CA2236096A1 - Aromatic keto-acids and their derivatives as inhibitors of matrix metalloproteinases - Google Patents
Aromatic keto-acids and their derivatives as inhibitors of matrix metalloproteinases Download PDFInfo
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Abstract
Aromatic keto-acid compounds of formula (I) and derivatives are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A (72 kD gelatinase) and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, arthritis, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes. Ar, Y, W, R1-R4, n are as defined in the application.
Description
CA 02236096 l998-04-28 W O 97/23459 PCT~US96/18925 AROMATIC KETO-ACIDS AND THEIR DERIVATIVES AS INHIBITORS
OF MATRIX METALLOPROTEINASES
BACKGROUND OF THE INVENTION
The present invention relates to novel aromatic keto-acid compounds and their derivatives useful as ph~rm~ceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a phA~m~ceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., gelatinase A (72 kDa gelatinase) and stromelysin-1. More particularly, the novel compounds of the present invention are use~ul in the treatment of atherosclerotic plaque rupture, aortic aneurism, ~eart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, arthritis, multiple sclerosis, and other auto;mmllne or inflammatory disorders dependent on the tissue invasion of leukocytes or other activated migrating cells.
Gelatinase A and stromelysin-1 are members of the matrix metalloproteinase (MMP) family (Woessner J.F., FASFR J. 1991;5:2145-2154). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3 ~Freije J.M., Diez-Itza I., Balbin M., Sanchez L.M., Blasco R., Tolivia J., and Lopez-Otin C. ~. Biol. ~hem., 1994;269:16766-16773), and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., ~ao ~., S~;n~gawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
W O 97~3459 PCTAUS96/18925 The catalytic zinc in matrix metalloproteinases is the focal point for inhibitor design. The modification of substrates by introducing chelating groups has ~enerated potent inhibitors such as peptide hydroxymates and thiol-cont~; n i ng peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat An;m~l models of cancer and inflammation.
The ability of the m.atrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of atherosclerotic pla~ues is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrolln~; n~ these pla~ues by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in mAn atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-l, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Z.S., Sukhova G.K., Lark M.W., and Libby P., "Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of ~llm~n atherosclerotic plaques", J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic pla~ues Lel-.oved from heart transplant patients at the time of surgery (Henney A.M., Wakeley P.R., Davies M.J., Foster K., Hembry R., Murphy G., and ~l-mphries S., "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad. Sci., 1991;88:8154-8158).
W O 97/234~9 PCTrUS96/18925 Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with th; nn; ng of the medial aortic wall.
Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms ~nd aortic stenosis (Vine N. and Powell J.T., ~'Metalloproteinases in degenerative aortic diseases", Clin. Sci., 1991;81:233-239).
Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T.H., Hamilton M.A., Stevenson L.W., Moriguchi J.D., Fonarow G.C., Child J.S., Laks H., and Walden J.A., "Impact o~ left ventricular size on the survival in advanced heart failure'l, Am. J. Cardiol., 1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure ~Reddy H.K., Tyagi S.C., Tjaha I.E., Voelker D.J., Campbell S.E., Weber K.T., "Activated myocardial collagenase in idiopathic dilated cardiomyopathy", Clin. Res., 1993;41:660A; Tyagi S.C., Reddy H.K., Voelker D., Tjara I.E., Weber K.T., "Myocardial collagenase in failing hllm~n heart", Clin. Res., 1993;41:681A).
~n; mA 1 models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P.W., Moe G.W., Howard R.J., Grima E.A., Cruz T.F., "Structural remodeling in heart failure: gelatinase induction", Can. J. ~ardiol., ~ 1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (~Ahh~h H.N., Kono T., Stein P.D., Mancini G.B., Goldstein S., "Left ventricular shape changes during the course of evolving heart failure", ~m. J. Phvsiol., 1992;263:H266-H270~.
W O 97/234S9 PCT~US96/18925 Neointimal proliferation, 1~A~; ng to restenosis, fre~uently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica me~; A to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence o~ mechanical injury to the blood vessel (Bendeck M.P., Zempo N., Clowes A.W., Galardy R.E., Reidy M., "Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat", Circulation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC
migration across basement m~~ ~ne barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSCMs underwent the transition ~rom a quiescent state to a proliferating, motile phenotype after injury to the vessel (Pauly R.R., Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gl~ An~ Y.A., Smith L., Weinstein C., Lakatta E., Crow M.T., "Migration o~ cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular di~ferentiation", Circulation ~es~ch, 1994;7~:41-54).
Collagenase and stromelysin activities have been ~P~o~trated in fibroblasts isolated from inflamed gingiva (Uitto V.J., A~plegren R., Robinson P.J., "Collagenase and neutral metalloproteinase activity in extracts ~rom inflamed human gingiva", ~. Periodontal Re~., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C.M., Wiebkin O.W., Thonard J.C., "Demonstrations of tissue collagenase activity in vivo CA 02236096 l998-04-28 and its relationship to inflammation severity in human gingiva", J. Periodontal Res., 1987;22:81-88).
Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burns tBrown S.I., Weller C.A., Wasserman H.E., "Collagenolytic activity of alkali burned corneas", ~rch. Oohtha~mol., 1969;81:370-373~. Thiol-contAin;ng peptides inhibit the collagenase isolated from alkali-burned rabbit corneas tBurns F.R., Stack M.S., Gray R.D., Paterson C.A., Invest. O~hthalmol., lg89;30:1569-1575).
Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U.K., Ulpu K., Pentland A.P., Birkedal-Hansen H., Parks W.O., Welgus H.G., ~'Distinct Populations of Basal Keratinocytes Express Stromelysin-l and Stromelysin-2 in Chronic Wounds", J. Clin. Invest., 1994;94:79-88).
Stromelysin-l mRNA and protein were detected in basal keratinocytes adjacent to but distal from the 2 0 wound edge in what probably represents the sites of the proliferating epi~m;s. Stromelysin-l may thus prevent the epi~erm;s from healing.
Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxymate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing ~llmAn ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement 3 0 membrane (Melchiori A., Albili A., Ray 3.M., and Stetler-Stevenson W.G., Cancer Res., l9g2;52:2353-2356), and the natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Y.A., Perez N., S~; m~ H., Boone T.C., Langley K.E., and ~aylor S.M., Ca~cer Res., l9g2;52:701-708). Studies of W O 97/23459 PCT~US96/18925 human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (A.Y. Strongin, B.L. Marmer, G.A. Grant, and G.I. Goldberg, J. B;ol.
t~h~m., 1993j268:14033-14039) and is retA;ne~ there through interaction with a receptor-like molecule (Monsky W.L., Kelly T., Lin C.-Y., Yeh Y., Stetler-Stevenson W.G., Nueller S.C., and Chen W.-T., Cancer Res., 1993;53:3159-3164).
Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., ~rown P.D., and Giavazzi R., Journal of the National ~n~er Institute, 1995j87:293 and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W.G., Santi L., and Albini A, Oncoloov Research, 1994j6:251-257).
Several investigators have ~mo~trated consistent elevation of stromelysin and collagenase in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls (Walakovits L.A., Moore V.L., Bhardwaj N., Gallick G.S., and Lark M.W., "Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury", Arthritis Rheum., 199~;35:35-42;
Zafarullah M., Pelletier J.P., Cloutier J.M., and Marcel-Pelletier J., "Elevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in hllm~n osteoarthritic synovia", J. Rhellm~tol., 1993;20:693-697). TIMP-l and TIMP-2 prevented the formation of collagen ~ragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H.J., Plumpton T.A., Harper G.P., and Cawston T.E., Aaents Actions, 1992;37:147-154; Ellis A.J., Curry V.A., W O 97/23459 PCT~US96/18925 Powell E.K., and Cawston T.E., Biochem. Bio~hvs. Res.
Commun., 1994;201:94-101).
Gijbels, et al., (J. Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental allergic encephalomyelitis (EA~:) in a dose dependent m~nnF.~, suggesting the use of MMP inhibitors in the treatment of auto;mmlln~ inflammatory disorders such as multiple sclerosis.
A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (R~m~n;c A.M., and Madri J.A., "The Induction of 72-kDa ~elatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-l Dependent", J. Cell Biolo~sr, 1994j125:1165-1178). This transmigration past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by b;n~i;ng to the vascular cell a&esion molecule-l (VCAM-l). Once the barrier is compromised, edema and inflammation are produced in the CNS.
Leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
These studies provide the basis for the expectation that an effective inhibitor of gelatinase A
and/or stromelysin-l would have value in the treatment of diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.
W O 97/23459 PCT~US96/18925 We have identified a series of aromatic keto-acid compounds and derivatives that are inhibitors of matrix metalloproteinases, particularly stromelysin-l and ~elatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic pla~ue rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, arthritis, or other auto;mml-ne or inflammatory diseases dependent upon tissue invasion by leukocytes.
SUMMARY OF THE INVENTION
Accordingly, the present invention is a compound of ~ormula I
Ar - Y N ~ Z
~ (W)n ~ R4 ~1 R2 R3 Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, oR5 wherein R5 is hydrogen or alkyl, CN, Co2R5 wherein R5 is as defined above, So3R5 wherein R5 is as defined above, CHO, CoR5 wherein R5 is as defined above, CoNHR5 wherein R5 is as defined above, or NHCoR5 wherein R5 is as defined abo~e, 2-naphthyl, or heteroaryl;
W O 97/23459 PCT~US96/18925 Rl is selected from hydrogen, methyl, ethyl, N02 ~
halogen, oR5 wherein R5 is as defined above, CN, Co2R5 wherein R5 is as defined above, So3R5 wherein R5 is as defined above, CHO, or CoR5 wherein R5 is as de~ined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)~-aryl wherein X is O or S
and p and g is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -~CH2)p-X-(CH2)q-heteroaryl wherein X, p, and g are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of ~rom 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)VSR5, wherein v and R5 are as defined above, -(CH2)VCo2R5, wherein v and R5 are as defined ~ above, or W O 97/23459 PCT~US96/18925 -(CH2)VCONR6R6a~ wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo-benzo[f]
isoindol-2-yl;
Y is CH or N;
~OH
C~Rl() wherein R10 is as defined above for R2 and R3, and is independently the same or different from OH
R2 and R3 provided that when Z is C ~ 10 then R4 must be OH, C=O, C=NoR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W iS -CHR5 wherein R5 is as defined above;
n is zero or an integer of l;
R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C=0 or NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and correspon~;ng isomers thereof; or a~0 pharmaceutically acceptable salt thereof.
As matrix metalloproteinase inhibitors, the compounds of ~ormula I are useful as agents for the treatment of multiple sclerosis. They are also use~ul as agents for the treatment of atherosclerotic pla~ue rupture, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound W O 97/23459 PCT~US96/18925 .
repair, cancer metastasis, tumor angiogenesis, arthritis, and other inflammatory disorders dependent upon tissue invasion by leukocytes.
A still further em.bodiment of the present invention is a pharmaceutical composition for ~m;n; stering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term "alkyl"
means a straight or brAnch~ hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl".
The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, tri~luoromethyl, amino, alkyl;lm; no as defined above for alkyl, dialkylamino as defined above O
for alkyl, nitro, cyano, carboxy, SO3H, CHO, C-alkyl O O
Il 11 as defined above for alkyl, -C-NH2, -C-NH-alkyl, O O
NH-C-alkyl, as defined abo~e for alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2)n2-NH2 wherein n2 is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n2, -~CH2)n2-Ntalkyl)2 as defined above for alkyl and n2.
