ZA200105222B - Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (MMP) inhibitors/TNF-alpha converting enzyme (TACE) inhibitors. - Google Patents

Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (MMP) inhibitors/TNF-alpha converting enzyme (TACE) inhibitors. Download PDF

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ZA200105222B
ZA200105222B ZA200105222A ZA200105222A ZA200105222B ZA 200105222 B ZA200105222 B ZA 200105222B ZA 200105222 A ZA200105222 A ZA 200105222A ZA 200105222 A ZA200105222 A ZA 200105222A ZA 200105222 B ZA200105222 B ZA 200105222B
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Prior art keywords
phenyl
sulfonyl
methyl
ynyloxy
hydroxy
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ZA200105222A
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Jeremy Ian Levin
James Ming Chen
Vincent Premarana Sandanayaka
Jannie Lea Baker
Aranapakam Mudumbai Venkatesan
Arie Zask
Mila Ti Du
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

© WO'00/44723 PCT/US00/01864
ALKYNYL CONTAINING HYDROXAMIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR
USE AS MATRIX METALLOPROTEINASE (MMP) INHIBITORS / TNF-ALPHA CONVERTING
ENZYME (TACE) INHIBITORS
FIELD OF INVENTION
This invention relates to acetylenic hydroxamic acids which act as inhibitors of TNF-a converting enzyme (TACE). The compounds of the present invention are useful in disease conditions mediated by TNF-a, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement _ membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology.
Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture ) associated with atherosclerosis. Other conditions mediated by MMPs are restenosis,
MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal : ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren’s syndrome, myopia, ocular tumors, ocular angiogenesis/neo-
vascularization and corneal graft rejection. For recent reviews, see: (1) Recent
Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H.
Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal
Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5)
Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3): 281-259.
TNF-a converting enzyme (TACE) catalyzes the formation of TNF-o from membrane bound TNF-a precursor protein. TNF-o is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W.
Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women's
Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi,
G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al. J. Clin. Invest. —— - © 1988, 81; 1925; Miethke; et. al- J. Exp. Med. 1992, 175,91}, graft rejection {Piguet, = _ ‘ 15 P. F; Grau, G. E;; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; ‘ Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.), anorexia, inflammation [Ksontini,
R,; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558.1], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379: Ferrari, R.; Bachetti, T.; et. al.
Circulation, 1995, 92(6), 1479.], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87.1 and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15(6), 533.]], in addition to its well-documented antitumor properties [OId, L.
Science, 1985, 230, 630.]. For example, research with anti-TNF-o antibodies and transgenic animals has demonstrated that blocking the formation of TNF-a, inhibits the progression of arthritis [Rankin, E.C.; Choy, EH.; Kassimos, D.; Kingsley, G.H.;
Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334;
Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), aul97-M2Z.}. This observation has recently been extended to humans as well as described in “TNF-q in
Human Diseases", Current Pharmaceutical Design, 1996, 2, 662.
© WO 00/44723 PCT/US00/01864
It is expected that small molecule inhibitors of TACE would have the potential for treating a variety of disease states. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20] Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.
Sulfone hydroxamic acid inhibitors of MMPs, of general structure I have been disclosed [Burgess, L.E.; Rizzi, J.P.; Rawson, D.J. Eur Patent Appl. 818442.
Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns,
C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W.
PCT Int. Appl. WO 97/24117. Bender, S.L.; Broka, C.A.; Campbell, JA; Castelhano,A.L.; Fisher, L.E.; Hendricks, R.T.; Sarma, K. Eur. Patent Appl. 780386. Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Hu, B.; O'Dell, M. J. PCT i
Int. Appl. WO 98/38163.]. An exemplification of this class of MMP inhibitor is RS- 130830, shown below.
Ky
HO S
1 Ry" O2 . l a ok cl
RS-130830
Within the sulfone-hydroxamic acid class of MMP inhibitor, the linker between the sulfone and hydroxamic acid moieties has been extended to three carbons (I, n = 2) without significant loss in potency [Barta, T. E.; Becker, D. P.; Villamil, C. L;
Freskos, J. N.; Mischke, B. V.; Mullins, P. B.; Heintz, R. M.; Getman, D. P.;
McDonald, J. J. PCT Int. Appl. WO 98/39316. McDonald, J. J.: Barta, T. E ;
Becker, D. P.; Bedell, L. J; Rao, S. N.; Freskos, J. N.; Mischke, B. V. PCT Int.
Appl. WO 98/38859.].
