.

1. Technical Field
This disclosure relates generally to security systems for computer networks.
2. Background of the Related Art
When defining an access control policy for an organization a common approach is to implement Role Based Access Control (RBAC). Using RBAC, entitlements to perform particular functions are assigned to roles instead of directly to users. The way a user gets the entitlements is by being assigned to roles or requesting membership of the role. Thus, to define an RBAC-based policy for an organization, an understanding of the user roles and the entitlements for those roles is required. Once this information is understood for an organization, the appropriate RBAC policy can be defined and deployed to an Identity Management system, such as IBM® Tivoli® Identity Manager™. Use of such tools greatly simplifies access management as compared with directly defining a user-to-entitlement relationship.
A problem, however, is how to create an initial RBAC policy for an organization. A particular issue is how to discover the roles and the entitlements for those roles, especially in a large organization. There are a number of common approaches that together are used to address these issues and to facilitate the defining of the RBAC policy. A typical approach involves several manual steps including interviewing each employee (about their job function and application entitlements), interviewing management (asking their view on employee roles and entitlements), performing system review (e.g., examining application user directories for user entitlements such as group membership), reviewing documentation (e.g., examining documents that define the management structure of an organization and job definitions), and evaluating best practices (i.e., trying to use roles and entitlements defined in other organizations and then tailoring these to the current enterprise). These approaches, however, are very expensive and time-consuming, and they rarely result in a meaningful RBAC policy. Indeed, it is not uncommon for an enterprise to embark on a role-defining exercise and then much later decide that no useful policy has resulted (in which case the entire exercise may then be abandoned). This is because manual processes just are not efficient at discovering the true roles and entitlements of an organization.
Another problem is that, with respect to an identity solution, the definition of what is or is not a role is often confusing (especially to individuals being questioned about employee "roles"), because most organizations use the term to identify job description rather than the person's need for access to systems. Indeed, some individuals being interviewed about roles may not even understand or appreciate the distinction (between an IT-based RBAC role and an employment role), which further skews any results toward a negative or un-useful outcome.
It is also known in the art to provide automated organizational role modeling for role based access controls. This approach inspects permission settings within IT systems, and these settings are then analyzed to determine whether there are any patterns within these permissions. Automated role modeling using the above-described approach, however, tends to produce roles that track existing policy set by the organization as opposed to roles that more closely indicate the actual behavior of users within the organization. Another approach, which typically is implemented in identity management systems, provides for role mining capabilities and the ability to model new roles based on policy information. That approach, however, typically relies upon static information.
There remains a need in the art to provide enhanced role and entitlements mining that addresses these and other problems.

Automated role and entitlements mining using network observations

International Business Machines Corporation