The term "heteroaryl" means a heteroaromatic radical and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazol-6-yl, lH-benzimidazol-5-yl.
"Halogen" is fluorine, chlorine, bromine, or iodine.
Phenyl is abbreviated "Ph".
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nonto~ic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosul~ate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, m~n~elate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methAn~culfonate, and the like.
Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional m~nnen. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional m~nne~. The free base forms differ from their respective salt ~orms somewhat in certain physical properties such as solubility in polar solvents, ~ut otherwise the salts are e~uivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic ~m;neC~ Examples of metals used as cations are sodium, potassium, m~gn~ium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloro-procaine, choline, diethanol~m;ne~ dicyclohexylamine, ethylene~;~m;ne, N-methylgluc~m;ne, and procaine (see, for example, Berge S.M., et al., "Pharmaceutical Salts," J. of Pharma Sci., 1977;66:1).
The base additio~ salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional m~nne~. The free acid form W O 97/23459 PCT~US96/18925 may be regenerated by contactin~ the salt form with an acid and isolating the free acid in the conventional m~nne~. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are e~uivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated ~orms, are e~uivalent to unsolvated forms and are int~n~ to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen ~Z) isomers as well as the ~ppropriate mixtures thereof.
In one embodiment of the invention, a preferred compound of Formula I is one wherein Ar is phenyl; and correspo~;n~ isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Y is CH; and correspon~;n~
isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Z is C=O; and correspo~;n~
isomers thereof; or a ~rm~ceutically acceptable salt thereof.
W O 97/23459 PCT~US96/18925 Another preferred compound of Formula I of this embodiment is one wherein n is zero; and correspo~; ng isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I o~ this embodiment is one wherein Rl, R2, and R3 are hydrogen;
and correspo~;ng isomers thereof; or a p~Arm~ceu-tically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein R4 is OH; and correspon~; n~
isomers thereof; or a p~A~m~ceutically acceptable salt thereof.
In another embodiment of the invention, a preferred compound of Formula I is one wherein Z is C=NoR5; and correspon~; n~ isomers thereof; or a pharmaceutically acceptable salt, thereof.
Another preferred compound of Formula I of this embodiment is one wherein Y is N; and correspo~;n~
isomers thereof; or pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein n is l; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C-O; Y is CH; and R4 is OH; and correspon~;n~ isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; Rl, R2, and R3 are hydrogeni and R4 is OH; and correspo~;n~ isomers thereof, or a phAr~ceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; Rl, R2, and R3 are hydrogen; R4 is OH; and n is zero; and W O 97/23459 PCT~US96/18925 correspo~;n~ isomers thereo~; or a pharmaceutically acceptable salt thereof.
Another pre~erred compound o~ Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; R1, R2, and R3 are hydrogen; R4 is NHOH; and n is zero; and correspo~; n~ isomers thereof; or a phArm~ceutically acceptable salt thereof.
Another preferred compound o~ Formula I o~ this embo~;m~nt is one wherein Ar is phenyl; Z is C=N-OH;
R1, R2, and R3 are hydrogen; R4 is OH; and n is zero;
and correspo~;~g isomers thereo~; or a p~rmAceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein R1 and R2 are hydrogen; and correspo~; n~ isomers thereof, or a ph~rmAceutically acceptable salt thereo~.
Particularly valuable is a compound selected ~rom the group consisting o~:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl~-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and (i)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid; and correspo~;n~ isomers thereo~; or a phA~m~ceutically acceptable salt thereo~.
More particularly valuable are 4-oxo-4-[4-(4-phenyl-piperidin-1-yl~-phenyl]-butyric acid; N-hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-W O 97/23459 PCT~US96/18925 butyramide; E~Z-4-hydroxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; and correspo~;n~
isomers thereof; or a E~hAnm~ceutically acceptable salt thereof.
The compounds of Formula I are valuable inhibitors of gelatinase A and/or stromelysin-l. It has been shown previously that inhibitors of matrix metallopro-teinases have efficacy in models of disease states like arthritis and metastasis that depend on modification of the extracellular matrix.
In vitro ex~eriments were carried out which ~m~ trate the efficacy of compounds of Formula I as potent and specific inhibitors of gelatinase A and stromelysin-l. E~periments were carried out with the catalytic ~om~; nq of the proteinases. Table I shows the activity of Examples 1-7 versus GCD (recombinant gelatinase A catalytic ~om;l; n ) and SCD (stromelysin-l catalytic domain). IC50 values were dete~m;ne~ using a thiopeptolide substrate, Ac-Pro-heu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson L.L., Hupe D.J., and Baragi V., ~Purification and Characterization of the m~n Stromelysin Catalytic Domain Ex3?ressed in Escherichia coli", E3iochemistrv, 1992;31:11231-11235).
TABLE
IC50 (~M) Example SCD GCD
0.14 1.3 2 0.08 0.56 3 0.02 0.04 30 4 0.02 0.15 2.9 6.3 6 0.25 1.6 7 0.40 14 W O 97/23459 PCTrUS96/1892S
The following list contains abbreviations and acronyms used within the sch~mes and text:
AcOH Acetic acid CDI Carbonyl diimidazole DCC Dicyclohexylcarbodiimide DCM Dichloromethane kDa Kilo dalton DMF Dimethylformamide DMSO Dimethylsulfoxide EtOH Ethanol HCl Hydrochloric acid HPLC High performance liguid chromatography IC50 Concentration of compound re~uired to inhibit 50~ of matrix metalloproteinase activity KHMDS Potassium hexamethyldisila~ide KOH Potassium hydroxide NaBH4 Sodium borohydride NaH Sodium hydride LioH Lithium hydroxide MeOH Methanol mRNA Messenger ribonucleic acid n-BuLi n-butyl lithium Pd/C Palladium on carbon psi Pounds per sguare inch Py Pyridine THF Tetrahydrofuran TIMPs Tissue inhibitors of metalloproteinases TMSCl Trimethylsilyl chloride TsOH Para-toluenesulfonic acid W O 97/23459 PCT~US96/18925 A compound of Formula I can be made by one of three general routes, as set forth in Scheme 1.
Route A involves reaction of a compound of Formula II with a compound of Formula III under basic conditions, for example, K2CO3 in a polar solvent such as DMSO, to afford a compound of Formula Ia, Formula I
where R4 = OH.
Route B involves a Friedel-Crafts acylation of a compound of Formula IV with a compound of Formula V as an acid chloride derivative or Va as an anhydride either neat or in an inert solvent such as, ~or example, dichloromethane, or nitrobenzene, and the like in the presence of a Lewis acid such as FeC13, AlC13, ZnC12, and the like at about -40~C to 150~C to af~ord a compound of Formula Ia, Formula I where R4 = OH.
Route C involves reaction of a compound o~
Formula VI, wherein M is hi, Mg-halogen or (Cu-halogen)lh with a compound of Formula VII wherein L
is halogen, or -N(Me)OMe, and Ar, W, n, R2, and R3 are as defined above, and R4 is a suitably protected ester, e.g., benzyl, using conventional methodology such as, for example, methodology described by Nahm S. and Weinreb S.M., Tetrahedron Letters, 1981;22:3815 to afford a compound of Formula Ia, Formula I where R4 = O~.
Specific compounds of the present invention can be prepared by various routes, all of which are generally known in the art. Compounds of Formula I, wherein n = 0, Ar and Z are defined as in Formula I, and Rl, R2, and R3 are hydrogen, Y = CH, and R4 is OH, can be synthesized according to the se~uence described in Scheme 2.
An aryl halide (1), wherein halo is defined as iodine, bromine, or chlorine, is reacted with a suitable alkyl lithium such as n-butyl lithium in a suitable solvent such as THF or diethyl ether at W O 97/23459 PCTrUS96/18925 temperatures between -80~C and 25~C, and the resulting product, an aryl lithium, (Scheme 2) is reacted with l-(phenylmethyl)-4-piperi~;no~ at temperatures between -80~C and 25~C to yield the 4-aryl-4-piperidinol (2).
The alcohol (2) is dehydrated to yield the 1,2,5,6-tetrahydropyridine (3) as an acid salt by stirring in a suitable solvent such as acetic acid with a strong acid catalyst such as concentrated HCl at temperatures between 20~C and reflux. The 1,2,5,6-tetrahydro-pyridine (3) is reduced to yield the 4-aryl-piperidine hydrochloride (4) by catalytic reduction using a suitable catalyst such as 10~ palladium on carbon and hydrogen gas (H2) at pressures between 10 psi and 100 psi in a suitable solvent such as absolute ethanol, acetic acid, or THF.
The keto-acid (5) is reacted with the 4-aryl-piperidine hydrochloride ~4) to yield the c~; ph~nyl-piperidine (6) by stirring in a suitable solvent such as dimethylsul~oxide (DMSO) or dimethyl~ormamide (DMF) in the presence of a base such as potassium or sodium carbonate at temperatures between 20~C and reflux.
The keto-acid (6) can be converted to the oxime-acid (7), keto-hydroxamic acid (9), oxime-hydroxamic acid (12), hydrazone (14), or alcohol derivative Z is C(H)OH (13) by employing the methods outlined in Scheme 3.
The keto-acid ~6) is reacted with hydroxylamine hydrochloride (H2NOH HCl) to yield the oxime-acid (7) by stirring in a suitable solvent such as ethanol in the presence o~ a mild base such as sodium carbonate (Na2C03) or pyridine at temperatures between 25~C and re~lux as shown in Scheme 3. In a similar fashion, O-substituted compounds such as O-benzylhydroxylamine react to yield the O-substituted o~;m~s.
3~ The keto-acid (6) can be reacted with an O-protected hydroxylamine such as O-benzylhydroxylamine hydrochloride (H2NOCH2C6H5-HCl) to yield the keto-O-protected hydroxamic acid (8) by first stirring the keto-acid (6) with ~ coupling agent such as 1,1~-carbonyldiimidazole (CDI) or N,N'-dicyclohexyl-carbodiimide (DCC) in a suitable solvent such as THF,DCM, or DMF at temperatures between 0~C and 100~C. The keto-O-protected hydroxamic acid (o) can be reduced to yield the keto-hydroxamic acid (9) by catalytic reduction using hydrogen gas at pressures between 10 psi and 100 psi and a suitable catalyst such as 10~
palladium on barium sulfate in a suitable solvent such as THF or ethanol.
The keto-O-protected hydroxamic acid (8) can be reacted with hydrox~ Am; ne to yield the oxime-O-protected hydroxamic acid (11) by employing conditionssimilar to those described previously for compound (7).
The oxime-O-protected hydroxamic acid (11) can be reduced to yield the oxime-hydroxamic acid (12) by employing conditions similar to those described for compound ~9).
The alcohol derivative (13) can be synthesized via reduction of (6) under st~n~A~d conditions, for example with NaBH4 in a suitable solvent such as ethanol.
The alcohol derivative (13a) can be synthesized by addition of a Grignard reagent of the formula RlOMgBr to the ketone (6) under st~n~d conditions. For instance two mole eguivalents of the Grignard can be reacted with one mole equivalent of (6) in a suitable solvent such as THF or diethyl ether at temperatures between -78~C and 25~C.