Piperidine sulfone hydroxamic acids, I (n = 1) have been reported [Becker,
D. P.; Villamil, C. I; Boehm, T. L.; Getman, D. P.; McDonald, J. J.; DeCrescenzo,
G. A. PCT Int. Appl. WO 98/39315.]). Similar piperidine derivatives in which the methylene linking the piperidine ring to the sulfone has been deleted (IL, n = 0) have been reported [ Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Baker, J. L. PCT Int.
Appl. WO 98/37877.].
Ry ), if
Sulfone-hydroxamic acids II, in which a hydroxy! group has been placed alpha to the hydroxamic acid, have been disclosed [Freskos, J. N.: Boehm, T. L,; Mischke, B. V.; Heintz, R. M.; McDonald, J. J.; DeCrescenzo, G. A.; Howard, S. C.
PCT Int. Appl. WO 98/39326. Robinson, R. P. PCT Int. Appl. WO 98/34915 ]. oncdocg
HO Ry 2 1]
Sulfone-based MMP inhibitors of general structure IV, which utilize a thiol as the zinc chelator, have been reported [Freskos, J.N.; Abbas, Z.S.; DeCrescenzo, G.A.;
Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. PCT Int. Appl.
WO 98/03164).
O2
HS.
TO
Iv
Inhibitors of stromelysin with general structure V have been disclosed [Shuker, S.B.; Hajduk, P.J.; Meadows, R.P.; Fesik, S.W. Science, 1996, 274, 1531- 1534. Hajduk, P.J.; Sheppard, G.; Nettesheim, D.G.; Olejniczak, E.T.; Shuker, S.B.;
Meadows, R.P.; Steinman, D.H.; Carrera, Jr., G.M.; Marcotte, P.A.; Severin, J.;
Walter, K.; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T.F.; Morgan, D.W_;
Davidsen, S.K.; Summers, J.B.; Fesik, SW. J. Am. Chem. Soc. 1997, 119, 5818- 5827. Olejniczak, E.T.; Hajduk, P.J.; Marcotte, P.A.; Nettesheim, D.G.; Meadows,
R.P.; Edalji, R.; Holzman, T.F.; Fesik, SW. J. Am. Chem. Soc. 1997, 119, 5828- 5832. Fesik, S. W.; Summers, J. B.; Davidsen, S. K.; Sheppard, G. S.; Steinman, D.
H.; Carrera, G. M.; Florjancic, A.; Holms, J. H. PCT Int. Appl. WO 97/18188.].
Poi HOH
Ri
R2
Vv
Salah et al, Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction.
Subsequently, they were tested for their fungicidal activity. . [L ~ _Mannich Reaction [LL ~~
R Z « conton RH Z S$ ° : J, J, HN ~—
N
1
Some sulfone carboxylic acids are disclosed in U.S. patent 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-oo converting enzyme } . (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal i. 5 wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and
HIV infection.
In accordance with this invention there is provided a group of compounds of general formula I:
R2 0 ~ Y. nd A Riz ak Na (C)n ; Ri A i
Lo 10 OH wherein:
R, is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl! of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C4-
Cg-cycloheteroalkyl;
R, and R, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH,; .
R, is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 } carbon atoms, -C(O)-R,, -SO,-R,, -C(0)-NHR, -C(O)NR,R,, -C(O)R NR.R,, -C(0)-OR,, -C(NH)-NH.,.
R, and R, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C4-Cg- cycloheteroalkyl;
© WO 00/44723 PCT/US00/01864
R, R, R. and R. are each, independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-Cg-cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and R10 or R10 and R11, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a -C4-Cg-cycloheteroalkyl ring;
R12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-Cg-cyclo- heteroalkyl, or alkyl of 1-6 carbon atoms;
AisO,S, SO, SO,, NR,, or CH,;
Xis 0, §, SO, SO,, NR,, or CH,;
Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and n is 0-2; or a pharmaceutically acceptable salt thereof.
In some preferred aspects of the invention, Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl, with the proviso that A and X are not bonded to adjacent atoms of Y.
In still other preferred embodiments of the invention Y is phenyl, thienyl or . furanyl. :
In accordance with certain preferred embodiments of the invention R, and R,, : together with the carbon atom to which they are attached form a C,-C, cyclohetero- alkyl ring and K is NR.