The Grignard reagent RlOMgBr can be prepared in situ by reacting an alkyl halide of the formula RlOBr with ~gnefiium metal in a suitable solvent such as THF or diethyl ether at temperatures between 0~C and reflux. The alkyl halide of formula RlOBr is either WO 97/23459 PCT~US96/18925 commercially available or can be prepared by methods known by one skilled in the art.
The ketone (6) can be reacted with a hydrazine of formula H2NNR6R6a, wherein R6 and R6a are as defined in Formula I, to yield the hydrazone (14) under st~n~A~d conditions such as refluxing in suitable solvent such as methanol or ethanol.
The keto acid (6) is reacted with amine (R6R6aNH) to yield the amide 13b by first stirring the keto acid (6) with a coupling agent such as CDI or DCC in a suitable solvent such as THF, DCM, or DMF at temperatures between 0~C and 100~C.
Compounds of Formula I wherein n = 0, Ar is as defined in Formula I, and Rl, R2, and R3 are hydrogen, Y = N, and R4 is OH can be synthesized according to the se~uence described in Scheme 4.
Aniline derivatives (15) are condensed with bis(2-chloroethyl)amine hydrochloride (16) in a solvent such as chlorobenzene at temperatures between 95~C and reflux to ~urnish the arylpiperazine hydrochloride (17). The aryl piperazine (17) is reacted with the aryl fluoride (5) in a m~nner similar to that described for compound (6) in Scheme 2 to obtain the correspo~; ng piperazine (18).
The compounds of Formula I wherein n = 1, Rl, R2, and R3 are hydrogen, R4 is OH, and Ar and Y are as defined in Formula I can be prepared as set forth in Scheme 5.
In Scheme 5, the phosphonoacetate (19) is reacted with an aldehyde of formula R8CHO to yield the 2-alkenoic ester t20) by stirring in a suitable solvent such as tetrahydrofuran (THF) in the presence of a strong base such as sodium hydride or lithium diisopropylamide at temperatures between 0~C and reflux. The 2-alkenoic ester (20) is reacted with the malonate of ~ormula CH2(CO2CH2CH3)2 to yield the =
W O 97/23459 PCTnUS96/18925 triester (21) by stirring in a suitable solvent such as absolute ethanol in the presence of a strong base such as sodium ethoxide at temperatures between 20~C and reflux. The triester (21) is hydrolyzed and decarboxylated in one pot to yield the diacid (22) by stirring in an as~ueous acid such as hydrochloric acid (1 to 12 M) at temperatures between 20~C and reflux.
The diacid (22) is cyclodehydrated to yield the cyclic anhydride (23) by stirring with a suitable dehydrating agent such as acetic anhydride in a suitable solvent such as acetic acid at temperatures between room temperature and reflux. The cyclic anhydride (23) is reacted with a halo-benzene of the formula C6H5-halo, where halo is fluorine or chlorine, to yield the keto-acid (24) by stirring in a suitable solvent such as dichloromethane or nitrobenzene in the presence of a catalyst such as all~m;nllrr chloride (AlC13) at temperatures between -40~C and 100~C. The keto-acid (24) is then converted to acid (25) by reaction with either (4) or (17) represented by the general Formula II in a milnne~ similar to that described for compound (6).
Compounds of ~ormula I wherein n = 0, Ar, R2, and R3 are as defined in Formula I, Rl is hydrogen, and R4 is OH can be synthesized according to the secauence described in Scheme 6.
R or S 4-benzyl-2-oxazolidinone is acylated with (26) via deprotonation with a suitable base such as NaH
and reaction with the acid chloride (26) to afford a compound of formula (27). The compound of formula (27) is deprotonated with potassium hexamethyldisilazide at -78~C and reacted with halide (28) at temperatures from -78~C to room temperature to give a compound of formula (29). Diastereomers of (29) are separated by a suitable method such as column chromatography on silica gel or HPLC, the oxazolid;no~e is le~-lov~d with LiOH and W O 97/23459 PCT~US96/18925 hydrogen peroxide to give the carboxylic acid derivative, and the carboxylic acid is converted to an acid chloride with oxalyl chloride in a suitable solvent such as THF to give a compound of formula (30).
A compound of formula (30) is reacted with N,O-dimethyl hydroxylamine hydrochloride in the presence of pyridine to afford a compound of formula (31).
Aryl anhydride (23a) is synthesized from an aldehyde of formula ArCHO as set forth in Scheme 5 for compound (23) or from commercially available intermediates correspo~ng to (20-22). Compound (23a) is con~nqed with 4-bromoaniline in a suitable solvent such as toluene, at room temperature to reflux. The resulting adduct is cyclized with acetic anhydride in acetic acid to afford imide (32), which is reduced with LiBH4JTMSCl in a solvent such as THF to yield the compound of formula (33). The aryl bromide (33) is reacted with a suitable alkyl lithium such as n-butyl lithium in a suitable solvent such as THF or diethyl 2~ ether at temperatures between -80~C and 25~C, and the resulting product, an aryl lithium, is reacted with Weinreb amide (31) to afford the adduct (34), which is debenzylated under st~n~rd conditions such as catalytic reduction using hydrogen gas and a suitable catalyst such as 5% palladium on barium sulfate in a suitable solvent such as THF or ethanol, to afford compounds of formula ( 35).
Compounds of Formula I, wherein n = 0, Ar, and Rl, R2, and R3, are as defined in Formula I, and R4 is OH
can be synthesized according to the se~uence described in Scheme 7.
A compound of formula (36), commercially available or synthesized by methods known in the art, is converted to a compound o~ formula (37) as described for compound (6) in Scheme (2). The ester (37) is hydrolyzed to the carboxylic acid under st~n~A~d W O 97/234~9 PCT~US96/18925 conditions such as KOH in ethanol, and the acid is reacted with a suitable coupling agent such as carbonyl diimidazole in dichloromethane or THF and N,O-dimethylhydroxylamine to give the amide (38). A
compound of formula (38) is reacted with a Grignard reagent of formula R2CH2MgX (X = Cl,Br) commercially available or synthesized by stAn~d methods known in the art, in a solvent such as THF or diethyl ether to give a ketone of formula (39). The ketone (39) is converted to the a-bromoketone (40) by reaction with N-bromosuccinimide.
A compound of formula (41) is synthesized via a method analogous to that described for compound (27) from R or S 4-benzyl-2-oxazoli~ino~e. Compound (41) is deprotonated with potassium h~m~thyldisilazide and reacted with a-bromoketone (40) to afford compound (42). Diastereomers of (42) are separated by a suitable method such as column chromatography on silica gel or HP~C, and the oxazolidinone is removed with LioH
and hydrogen peroxide to afford compounds of formula (43).
The compounds of formula (18, 25, 35, and 43) shown in Sc~m~s 4, 5, 6, and 7, respectively, can be converted to their correspo~fl; ng keto-acid derivatives as set forth in Scheme 3 by substituting compounds (18, 25, 35, and 43) for compound (6) in Scheme 3.
The compounds of Formula la where R2 or R3 is NH2 are synthesized by general route B depicted in Scheme 1 utilizing Va where R2 or R3 is NHCOCF3 (trifluromethylamide). The amide is then deprotected to afford la (R2 or R3 is NH2) under st~n~d conditions such as potassium or sodium carbonate in a suitable solvent such as MeOH or EtOH at temperatures between 0~C and reflux.
W O 97/Z3459 PCTnJS96/18925 Scheme 1 Route A
5Ar--Y~NH + F~ ~ K2C03 II ~1 III
10Route B O O
~ /~~~\ 11 . ~ Lewis Ar--Y~N~> + Cl~ (W)n~ : 3 ACid IV R V
o O O
Va Ar--Y N~M + LJ~ (W)n~R4 ~ Ia VI VI I
W O 97/23459 PCT~US96118925 Scheme 2 1. nBuLi, THF, -78~C HO ~ conc. HCl ArBr N ~ ~ Ar ~ N ~ Ph AcOH
Ph (2) ~ H2, 50 psi ~
Ar ~ N ~ ~HCl ~ Ar ~ NH ~HCl Ph 10% Pd/C
(3) 25-50~C (4) 3K2CO3 ~ Ar ~ N ~ CO2H
F ~C~2H ( 6 ) (5) W O 97~3459 PCT~US96/~892S
C~
_ _O
a (~
FL~ @~ O ~ <O ~
r¢
W O 97/23459 PCT~US96/1892 Scheme 4 Cl ArNH2 ~HCl+ HCl-IID ~ ~ Ar--N NH ~HCl 2 ~ Ar--N N~C02 H
(5) (18) Scheme 5 CO 2Et tEto)2 p CO2Et R3CHo ~ ~ C~2Et CO2Et (19) NaH, THF (20) NaOEt, EtoH
10 EtO2C ~ 6M HCl> HO2C ~ 2 Ac2O
EtO2C CO2Et AcOH
(21) (22) ~ ~ O AlC13, CH2C12~ CO2H
(24) (23) ~8 DYSO ~ ~ CO2H
(25) W O 97/23459 PCT~US96/18925 Scheme 6 HN O
~ 1. NaH
Ph - 2.R2 ~ Cl (26) ~ O
~ (27) - Ph o 1. C}~S
~ 2. Br ~ CO2CH2Ph Ar ~ O (23a) 3 (28) O O N ~ CO2CH2Ph 1. H2N ~ Br ~ R2 t29) 2. Ac20, AcOH Ph 1. Separate dia6tereomers ~ /~~~~ 2. LioH/H2o2 Ar ~ N ~ Br (32) ~ R3 1LiBH4, TMSCl Cl ~ C02CH2Ph Ar ~ N ~ Br (33) 1 HIMe Me-lN ~ CO2CH2Ph (31) ~ MeO R2 Ar ~ N ~ CO2CH2Ph (34) * designates R or S
H2, Pd/C R3 Ar ~ N ~ CO2H (35) CA 02236096 l998-04-28 WO 97/23459 PCT~US96/18925 Scheme 7 halo R 3K2CO3 ~ ~ ~ C~23t 1. KOH, EtOH ~ N ~ ,OMe R MgX
2. CDI, MeOH \~ ~ / N~ THF
(MeO)MeNH '- ~ Me (38) ~ ~1 ~ SllN~riBrl~m;~~ ~
Ar ~ N ~ ~Ar ~ N ~Br (39) R1 R2 (40)R1 R2 O O O
Ph ~ R3 ~
C1 (41) (26a) ~ N O
1. Separa~e 2 O
2. LiOH/H2O2 ~ ~42) R Ph Ar ~ N ~ CO2H * designates R or S
~ 3) R
W O 97/23459 PCT~US96/18925 The compounds o~ the present invention can be prepared and A~m; n; stered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be ~m; n; stered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be ~m; n; stered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be ~m;n; stered trans~erm~lly. It will be obvious to those skilled in the art that the following dosage ~orms may comprise as the active component, either a compound of Formula I or a correspo~;ng pharmaceutically acceptable salt of a compound o~ Formula I.
For preparing phArm~ceutical compositions from the compounds of the present invention, ph~m~ceutically acceptable carriers can be either solid or li~uid.
Solid form preparations include powders, tablets, pil}s, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, susp~n~;ng agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the ~inely divided active component.