The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are: 1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4- carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperdine-4- carboxylic acid hydroxyamide;

Claims (1)

1. A compound of formula Ry Rs Re Ro 1 CA a% “Na (Chn Ry 4, ki OH I wherein: R, is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -Cy4- } Cg-cycloheteroalkyl; ’ R, and R, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R, 1s hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C(O)-R,, -SO,-R,, -C(0)-NHR,, -C(O)NRR,, -C(O)R,NR.R,, -C(0)-OR,, -C(NH)-NH.,. R, and R, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C4-Cg- . cycloheteroalkyl; R, R, R, and R are each, independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-Cg-cycloheteroalkyl, alkyl of 1-18 carbon atoms, : alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso : that one of the pairs R8 and R9, R9 and R10 or R10 and R11, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a -C4-Cg-cycloheteroalkyl ring; R12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-Cg-cyclo- heteroalkyl, or alkyl of 1-6 carbon atoms;
Ais OQ, SS, SO, SO,, NR, or CH,; XisO,S§, 80, SO, NR, or CH,; Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and nis 0-2; or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl or triazolyl or thiadiazolyl.
3. A compound of Claim 1 selected from the group consisting of: 1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4- carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4- i carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-chloro-benzyl)-piperdine-4- carboxylic acid hydroxyamide; 1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxamide; 1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4- carboxylic acid hydroxyamide; : 1-(4-Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4- carboxylic acid hydroxyamide, 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-fluoro-benzyl)-piperdine-4- carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4- . carboxylic acid hydroxamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4- i carboxylic acid hydroxamide; oo
. 4-(4-But-2-ynyloxy-benzenesulfonyl)- 1-(3,4- dichloro-benzyl)-piperidine-4- carboxylic acid hydroxamide; - 1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4- carboxylic acid hydroxyamide;
A. 5 1-(4-Bromo-benzyl)-4-[4- (4-piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl]- piperdine-4-carboxylic acid hydroxyamide; N 1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzene- sulfonyl]-piperdine-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1 - carboxylic acid tert-butyl ester; 3 4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide : i 1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfany})-piperidine-4- BN ) BN carboxylic acid hydroxyamide; — — — = -— - } 15 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic ) ) acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic ; acid hydroxyamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl }-N-hydroxytetrahydro-2H-pyran-4- carboxamide; 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine carboxamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl }-N-hydroxy-1-isopropyl-4-piperidine carboxamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl }-N-hydroxy-1-(3-pyridinylmethyl)-4- piperidine carboxamide; 3-{[4-(2-Butynyloxy)phenyl]sulfonyl } - 1-ethyl-N-hydroxy-3-piperidine- carboxamide;
© WO 00/44723 PCT/US00/01864
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-N-hydroxy-3- piperidinecarboxamide; 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]- piperidine-4-carboxylic acid hydroxyamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide; 1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4- carboxylic acid hydroxyamide; 1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-
carboxylic acid hydroxyamide; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl} methyl)-4-[ (hydroxyamino)- carbonyl}-1-piperidinecarboxylate; 4-({[4-(But-2-ynyloxy)phenyl]thio } methyl)-N-hydroxypiperidine-4- carboxamide;
tert-Butyl-4-({ [4-(2-butynyloxy)phenyl]sulfinyl } methyl)-4- [(hydroxyamino)- carbonyl]-1-piperidinecarboxylate; 4-[[[4-(2-Butynyloxy)phenyl]sulfinylJmethyl]-N-hydroxy-4-piperidine- carboxamide; tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl } methyl)-4-[(hydroxyamino)-
carbonyl]piperidine- 1-carboxylate; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl} methyl)-4-[ (hydroxyamino)- carbonyl]-1-piperidinecarboxylate; : 1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl}methyl]-N-hydroxy-4- piperidinecarboxamide; 1-(2-Butynyl)-4-({ [4-(2-butynyloxy)phenyl]sulfonyl }methyl)-N-hydroxy-4- piperidinecarboxamide hydrochloride;
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl] sulfonyl }methyl)-N-4-hydroxy- 1,4-[4-(2-butynyloxy)phenyl]sulfonyl } methyl)-N-4-hydroxy- 1,4-1]sulfonyl} -
= .. methyl)-N-4-hydroxy-1,4-piperidinedicarboxamide; Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl } methyl)-4-[ (hydroxyamino)- ip 5 carbonyl}- 1-piperidinecarboxylate; Benzyl 4-({[4-(2-butynyloxy)phenyl}sulfonyl} methyl)-4-[ (hydroxyamino)-