In tablets, the active component is mixed with the carrier having the necessary b;n~;ng properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, W O 97/2345~ PCT~US96/1892 dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term ~preparation~ is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral A~m;n;stration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liguid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in agueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thicken;ng agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known SUSp~n~; ng agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liguid form preparations for oral ~m; n; stration. Such W O 97/Z3459 PCT~US96/1892 liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses cont~; n; ng appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the pac~age cont~;n;ng discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate nl7mhe~ of any of these in packaged form.
The guantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, arthritis, or other auto;mml~ne or inflammatory disorders dependent upon tissue invasion by leukocytes, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
The dosages, however, may be varied dep~n~; ng upon the reguirements of the patient, the severity of the condition being treated, and the compound being CA 02236096 l998-04-28 W O 97/23459 PCTrUS96/1892S
employed. Determ~n~tion of the proper dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased ~y small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and ~m;~; stered in portions during the day if desired.
The following nonlimiting examples illustrate the inventors' preferred methods ~or preparing the compounds of the invention.
4-Oxo-4-r4-(4-~henvl-~i~eridin-1-vl)-~henYll-butYric ~cid A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol), 3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassium carbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under an atmosphere of nitrogen at 120~C :Eor 18 hours. The mixture was allowed to cool, diluted with water (100 mL), and brought to pH 2 dropwise with 1 M HCl. The resulting solid was filtered, washed with water, and dried in vacuo to yield a pale orange solid as the title compound (11.2 g, %C,H,N found: 74.54, 6.98, 4.07).
4-~xo-4-r4-(4-~henvl-~i~eridin-1-Yl)-PhenYll-butyric acid ~otassium salt A stirred mixture of 4-phenyl-piperidine (8.1 g, 0.05 mol), 3-(4-fluorobenzoyl)-propionic acid (9.9 g, 0.05 mol), and potassium carbonate (7.0 g, 0.05 mol) in DMSO (50 mL) was heated under an atmosphere of nitrogen at 120~C for 18 hours. The mixture was allowed to cool and diluted with water (100 mL). The resulting solid W O 97/23459 PCT~US96/18925 was filtered and washed with water. The xesulting solid was recrystalized from boiling methanol and dried in vacuo to yield a pale brown solid as the title compound hydrate [6.6 g, 300 MHz];
lH NMR (DMSO): 8 7.82 (d, 2H, J = 8.1 Hz), 7.33-7.20 (m, 5H), 7.01 (d, 2H, J = 8.1 Hz), 4.06 (d br, 2H, J = 12.9 Hz), 2.97-2.90 (m, 4H), 2.78 (m, lH), 2.11 (t, 2H, J = 7.5 Hz), 1.86 (br d, 2H, J = 11.7 Hz), 1.70 (m, 2H)].
N-Hvdroxv-4-oxo-4- r 4-t4-phenYl-~i~eridin-l-~l)-~henYll-butvramide (a) 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (1.0 g, 2.96 mmol) (Example 1) and carbonyldimidazole (0.51 g, 3.11 mmol) were stirred for 18 hours at room temperature under nitrogen. A slurry of O-Benzylhydroxylamine (0.57 g, 3.55 mmol) and triethylamine (0.49 mL, 3.55 mol) in THF (5 mL) was added in one portion and the resulting mixture refluxed for 18 hours, filtered, and washed with THF (50 mL).
The filtrate was concentrated and columned on silica gel eluting with 50~ ethyl acetate in hexanes to give 4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.68 g, %C,H,N found: 76.01, 6.89, 6.26).
(b) N-benzyloxyimino-4-~4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.41 g, 0.93 mmol) was stirred at room temperature with 5% Pd/BaSO4 (0.04 g) in methanol (50 mL) under 50 psi o~ H2 for 10 hours. The mixture was filtered and washed with MeOH, and the filtrate was concentrated and triturated with ethyl acetate to yield the title compound as a white solid (0.25 g, %C,H,N
found: 71.03, 7.05, 7.65).
W O 97/234~9 PCT~US96/18925 E~ PLE 4 E/Z-4-HvdroxYimino-4-r4-(4-~henYl-~i~eridin-l-vl)-~henYll-butvric acid Sodium carbonate (0.80 g, 5.76 mmol) was q~l~e~l to hydroxyl~m;n~ hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred ~or 1~ minutes with ice cooling. The resulting mixture was added to 4-oxo-4-~4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) ~Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool.
The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with lM HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N
~ound: 71.77, 6.79, 7.88).
E/Z-4-Benzvloxvimino-4-r4-~4-~henYl-~i~eridin-l-Yl)-~henYll-butvric acid The title compound was synthesized (0.33 g, E/Z 10:1, %~,H,N found: 76.01, 7.05, 6.20) using the method of Example 4, substituting O-benzylhydroxylamine for hydroxYl~m; ne .
4-Oxo-4-r4-~4-~henYl-~i~erazin-l-vl)-~henYll-butYri~
~cid The title compound was prepared (0.11 g, 400 MHz) using the method of Example 1 substituting N-phenylpiperazine ~or 4-phenylpiperidine.
H NMR (DMSO): ~ 7.86 (d, 2H, J = 8.8 Hz), 7.26-7.22 (m, 2H), 7.06-6.99 ~m, 4H), 6.81 (t, lH, J = 7.2 Hz), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 2H), 3.12 (t, 2H, J = 6.0 Hz), 2.5 (t, 2H).
W O 97/23459 PCT~US96/18925 EX~PLE 7 ) 3-MethYl-5-oxo-5- r4- (4-~henvl-~i~eridin-1-vl)-~henvll-~entanoic acid A stirred mixture of 4-phenylpiperidine (0.161 g, 1.00 mmol), (i)3-methyl-5-(4-chloro-phenyl)-pentanoic acid (0.241 g, 1.00 mol), and potassium carbonate (0.276 g, 2.00 mol) in dry dimethyl sulfoxide was heated in a sand bath (160~C) under nitrogen for 15 hours. The mixture was cooled and diluted with water. The a~ueous solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH = 6. A brown gum formed. The li~uid was decanted, and the residue was chromatographed on silica gel (38 g, 230-400 mesh~ eluting with dichloromethane-methanol (20:1, 15 x 40 mL). Fractions cont~;n;ng product were combined and rotary evaporated to give a brown glass. The glass was crystallized from methanol after a hot gravity filtration to give the title compound as a tan solid; yield 0.0360 g (10%, mp = 134-135~C).
OF MATRIX METALLOPROTEINASES
BACKGROUND OF THE INVENTION
The present invention relates to novel aromatic keto-acid compounds and their derivatives useful as ph~rm~ceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a phA~m~ceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., gelatinase A (72 kDa gelatinase) and stromelysin-1. More particularly, the novel compounds of the present invention are use~ul in the treatment of atherosclerotic plaque rupture, aortic aneurism, ~eart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, arthritis, multiple sclerosis, and other auto;mmllne or inflammatory disorders dependent on the tissue invasion of leukocytes or other activated migrating cells.
Gelatinase A and stromelysin-1 are members of the matrix metalloproteinase (MMP) family (Woessner J.F., FASFR J. 1991;5:2145-2154). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3 ~Freije J.M., Diez-Itza I., Balbin M., Sanchez L.M., Blasco R., Tolivia J., and Lopez-Otin C. ~. Biol. ~hem., 1994;269:16766-16773), and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., ~ao ~., S~;n~gawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
W O 97~3459 PCTAUS96/18925 The catalytic zinc in matrix metalloproteinases is the focal point for inhibitor design. The modification of substrates by introducing chelating groups has ~enerated potent inhibitors such as peptide hydroxymates and thiol-cont~; n i ng peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat An;m~l models of cancer and inflammation.
The ability of the m.atrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of atherosclerotic pla~ues is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrolln~; n~ these pla~ues by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in mAn atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-l, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galla Z.S., Sukhova G.K., Lark M.W., and Libby P., "Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of ~llm~n atherosclerotic plaques", J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic pla~ues Lel-.oved from heart transplant patients at the time of surgery (Henney A.M., Wakeley P.R., Davies M.J., Foster K., Hembry R., Murphy G., and ~l-mphries S., "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad. Sci., 1991;88:8154-8158).
W O 97/234~9 PCTrUS96/18925 Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with th; nn; ng of the medial aortic wall.
Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms ~nd aortic stenosis (Vine N. and Powell J.T., ~'Metalloproteinases in degenerative aortic diseases", Clin. Sci., 1991;81:233-239).
Heart failure arises from a variety of diverse etiologies, but a common characteristic is cardiac dilation which has been identified as an independent risk factor for mortality (Lee T.H., Hamilton M.A., Stevenson L.W., Moriguchi J.D., Fonarow G.C., Child J.S., Laks H., and Walden J.A., "Impact o~ left ventricular size on the survival in advanced heart failure'l, Am. J. Cardiol., 1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure ~Reddy H.K., Tyagi S.C., Tjaha I.E., Voelker D.J., Campbell S.E., Weber K.T., "Activated myocardial collagenase in idiopathic dilated cardiomyopathy", Clin. Res., 1993;41:660A; Tyagi S.C., Reddy H.K., Voelker D., Tjara I.E., Weber K.T., "Myocardial collagenase in failing hllm~n heart", Clin. Res., 1993;41:681A).
~n; mA 1 models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P.W., Moe G.W., Howard R.J., Grima E.A., Cruz T.F., "Structural remodeling in heart failure: gelatinase induction", Can. J. ~ardiol., ~ 1994;10:214-220), and cardiac dilation precedes profound deficits in cardiac function (~Ahh~h H.N., Kono T., Stein P.D., Mancini G.B., Goldstein S., "Left ventricular shape changes during the course of evolving heart failure", ~m. J. Phvsiol., 1992;263:H266-H270~.
W O 97/234S9 PCT~US96/18925 Neointimal proliferation, 1~A~; ng to restenosis, fre~uently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica me~; A to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence o~ mechanical injury to the blood vessel (Bendeck M.P., Zempo N., Clowes A.W., Galardy R.E., Reidy M., "Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat", Circulation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC
migration across basement m~~ ~ne barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSCMs underwent the transition ~rom a quiescent state to a proliferating, motile phenotype after injury to the vessel (Pauly R.R., Passaniti A., Bilato C., Monticone R., Cheng L., Papadopoulos N., Gl~ An~ Y.A., Smith L., Weinstein C., Lakatta E., Crow M.T., "Migration o~ cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular di~ferentiation", Circulation ~es~ch, 1994;7~:41-54).
Collagenase and stromelysin activities have been ~P~o~trated in fibroblasts isolated from inflamed gingiva (Uitto V.J., A~plegren R., Robinson P.J., "Collagenase and neutral metalloproteinase activity in extracts ~rom inflamed human gingiva", ~. Periodontal Re~., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C.M., Wiebkin O.W., Thonard J.C., "Demonstrations of tissue collagenase activity in vivo CA 02236096 l998-04-28 and its relationship to inflammation severity in human gingiva", J. Periodontal Res., 1987;22:81-88).
Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burns tBrown S.I., Weller C.A., Wasserman H.E., "Collagenolytic activity of alkali burned corneas", ~rch. Oohtha~mol., 1969;81:370-373~. Thiol-contAin;ng peptides inhibit the collagenase isolated from alkali-burned rabbit corneas tBurns F.R., Stack M.S., Gray R.D., Paterson C.A., Invest. O~hthalmol., lg89;30:1569-1575).
Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U.K., Ulpu K., Pentland A.P., Birkedal-Hansen H., Parks W.O., Welgus H.G., ~'Distinct Populations of Basal Keratinocytes Express Stromelysin-l and Stromelysin-2 in Chronic Wounds", J. Clin. Invest., 1994;94:79-88).
Stromelysin-l mRNA and protein were detected in basal keratinocytes adjacent to but distal from the 2 0 wound edge in what probably represents the sites of the proliferating epi~m;s. Stromelysin-l may thus prevent the epi~erm;s from healing.
Davies, et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxymate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing ~llmAn ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement 3 0 membrane (Melchiori A., Albili A., Ray 3.M., and Stetler-Stevenson W.G., Cancer Res., l9g2;52:2353-2356), and the natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Y.A., Perez N., S~; m~ H., Boone T.C., Langley K.E., and ~aylor S.M., Ca~cer Res., l9g2;52:701-708). Studies of W O 97/23459 PCT~US96/18925 human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (A.Y. Strongin, B.L. Marmer, G.A. Grant, and G.I. Goldberg, J. B;ol.
t~h~m., 1993j268:14033-14039) and is retA;ne~ there through interaction with a receptor-like molecule (Monsky W.L., Kelly T., Lin C.-Y., Yeh Y., Stetler-Stevenson W.G., Nueller S.C., and Chen W.-T., Cancer Res., 1993;53:3159-3164).
Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., ~rown P.D., and Giavazzi R., Journal of the National ~n~er Institute, 1995j87:293 and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W.G., Santi L., and Albini A, Oncoloov Research, 1994j6:251-257).
Several investigators have ~mo~trated consistent elevation of stromelysin and collagenase in synovial fluids from rheumatoid and osteoarthritis patients as compared to controls (Walakovits L.A., Moore V.L., Bhardwaj N., Gallick G.S., and Lark M.W., "Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury", Arthritis Rheum., 199~;35:35-42;
Zafarullah M., Pelletier J.P., Cloutier J.M., and Marcel-Pelletier J., "Elevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in hllm~n osteoarthritic synovia", J. Rhellm~tol., 1993;20:693-697). TIMP-l and TIMP-2 prevented the formation of collagen ~ragments, but not proteoglycan fragments, from the degradation of both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H.J., Plumpton T.A., Harper G.P., and Cawston T.E., Aaents Actions, 1992;37:147-154; Ellis A.J., Curry V.A., W O 97/23459 PCT~US96/18925 Powell E.K., and Cawston T.E., Biochem. Bio~hvs. Res.
Commun., 1994;201:94-101).
Gijbels, et al., (J. Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental allergic encephalomyelitis (EA~:) in a dose dependent m~nnF.~, suggesting the use of MMP inhibitors in the treatment of auto;mmlln~ inflammatory disorders such as multiple sclerosis.
A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (R~m~n;c A.M., and Madri J.A., "The Induction of 72-kDa ~elatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-l Dependent", J. Cell Biolo~sr, 1994j125:1165-1178). This transmigration past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by b;n~i;ng to the vascular cell a&esion molecule-l (VCAM-l). Once the barrier is compromised, edema and inflammation are produced in the CNS.
Leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
These studies provide the basis for the expectation that an effective inhibitor of gelatinase A
and/or stromelysin-l would have value in the treatment of diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.
W O 97/23459 PCT~US96/18925 We have identified a series of aromatic keto-acid compounds and derivatives that are inhibitors of matrix metalloproteinases, particularly stromelysin-l and ~elatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic pla~ue rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, arthritis, or other auto;mml-ne or inflammatory diseases dependent upon tissue invasion by leukocytes.
SUMMARY OF THE INVENTION
Accordingly, the present invention is a compound of ~ormula I
Ar - Y N ~ Z
~ (W)n ~ R4 ~1 R2 R3 Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, oR5 wherein R5 is hydrogen or alkyl, CN, Co2R5 wherein R5 is as defined above, So3R5 wherein R5 is as defined above, CHO, CoR5 wherein R5 is as defined above, CoNHR5 wherein R5 is as defined above, or NHCoR5 wherein R5 is as defined abo~e, 2-naphthyl, or heteroaryl;
W O 97/23459 PCT~US96/18925 Rl is selected from hydrogen, methyl, ethyl, N02 ~
halogen, oR5 wherein R5 is as defined above, CN, Co2R5 wherein R5 is as defined above, So3R5 wherein R5 is as defined above, CHO, or CoR5 wherein R5 is as de~ined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)~-aryl wherein X is O or S
and p and g is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -~CH2)p-X-(CH2)q-heteroaryl wherein X, p, and g are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of ~rom 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)VSR5, wherein v and R5 are as defined above, -(CH2)VCo2R5, wherein v and R5 are as defined ~ above, or W O 97/23459 PCT~US96/18925 -(CH2)VCONR6R6a~ wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3-dihydro-1,3-dioxo-benzo[f]
isoindol-2-yl;
Y is CH or N;
~OH
C~Rl() wherein R10 is as defined above for R2 and R3, and is independently the same or different from OH
R2 and R3 provided that when Z is C ~ 10 then R4 must be OH, C=O, C=NoR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W iS -CHR5 wherein R5 is as defined above;
n is zero or an integer of l;
R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C=0 or NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and correspon~;ng isomers thereof; or a~0 pharmaceutically acceptable salt thereof.
As matrix metalloproteinase inhibitors, the compounds of ~ormula I are useful as agents for the treatment of multiple sclerosis. They are also use~ul as agents for the treatment of atherosclerotic pla~ue rupture, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound W O 97/23459 PCT~US96/18925 .
repair, cancer metastasis, tumor angiogenesis, arthritis, and other inflammatory disorders dependent upon tissue invasion by leukocytes.
A still further em.bodiment of the present invention is a pharmaceutical composition for ~m;n; stering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
In the compounds of Formula I, the term "alkyl"
means a straight or brAnch~ hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "alkyl".
The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term "aryl" means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, tri~luoromethyl, amino, alkyl;lm; no as defined above for alkyl, dialkylamino as defined above O
for alkyl, nitro, cyano, carboxy, SO3H, CHO, C-alkyl O O
Il 11 as defined above for alkyl, -C-NH2, -C-NH-alkyl, O O
NH-C-alkyl, as defined abo~e for alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2)n2-NH2 wherein n2 is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n2, -~CH2)n2-Ntalkyl)2 as defined above for alkyl and n2.
The term "heteroaryl" means a heteroaromatic radical and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, lH-indol-6-yl, lH-indol-5-yl, lH-benzimidazol-6-yl, lH-benzimidazol-5-yl.
"Halogen" is fluorine, chlorine, bromine, or iodine.
Phenyl is abbreviated "Ph".
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nonto~ic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosul~ate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, m~n~elate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methAn~culfonate, and the like.
Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M., et al., "Pharmaceutical Salts," J. of Pharma. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional m~nnen. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional m~nne~. The free base forms differ from their respective salt ~orms somewhat in certain physical properties such as solubility in polar solvents, ~ut otherwise the salts are e~uivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic ~m;neC~ Examples of metals used as cations are sodium, potassium, m~gn~ium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloro-procaine, choline, diethanol~m;ne~ dicyclohexylamine, ethylene~;~m;ne, N-methylgluc~m;ne, and procaine (see, for example, Berge S.M., et al., "Pharmaceutical Salts," J. of Pharma Sci., 1977;66:1).
The base additio~ salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional m~nne~. The free acid form W O 97/23459 PCT~US96/18925 may be regenerated by contactin~ the salt form with an acid and isolating the free acid in the conventional m~nne~. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are e~uivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated ~orms, are e~uivalent to unsolvated forms and are int~n~ to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen ~Z) isomers as well as the ~ppropriate mixtures thereof.
In one embodiment of the invention, a preferred compound of Formula I is one wherein Ar is phenyl; and correspo~;n~ isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Y is CH; and correspon~;n~
isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Z is C=O; and correspo~;n~
isomers thereof; or a ~rm~ceutically acceptable salt thereof.
W O 97/23459 PCT~US96/18925 Another preferred compound of Formula I of this embodiment is one wherein n is zero; and correspo~; ng isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I o~ this embodiment is one wherein Rl, R2, and R3 are hydrogen;
and correspo~;ng isomers thereof; or a p~Arm~ceu-tically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein R4 is OH; and correspon~; n~
isomers thereof; or a p~A~m~ceutically acceptable salt thereof.
In another embodiment of the invention, a preferred compound of Formula I is one wherein Z is C=NoR5; and correspon~; n~ isomers thereof; or a pharmaceutically acceptable salt, thereof.
Another preferred compound of Formula I of this embodiment is one wherein Y is N; and correspo~;n~
isomers thereof; or pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein n is l; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C-O; Y is CH; and R4 is OH; and correspon~;n~ isomers thereof; or a pharmaceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; Rl, R2, and R3 are hydrogeni and R4 is OH; and correspo~;n~ isomers thereof, or a phAr~ceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; Rl, R2, and R3 are hydrogen; R4 is OH; and n is zero; and W O 97/23459 PCT~US96/18925 correspo~;n~ isomers thereo~; or a pharmaceutically acceptable salt thereof.
Another pre~erred compound o~ Formula I of this embodiment is one wherein Ar is phenyl; Z is C=O; R1, R2, and R3 are hydrogen; R4 is NHOH; and n is zero; and correspo~; n~ isomers thereof; or a phArm~ceutically acceptable salt thereof.
Another preferred compound o~ Formula I o~ this embo~;m~nt is one wherein Ar is phenyl; Z is C=N-OH;
R1, R2, and R3 are hydrogen; R4 is OH; and n is zero;
and correspo~;~g isomers thereo~; or a p~rmAceutically acceptable salt thereof.
Another preferred compound of Formula I of this embodiment is one wherein R1 and R2 are hydrogen; and correspo~; n~ isomers thereof, or a ph~rmAceutically acceptable salt thereo~.
Particularly valuable is a compound selected ~rom the group consisting o~:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl~-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and (i)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid; and correspo~;n~ isomers thereo~; or a phA~m~ceutically acceptable salt thereo~.
More particularly valuable are 4-oxo-4-[4-(4-phenyl-piperidin-1-yl~-phenyl]-butyric acid; N-hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-W O 97/23459 PCT~US96/18925 butyramide; E~Z-4-hydroxyimino-4-[4-(4-phenyl-piperidin-l-yl)-phenyl]-butyric acid; and correspo~;n~
isomers thereof; or a E~hAnm~ceutically acceptable salt thereof.
The compounds of Formula I are valuable inhibitors of gelatinase A and/or stromelysin-l. It has been shown previously that inhibitors of matrix metallopro-teinases have efficacy in models of disease states like arthritis and metastasis that depend on modification of the extracellular matrix.
In vitro ex~eriments were carried out which ~m~ trate the efficacy of compounds of Formula I as potent and specific inhibitors of gelatinase A and stromelysin-l. E~periments were carried out with the catalytic ~om~; nq of the proteinases. Table I shows the activity of Examples 1-7 versus GCD (recombinant gelatinase A catalytic ~om;l; n ) and SCD (stromelysin-l catalytic domain). IC50 values were dete~m;ne~ using a thiopeptolide substrate, Ac-Pro-heu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson L.L., Hupe D.J., and Baragi V., ~Purification and Characterization of the m~n Stromelysin Catalytic Domain Ex3?ressed in Escherichia coli", E3iochemistrv, 1992;31:11231-11235).
TABLE
IC50 (~M) Example SCD GCD
0.14 1.3 2 0.08 0.56 3 0.02 0.04 30 4 0.02 0.15 2.9 6.3 6 0.25 1.6 7 0.40 14 W O 97/23459 PCTrUS96/1892S
The following list contains abbreviations and acronyms used within the sch~mes and text:
AcOH Acetic acid CDI Carbonyl diimidazole DCC Dicyclohexylcarbodiimide DCM Dichloromethane kDa Kilo dalton DMF Dimethylformamide DMSO Dimethylsulfoxide EtOH Ethanol HCl Hydrochloric acid HPLC High performance liguid chromatography IC50 Concentration of compound re~uired to inhibit 50~ of matrix metalloproteinase activity KHMDS Potassium hexamethyldisila~ide KOH Potassium hydroxide NaBH4 Sodium borohydride NaH Sodium hydride LioH Lithium hydroxide MeOH Methanol mRNA Messenger ribonucleic acid n-BuLi n-butyl lithium Pd/C Palladium on carbon psi Pounds per sguare inch Py Pyridine THF Tetrahydrofuran TIMPs Tissue inhibitors of metalloproteinases TMSCl Trimethylsilyl chloride TsOH Para-toluenesulfonic acid W O 97/23459 PCT~US96/18925 A compound of Formula I can be made by one of three general routes, as set forth in Scheme 1.
Route A involves reaction of a compound of Formula II with a compound of Formula III under basic conditions, for example, K2CO3 in a polar solvent such as DMSO, to afford a compound of Formula Ia, Formula I
where R4 = OH.
Route B involves a Friedel-Crafts acylation of a compound of Formula IV with a compound of Formula V as an acid chloride derivative or Va as an anhydride either neat or in an inert solvent such as, ~or example, dichloromethane, or nitrobenzene, and the like in the presence of a Lewis acid such as FeC13, AlC13, ZnC12, and the like at about -40~C to 150~C to af~ord a compound of Formula Ia, Formula I where R4 = OH.
Route C involves reaction of a compound o~
Formula VI, wherein M is hi, Mg-halogen or (Cu-halogen)lh with a compound of Formula VII wherein L
is halogen, or -N(Me)OMe, and Ar, W, n, R2, and R3 are as defined above, and R4 is a suitably protected ester, e.g., benzyl, using conventional methodology such as, for example, methodology described by Nahm S. and Weinreb S.M., Tetrahedron Letters, 1981;22:3815 to afford a compound of Formula Ia, Formula I where R4 = O~.
Specific compounds of the present invention can be prepared by various routes, all of which are generally known in the art. Compounds of Formula I, wherein n = 0, Ar and Z are defined as in Formula I, and Rl, R2, and R3 are hydrogen, Y = CH, and R4 is OH, can be synthesized according to the se~uence described in Scheme 2.
An aryl halide (1), wherein halo is defined as iodine, bromine, or chlorine, is reacted with a suitable alkyl lithium such as n-butyl lithium in a suitable solvent such as THF or diethyl ether at W O 97/23459 PCTrUS96/18925 temperatures between -80~C and 25~C, and the resulting product, an aryl lithium, (Scheme 2) is reacted with l-(phenylmethyl)-4-piperi~;no~ at temperatures between -80~C and 25~C to yield the 4-aryl-4-piperidinol (2).
The alcohol (2) is dehydrated to yield the 1,2,5,6-tetrahydropyridine (3) as an acid salt by stirring in a suitable solvent such as acetic acid with a strong acid catalyst such as concentrated HCl at temperatures between 20~C and reflux. The 1,2,5,6-tetrahydro-pyridine (3) is reduced to yield the 4-aryl-piperidine hydrochloride (4) by catalytic reduction using a suitable catalyst such as 10~ palladium on carbon and hydrogen gas (H2) at pressures between 10 psi and 100 psi in a suitable solvent such as absolute ethanol, acetic acid, or THF.
The keto-acid (5) is reacted with the 4-aryl-piperidine hydrochloride ~4) to yield the c~; ph~nyl-piperidine (6) by stirring in a suitable solvent such as dimethylsul~oxide (DMSO) or dimethyl~ormamide (DMF) in the presence of a base such as potassium or sodium carbonate at temperatures between 20~C and reflux.
The keto-acid (6) can be converted to the oxime-acid (7), keto-hydroxamic acid (9), oxime-hydroxamic acid (12), hydrazone (14), or alcohol derivative Z is C(H)OH (13) by employing the methods outlined in Scheme 3.
The keto-acid ~6) is reacted with hydroxylamine hydrochloride (H2NOH HCl) to yield the oxime-acid (7) by stirring in a suitable solvent such as ethanol in the presence o~ a mild base such as sodium carbonate (Na2C03) or pyridine at temperatures between 25~C and re~lux as shown in Scheme 3. In a similar fashion, O-substituted compounds such as O-benzylhydroxylamine react to yield the O-substituted o~;m~s.
3~ The keto-acid (6) can be reacted with an O-protected hydroxylamine such as O-benzylhydroxylamine hydrochloride (H2NOCH2C6H5-HCl) to yield the keto-O-protected hydroxamic acid (8) by first stirring the keto-acid (6) with ~ coupling agent such as 1,1~-carbonyldiimidazole (CDI) or N,N'-dicyclohexyl-carbodiimide (DCC) in a suitable solvent such as THF,DCM, or DMF at temperatures between 0~C and 100~C. The keto-O-protected hydroxamic acid (o) can be reduced to yield the keto-hydroxamic acid (9) by catalytic reduction using hydrogen gas at pressures between 10 psi and 100 psi and a suitable catalyst such as 10~
palladium on barium sulfate in a suitable solvent such as THF or ethanol.
The keto-O-protected hydroxamic acid (8) can be reacted with hydrox~ Am; ne to yield the oxime-O-protected hydroxamic acid (11) by employing conditionssimilar to those described previously for compound (7).
The oxime-O-protected hydroxamic acid (11) can be reduced to yield the oxime-hydroxamic acid (12) by employing conditions similar to those described for compound ~9).
The alcohol derivative (13) can be synthesized via reduction of (6) under st~n~A~d conditions, for example with NaBH4 in a suitable solvent such as ethanol.
The alcohol derivative (13a) can be synthesized by addition of a Grignard reagent of the formula RlOMgBr to the ketone (6) under st~n~d conditions. For instance two mole eguivalents of the Grignard can be reacted with one mole equivalent of (6) in a suitable solvent such as THF or diethyl ether at temperatures between -78~C and 25~C.
The Grignard reagent RlOMgBr can be prepared in situ by reacting an alkyl halide of the formula RlOBr with ~gnefiium metal in a suitable solvent such as THF or diethyl ether at temperatures between 0~C and reflux. The alkyl halide of formula RlOBr is either WO 97/23459 PCT~US96/18925 commercially available or can be prepared by methods known by one skilled in the art.
The ketone (6) can be reacted with a hydrazine of formula H2NNR6R6a, wherein R6 and R6a are as defined in Formula I, to yield the hydrazone (14) under st~n~A~d conditions such as refluxing in suitable solvent such as methanol or ethanol.
The keto acid (6) is reacted with amine (R6R6aNH) to yield the amide 13b by first stirring the keto acid (6) with a coupling agent such as CDI or DCC in a suitable solvent such as THF, DCM, or DMF at temperatures between 0~C and 100~C.
Compounds of Formula I wherein n = 0, Ar is as defined in Formula I, and Rl, R2, and R3 are hydrogen, Y = N, and R4 is OH can be synthesized according to the se~uence described in Scheme 4.
Aniline derivatives (15) are condensed with bis(2-chloroethyl)amine hydrochloride (16) in a solvent such as chlorobenzene at temperatures between 95~C and reflux to ~urnish the arylpiperazine hydrochloride (17). The aryl piperazine (17) is reacted with the aryl fluoride (5) in a m~nner similar to that described for compound (6) in Scheme 2 to obtain the correspo~; ng piperazine (18).
The compounds of Formula I wherein n = 1, Rl, R2, and R3 are hydrogen, R4 is OH, and Ar and Y are as defined in Formula I can be prepared as set forth in Scheme 5.
In Scheme 5, the phosphonoacetate (19) is reacted with an aldehyde of formula R8CHO to yield the 2-alkenoic ester t20) by stirring in a suitable solvent such as tetrahydrofuran (THF) in the presence of a strong base such as sodium hydride or lithium diisopropylamide at temperatures between 0~C and reflux. The 2-alkenoic ester (20) is reacted with the malonate of ~ormula CH2(CO2CH2CH3)2 to yield the =
W O 97/23459 PCTnUS96/18925 triester (21) by stirring in a suitable solvent such as absolute ethanol in the presence of a strong base such as sodium ethoxide at temperatures between 20~C and reflux. The triester (21) is hydrolyzed and decarboxylated in one pot to yield the diacid (22) by stirring in an as~ueous acid such as hydrochloric acid (1 to 12 M) at temperatures between 20~C and reflux.
The diacid (22) is cyclodehydrated to yield the cyclic anhydride (23) by stirring with a suitable dehydrating agent such as acetic anhydride in a suitable solvent such as acetic acid at temperatures between room temperature and reflux. The cyclic anhydride (23) is reacted with a halo-benzene of the formula C6H5-halo, where halo is fluorine or chlorine, to yield the keto-acid (24) by stirring in a suitable solvent such as dichloromethane or nitrobenzene in the presence of a catalyst such as all~m;nllrr chloride (AlC13) at temperatures between -40~C and 100~C. The keto-acid (24) is then converted to acid (25) by reaction with either (4) or (17) represented by the general Formula II in a milnne~ similar to that described for compound (6).
Compounds of ~ormula I wherein n = 0, Ar, R2, and R3 are as defined in Formula I, Rl is hydrogen, and R4 is OH can be synthesized according to the secauence described in Scheme 6.
R or S 4-benzyl-2-oxazolidinone is acylated with (26) via deprotonation with a suitable base such as NaH
and reaction with the acid chloride (26) to afford a compound of formula (27). The compound of formula (27) is deprotonated with potassium hexamethyldisilazide at -78~C and reacted with halide (28) at temperatures from -78~C to room temperature to give a compound of formula (29). Diastereomers of (29) are separated by a suitable method such as column chromatography on silica gel or HPLC, the oxazolid;no~e is le~-lov~d with LiOH and W O 97/23459 PCT~US96/18925 hydrogen peroxide to give the carboxylic acid derivative, and the carboxylic acid is converted to an acid chloride with oxalyl chloride in a suitable solvent such as THF to give a compound of formula (30).
A compound of formula (30) is reacted with N,O-dimethyl hydroxylamine hydrochloride in the presence of pyridine to afford a compound of formula (31).
Aryl anhydride (23a) is synthesized from an aldehyde of formula ArCHO as set forth in Scheme 5 for compound (23) or from commercially available intermediates correspo~ng to (20-22). Compound (23a) is con~nqed with 4-bromoaniline in a suitable solvent such as toluene, at room temperature to reflux. The resulting adduct is cyclized with acetic anhydride in acetic acid to afford imide (32), which is reduced with LiBH4JTMSCl in a solvent such as THF to yield the compound of formula (33). The aryl bromide (33) is reacted with a suitable alkyl lithium such as n-butyl lithium in a suitable solvent such as THF or diethyl 2~ ether at temperatures between -80~C and 25~C, and the resulting product, an aryl lithium, is reacted with Weinreb amide (31) to afford the adduct (34), which is debenzylated under st~n~rd conditions such as catalytic reduction using hydrogen gas and a suitable catalyst such as 5% palladium on barium sulfate in a suitable solvent such as THF or ethanol, to afford compounds of formula ( 35).
Compounds of Formula I, wherein n = 0, Ar, and Rl, R2, and R3, are as defined in Formula I, and R4 is OH
can be synthesized according to the se~uence described in Scheme 7.
A compound of formula (36), commercially available or synthesized by methods known in the art, is converted to a compound o~ formula (37) as described for compound (6) in Scheme (2). The ester (37) is hydrolyzed to the carboxylic acid under st~n~A~d W O 97/234~9 PCT~US96/18925 conditions such as KOH in ethanol, and the acid is reacted with a suitable coupling agent such as carbonyl diimidazole in dichloromethane or THF and N,O-dimethylhydroxylamine to give the amide (38). A
compound of formula (38) is reacted with a Grignard reagent of formula R2CH2MgX (X = Cl,Br) commercially available or synthesized by stAn~d methods known in the art, in a solvent such as THF or diethyl ether to give a ketone of formula (39). The ketone (39) is converted to the a-bromoketone (40) by reaction with N-bromosuccinimide.
A compound of formula (41) is synthesized via a method analogous to that described for compound (27) from R or S 4-benzyl-2-oxazoli~ino~e. Compound (41) is deprotonated with potassium h~m~thyldisilazide and reacted with a-bromoketone (40) to afford compound (42). Diastereomers of (42) are separated by a suitable method such as column chromatography on silica gel or HP~C, and the oxazolidinone is removed with LioH
and hydrogen peroxide to afford compounds of formula (43).
The compounds of formula (18, 25, 35, and 43) shown in Sc~m~s 4, 5, 6, and 7, respectively, can be converted to their correspo~fl; ng keto-acid derivatives as set forth in Scheme 3 by substituting compounds (18, 25, 35, and 43) for compound (6) in Scheme 3.
The compounds of Formula la where R2 or R3 is NH2 are synthesized by general route B depicted in Scheme 1 utilizing Va where R2 or R3 is NHCOCF3 (trifluromethylamide). The amide is then deprotected to afford la (R2 or R3 is NH2) under st~n~d conditions such as potassium or sodium carbonate in a suitable solvent such as MeOH or EtOH at temperatures between 0~C and reflux.
W O 97/Z3459 PCTnJS96/18925 Scheme 1 Route A
5Ar--Y~NH + F~ ~ K2C03 II ~1 III
10Route B O O
~ /~~~\ 11 . ~ Lewis Ar--Y~N~> + Cl~ (W)n~ : 3 ACid IV R V
o O O
Va Ar--Y N~M + LJ~ (W)n~R4 ~ Ia VI VI I
W O 97/23459 PCT~US96118925 Scheme 2 1. nBuLi, THF, -78~C HO ~ conc. HCl ArBr N ~ ~ Ar ~ N ~ Ph AcOH
Ph (2) ~ H2, 50 psi ~
Ar ~ N ~ ~HCl ~ Ar ~ NH ~HCl Ph 10% Pd/C
(3) 25-50~C (4) 3K2CO3 ~ Ar ~ N ~ CO2H
F ~C~2H ( 6 ) (5) W O 97~3459 PCT~US96/~892S
C~
_ _O
a (~
FL~ @~ O ~ <O ~
r¢
W O 97/23459 PCT~US96/1892 Scheme 4 Cl ArNH2 ~HCl+ HCl-IID ~ ~ Ar--N NH ~HCl 2 ~ Ar--N N~C02 H
(5) (18) Scheme 5 CO 2Et tEto)2 p CO2Et R3CHo ~ ~ C~2Et CO2Et (19) NaH, THF (20) NaOEt, EtoH
10 EtO2C ~ 6M HCl> HO2C ~ 2 Ac2O
EtO2C CO2Et AcOH
(21) (22) ~ ~ O AlC13, CH2C12~ CO2H
(24) (23) ~8 DYSO ~ ~ CO2H
(25) W O 97/23459 PCT~US96/18925 Scheme 6 HN O
~ 1. NaH
Ph - 2.R2 ~ Cl (26) ~ O
~ (27) - Ph o 1. C}~S
~ 2. Br ~ CO2CH2Ph Ar ~ O (23a) 3 (28) O O N ~ CO2CH2Ph 1. H2N ~ Br ~ R2 t29) 2. Ac20, AcOH Ph 1. Separate dia6tereomers ~ /~~~~ 2. LioH/H2o2 Ar ~ N ~ Br (32) ~ R3 1LiBH4, TMSCl Cl ~ C02CH2Ph Ar ~ N ~ Br (33) 1 HIMe Me-lN ~ CO2CH2Ph (31) ~ MeO R2 Ar ~ N ~ CO2CH2Ph (34) * designates R or S
H2, Pd/C R3 Ar ~ N ~ CO2H (35) CA 02236096 l998-04-28 WO 97/23459 PCT~US96/18925 Scheme 7 halo R 3K2CO3 ~ ~ ~ C~23t 1. KOH, EtOH ~ N ~ ,OMe R MgX
2. CDI, MeOH \~ ~ / N~ THF
(MeO)MeNH '- ~ Me (38) ~ ~1 ~ SllN~riBrl~m;~~ ~
Ar ~ N ~ ~Ar ~ N ~Br (39) R1 R2 (40)R1 R2 O O O
Ph ~ R3 ~
C1 (41) (26a) ~ N O
1. Separa~e 2 O
2. LiOH/H2O2 ~ ~42) R Ph Ar ~ N ~ CO2H * designates R or S
~ 3) R
W O 97/23459 PCT~US96/18925 The compounds o~ the present invention can be prepared and A~m; n; stered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be ~m; n; stered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be ~m; n; stered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be ~m;n; stered trans~erm~lly. It will be obvious to those skilled in the art that the following dosage ~orms may comprise as the active component, either a compound of Formula I or a correspo~;ng pharmaceutically acceptable salt of a compound o~ Formula I.
For preparing phArm~ceutical compositions from the compounds of the present invention, ph~m~ceutically acceptable carriers can be either solid or li~uid.
Solid form preparations include powders, tablets, pil}s, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, susp~n~;ng agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the ~inely divided active component.
In tablets, the active component is mixed with the carrier having the necessary b;n~;ng properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, W O 97/2345~ PCT~US96/1892 dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term ~preparation~ is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral A~m;n;stration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liguid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in agueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thicken;ng agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known SUSp~n~; ng agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liguid form preparations for oral ~m; n; stration. Such W O 97/Z3459 PCT~US96/1892 liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses cont~; n; ng appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the pac~age cont~;n;ng discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate nl7mhe~ of any of these in packaged form.
The guantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, arthritis, or other auto;mml~ne or inflammatory disorders dependent upon tissue invasion by leukocytes, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
The dosages, however, may be varied dep~n~; ng upon the reguirements of the patient, the severity of the condition being treated, and the compound being CA 02236096 l998-04-28 W O 97/23459 PCTrUS96/1892S
employed. Determ~n~tion of the proper dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased ~y small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and ~m;~; stered in portions during the day if desired.
The following nonlimiting examples illustrate the inventors' preferred methods ~or preparing the compounds of the invention.
4-Oxo-4-r4-(4-~henvl-~i~eridin-1-vl)-~henYll-butYric ~cid A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol), 3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassium carbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under an atmosphere of nitrogen at 120~C :Eor 18 hours. The mixture was allowed to cool, diluted with water (100 mL), and brought to pH 2 dropwise with 1 M HCl. The resulting solid was filtered, washed with water, and dried in vacuo to yield a pale orange solid as the title compound (11.2 g, %C,H,N found: 74.54, 6.98, 4.07).
4-~xo-4-r4-(4-~henvl-~i~eridin-1-Yl)-PhenYll-butyric acid ~otassium salt A stirred mixture of 4-phenyl-piperidine (8.1 g, 0.05 mol), 3-(4-fluorobenzoyl)-propionic acid (9.9 g, 0.05 mol), and potassium carbonate (7.0 g, 0.05 mol) in DMSO (50 mL) was heated under an atmosphere of nitrogen at 120~C for 18 hours. The mixture was allowed to cool and diluted with water (100 mL). The resulting solid W O 97/23459 PCT~US96/18925 was filtered and washed with water. The xesulting solid was recrystalized from boiling methanol and dried in vacuo to yield a pale brown solid as the title compound hydrate [6.6 g, 300 MHz];
lH NMR (DMSO): 8 7.82 (d, 2H, J = 8.1 Hz), 7.33-7.20 (m, 5H), 7.01 (d, 2H, J = 8.1 Hz), 4.06 (d br, 2H, J = 12.9 Hz), 2.97-2.90 (m, 4H), 2.78 (m, lH), 2.11 (t, 2H, J = 7.5 Hz), 1.86 (br d, 2H, J = 11.7 Hz), 1.70 (m, 2H)].
N-Hvdroxv-4-oxo-4- r 4-t4-phenYl-~i~eridin-l-~l)-~henYll-butvramide (a) 4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (1.0 g, 2.96 mmol) (Example 1) and carbonyldimidazole (0.51 g, 3.11 mmol) were stirred for 18 hours at room temperature under nitrogen. A slurry of O-Benzylhydroxylamine (0.57 g, 3.55 mmol) and triethylamine (0.49 mL, 3.55 mol) in THF (5 mL) was added in one portion and the resulting mixture refluxed for 18 hours, filtered, and washed with THF (50 mL).
The filtrate was concentrated and columned on silica gel eluting with 50~ ethyl acetate in hexanes to give 4-benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.68 g, %C,H,N found: 76.01, 6.89, 6.26).
(b) N-benzyloxyimino-4-~4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (0.41 g, 0.93 mmol) was stirred at room temperature with 5% Pd/BaSO4 (0.04 g) in methanol (50 mL) under 50 psi o~ H2 for 10 hours. The mixture was filtered and washed with MeOH, and the filtrate was concentrated and triturated with ethyl acetate to yield the title compound as a white solid (0.25 g, %C,H,N
found: 71.03, 7.05, 7.65).
W O 97/234~9 PCT~US96/18925 E~ PLE 4 E/Z-4-HvdroxYimino-4-r4-(4-~henYl-~i~eridin-l-vl)-~henYll-butvric acid Sodium carbonate (0.80 g, 5.76 mmol) was q~l~e~l to hydroxyl~m;n~ hydrochloride (0.80 g, 11.5 mmol) in water (3 mL), and the mixture stirred ~or 1~ minutes with ice cooling. The resulting mixture was added to 4-oxo-4-~4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid (2.99 g, 8.86 mmol) ~Example 1) in ethanol (50 mL) and the resulting mixture refluxed for 6 hours, concentrated to one-third volume, and allowed to cool.
The resulting precipitate was dissolved in hot sodium bicarbonate solution, filtered, and the filtrate acidified with lM HCl to yield a slurry which was filtered, washed with water, and dried in vacuo to give the title compound as a white solid (1.17 g, %C,H,N
~ound: 71.77, 6.79, 7.88).
E/Z-4-Benzvloxvimino-4-r4-~4-~henYl-~i~eridin-l-Yl)-~henYll-butvric acid The title compound was synthesized (0.33 g, E/Z 10:1, %~,H,N found: 76.01, 7.05, 6.20) using the method of Example 4, substituting O-benzylhydroxylamine for hydroxYl~m; ne .
4-Oxo-4-r4-~4-~henYl-~i~erazin-l-vl)-~henYll-butYri~
~cid The title compound was prepared (0.11 g, 400 MHz) using the method of Example 1 substituting N-phenylpiperazine ~or 4-phenylpiperidine.
H NMR (DMSO): ~ 7.86 (d, 2H, J = 8.8 Hz), 7.26-7.22 (m, 2H), 7.06-6.99 ~m, 4H), 6.81 (t, lH, J = 7.2 Hz), 3.50-3.45 (m, 2H), 3.29-3.26 (m, 2H), 3.12 (t, 2H, J = 6.0 Hz), 2.5 (t, 2H).
W O 97/23459 PCT~US96/18925 EX~PLE 7 ) 3-MethYl-5-oxo-5- r4- (4-~henvl-~i~eridin-1-vl)-~henvll-~entanoic acid A stirred mixture of 4-phenylpiperidine (0.161 g, 1.00 mmol), (i)3-methyl-5-(4-chloro-phenyl)-pentanoic acid (0.241 g, 1.00 mol), and potassium carbonate (0.276 g, 2.00 mol) in dry dimethyl sulfoxide was heated in a sand bath (160~C) under nitrogen for 15 hours. The mixture was cooled and diluted with water. The a~ueous solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH = 6. A brown gum formed. The li~uid was decanted, and the residue was chromatographed on silica gel (38 g, 230-400 mesh~ eluting with dichloromethane-methanol (20:1, 15 x 40 mL). Fractions cont~;n;ng product were combined and rotary evaporated to give a brown glass. The glass was crystallized from methanol after a hot gravity filtration to give the title compound as a tan solid; yield 0.0360 g (10%, mp = 134-135~C).
Claims (39)
1. A compound of Formula I
Ar is selected from phenyl, phenyl substituted with alkyl, N02, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 wherein R5 is as defined above, or NHCOR5 wherein R5 is as defined above, 2-naphthyl, or heteroaryl;
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and g is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)vSR5, wherein v and R5 are as defined above, -(CH2)vCO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z iS wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1;
R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C=O
or NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
Ar is selected from phenyl, phenyl substituted with alkyl, N02, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 wherein R5 is as defined above, or NHCOR5 wherein R5 is as defined above, 2-naphthyl, or heteroaryl;
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and g is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)vSR5, wherein v and R5 are as defined above, -(CH2)vCO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z iS wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1;
R4 is OH, NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5, when R4 is NR6R6a then Z must be C=O
or NHOR9 wherein R9 is hydrogen, alkyl, or benzyl;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
2. A compound according to Claim 1 wherein Ar is phenyl; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
3. A compound according to Claim 2 wherein Y is CH;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
4. A compound according to Claim 3 wherein Z is C=O;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
5. A compound according to Claim 3 wherein n is zero;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
6. A compound according to Claim 5 wherein R1, R2, and R3 are hydrogen; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
7. A compound according to Claim 1 wherein R4 is OH;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
8. A compound according to Claim 2 wherein Z is C=NOR5; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
9. A compound according to Claim 1 wherein Y is N;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
10. A compound according to Claim 9 wherein n is 1;
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
11. A compound according to Claim 10 wherein Ar is phenyl; Z is C=O; Y is CH; and R4 is OH; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
12. A compound according to Claim 10 wherein Ar is phenyl; Z is C=O; R1, R2, and R3 are hydrogen; and R4 is OH; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
13. A compound according to Claim 12 wherein Ar is phenyl; Z is C=O; R1, R2, and R3 are hydrogen;
R4 is OH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
R4 is OH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
14. A compound according to Claim 10 wherein Ar is phenyl; Z is C=O; R1, R2, and R3 are hydrogen;
R4 is NHOH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
R4 is NHOH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
15. A compound according to Claim 10 wherein Ar is phenyl; Z is C=N-OH; R1, R2, and R3 are hydrogen;
R4 is OH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
R4 is OH; and n is zero; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
16. A compound according to Claim 9 wherein R1 and R2 are hydrogen; and corresponding isomers thereof;
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
17. A compound according to Claim 5 which is selected from the group consisting of:
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and (~)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid.
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid, potassium salt;
N-Hydroxy-4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyramide;
E/Z-4-Hydroxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
E/Z-4-Benzyloxyimino-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid;
4-Oxo-4-[4-(4-phenyl-piperazin-1-yl)-phenyl]-butyric acid; and (~)3-Methyl-5-oxo-5-[4-(4-phenyl-piperidin-1-yl)-phenyl]-pentanoic acid.
18. A compound which is 4-oxo-4-[4-(4-phenyl-piperidin-1-yl)-phenyl]-butyric acid.
19. A method of inhibiting a matrix metalloproteinase comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
20. A method of inhibiting gelatinase A comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
21. A method of inhibiting stromelysin-1 comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
22. A method of preventing atherosclerotic plaque rupture comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
23. A method of inhibiting aortic aneurism comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
24. A method of inhibiting heart failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
25. A method of preventing restenosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
26. A method of controlling periodontal disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
27. A method of treating corneal ulceration comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
28. A method of treating burns comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
29. A method of treating decubital ulcers comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
30. A method of treatment for healing wounds comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
31. A method of treating cancer comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
32. A method of treating arthritis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
33. A method of treating autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 in unit dosage form.
34. A method of treating multiple sclerosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to Claim 1 acid in unit dosage form.
35. A pharmaceutical composition comprising a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
36. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a therapeutically acceptable excipient, diluent, or carrier.
37. A method for preparing a compound having the Formula Ia Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 wherein R5 is as defined above, or NHCOR5 wherein R5 is as defined above, 2-naphthyl, heteroaryl;
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)2SR5, wherein v and R5 are as defined above, -(CH2)vCO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is , wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula II
wherein Ar and Y are as defined above with a compound of Formula III
wherein W, n, R1, R2, and R3 are as defined above under basic conditions using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology.
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)2SR5, wherein v and R5 are as defined above, -(CH2)vCO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is , wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula II
wherein Ar and Y are as defined above with a compound of Formula III
wherein W, n, R1, R2, and R3 are as defined above under basic conditions using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology.
38. A method for preparing a compound having the Formula Ia Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR5 wherein R5 is hydrogen or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 wherein R5 is as defined above, or NHCOR5 wherein R5 is as defined above, 2-naphthyl, heteroaryl;
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)vSR5, wherein v and R5 are as defined above, -(CH2)v CO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is , wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C-NOR5 wherein R5 is as defined above, or C-N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula IV
wherein R1, Ar, and Y, are as defined above with a compound of Formula V or Va wherein W, n, R2, and R3 are as defined above in the presence of a Lewis acid at about 0°C to about 150°C using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)vSR5, wherein v and R5 are as defined above, -(CH2)v CO2R5, wherein v and R5 are as defined above, or -(CH2)vCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally -(CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is , wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C-NOR5 wherein R5 is as defined above, or C-N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula IV
wherein R1, Ar, and Y, are as defined above with a compound of Formula V or Va wherein W, n, R2, and R3 are as defined above in the presence of a Lewis acid at about 0°C to about 150°C using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology
39. A method for preparing a compound having the Formula Ia Ar is selected from phenyl, phenyl substituted with alkyl, NO2, halogen, OR5 wherein R5 is hydrogen, or alkyl, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, COR5 wherein R5 is as defined above, CONHR5 wherein R5 is as defined above, or NHCOR5 wherein R5 is as defined above, 2-naphthyl, heteroaryl;
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)VSR5, wherein v and R5 are as defined above, -(CH2)VCO2R5, wherein v and R5 are defined above, or -(CH2)VCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally (CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula VI
wherein M is Li, Mg-halogen or (Cu-halogen)1/2 and Ar, and Y, are as defined above with a compound of Formula VII
wherein L is halogen, or -N(Me)OMe, W, n, R2, and R3 are as defined above and D is a suitably protected ester which is subsequently removed using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology.
R1 is selected from hydrogen, methyl, ethyl, NO2, halogen, OR5 wherein R5 is as defined above, CN, CO2R5 wherein R5 is as defined above, SO3R5 wherein R5 is as defined above, CHO, or COR5 wherein R5 is as defined above;
R2 and R3 are the same or different and independently selected from hydrogen, alkyl, -(CH2)v-aryl wherein v is an integer from 1 to 5, -(CH2)v-heteroaryl wherein v is as defined above, -(CH2)v-cycloalkyl wherein v is as defined above, -(CH2)p-X-(CH2)q-aryl wherein X is O
or S and p and q is each zero or an integer of 1 to 5, and the sum of p + q is not greater than an integer of 5, -(CH2)p-X-(CH2)q-heteroaryl wherein X, p, and q are as defined above, -(CH2)tNR6R6a, wherein t is zero or an integer of from 1 to 9 and R6 and R6a are each the same or different and are as defined above for R5, -(CH2)VSR5, wherein v and R5 are as defined above, -(CH2)VCO2R5, wherein v and R5 are defined above, or -(CH2)VCONR6R6a, wherein R6 and R6a are the same or different and are as defined above for R5 and v is as defined above;
R3 is additionally (CH2)rR7 wherein r is an integer from 1 to 5 and R7 is 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, or 1,3,-dihydro-1,3-dioxo-benzo[f]isoindol-2-yl;
Y is CH or N;
Z is wherein R10 is as defined above for R2 and R3, and is independently the same or different from R2 and R3 provided that when Z is , then R4 must be OH, C=O, C=NOR5 wherein R5 is as defined above, or C=N-NR6R6a wherein R6 and R6a are the same or different and are as defined above for R5;
W is -CHR5 wherein R5 is as defined above;
n is zero or an integer of 1; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof may be prepared by reacting a compound of Formula VI
wherein M is Li, Mg-halogen or (Cu-halogen)1/2 and Ar, and Y, are as defined above with a compound of Formula VII
wherein L is halogen, or -N(Me)OMe, W, n, R2, and R3 are as defined above and D is a suitably protected ester which is subsequently removed using conventional methodology to afford a compound of Formula Ia and, if desired, converting a compound of Formula Ia to a pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology and, if further desired, converting the obtained pharmaceutically acceptable salt of a compound of Formula Ia by conventional methodology.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US948995P | 1995-12-22 | 1995-12-22 | |
| US60/009,489 | 1995-12-22 | ||
| PCT/US1996/018925 WO1997023459A1 (en) | 1995-12-22 | 1996-11-27 | Aromatic keto-acids and their derivatives as inhibitors of matrix metalloproteinases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2236096A1 true CA2236096A1 (en) | 1997-07-03 |
Family
ID=29405605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2236096 Abandoned CA2236096A1 (en) | 1995-12-22 | 1996-11-27 | Aromatic keto-acids and their derivatives as inhibitors of matrix metalloproteinases |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2236096A1 (en) |
-
1996
- 1996-11-27 CA CA 2236096 patent/CA2236096A1/en not_active Abandoned
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