. carbonyl]- 1-piperidinecarboxylate; 1-Benzyl-4-({[4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N-hydroxy-4- butynyloxy)phenyljsulfonyl } methyl)-N-hydroxy-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl }methyl)-N-hydroxy-1-[(2,2,5-trimethyl- 1,3-dioxan-5-yl)carbony!]-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl }methyl)-N-hydroxy-1-[3-hydroxy-2- (hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide; a “I-{Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl }methyl)-N- “ 15 + hydroxy-4-1]-4-({[4-(2-butynyloxy)phenyl]jsulfonyl } methyl)-N-hydroxy-4- oxy)phenyl]sulfonyl } methyl)-N-hydroxy-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy-1-(4-hydroxy-2- butynyl)- henyl}sulfonyl } methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4- + piperidinecarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl} methyl)-1-ethyl-N-hydroxypiperidine- 4- carboxamide triflouroacetic acid salt; 2-chloro-5-(chloromethyl) thiophene4-({[4-(But-2-ynyloxy)phenyl]-sulfonyl }- methyl)-1-[(5-chlorothien-2-yl)methyl]-N- hydroxypiperidine-4-carboxamide . triflouroacetic acid salt; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl} methyl)-N-hydroxy- 1-(pyridin-4- ylmethyl)piperidine-4-carboxamide triflouroacetic acid salt; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy-1-(pyridin-3 ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt; 1-Benzoyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy- piperidine-4- carboxamide;
© WO 00/44723 PCT/US00/01864
4-({[4-(But-2-ynyloxy)phenyl}sulfonyl } methyl)-N-hydroxy-1 -(thien-2- ylcarbonyl) piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl }methyl)-N-1-ethyl-N-4-hydroxy- piperidine-1,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl} methyl)-N-4-hydroxy-N-1- phenyl- piperidine-1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-1- N-1-diethyl-N-4- hydroxypiperidine-1,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy-1 -(morpholin-4-
ylcarbonyl)piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-4-hydroxy-N-1 -methyl-N-1- phenylpiperidine-1,4-dicarboxamide; Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl} methyl)-4-[(hydroxyamino)- carbonyl] piperidine-1-carboxylate;
4-Methoxyphenyl4-({ [4-(but-2-ynyloxy)phenyl]sulfonyl }methyl)-4-[ (hydroxy- ] amino) carbonyl]piperidine-1-carboxylate; 4~({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy-1 -(phenylsulfonyl) piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl ymethyl)-N-hydroxy-1-[(1 -methyl- 1H-
imidazol-4-yl)sulfonyl]piperidine-4-carboxamide; 1-[2-(Benzylamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]-sulfonyl }methyl)-N-
hydroxypiperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl}sulfonyl }methyl)-N-hydroxy- 1-(2-morpholin-4- ylacetyl)piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl } methyl)-N-hydroxy- 1-[2-(4-methyl- piperazin-1-yl)acetyl]piperidine-4-carboxamide; 1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide; 1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide;
oe 1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4- carboxylic acid hydroxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-1-carbonyl)-4- piperidinecarboxamide; _ 5 Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1- piperidinecarboxylate;
- . ~~ 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(triftuoromethyl)sulfonyl}- 4- piperidinecarboxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)- 4- piperidinecarboxamide; - : 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy- 1-(2-thienylcarbonyl)- 4- piperidinecarboxamide; = 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)- — : sulfonyl]-4-piperidinecarboxamide;, ~~ To EE oo 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan- oo © S-yl)carbonyl]-4-piperidinecarboxamide; Tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl }-4-[ (hydroxyamino)carbonyl]- 1-piperidinecarboxalate; 4-{ [4-(2-butynyloxy)phenyi] sulfonyl}-N-hydroxy-4-piperidinecarboxamide "hydrochloride; Methyl ({4-{[4-(2-butynyloxy)phenyl]suifonyl }-4-[(hydroxyamino)carbonyl]- 1-piperidinyl }methyl)benzoate hydrochloride; 4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl }-4-[(hydroxyamino)carbonyl]-1- piperidinyl }methyl)benzoic acid hydrochloride; 1-[4-(Aminocarbonyl)benzyl]-4- {[4-(2-butynyloxy)phenyl]sulfonyl} -N- hydroxy-4-piperidinecarboxamide hydrochloride; Tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl } -4-[(hydroxyamino)- carbonyl]piperidine- 1-carboxalate, 4-(4-(But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride; and
PCT/US99/01864 1-(4-Bromo-benzyl)-4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4- carboxylic acid hydroxamide hydrochloride; : and pharmaceutical salts thereof.
: 4. Use of a compound according to any one of Claims 1 to 3 in the preparation of a medicament for inhibiting pathological changes mediated by TNF-a converting enzyme (TACE) in a mammal.
5. Use according to Claim 4 wherein the condition treated is rheiimatoid arthritis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease or HIV infection.
6. A pharmaceutical composition comprising a compound having the formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof; oo and a pharmaceutically acceptable carrier. Co
7. - A process for preparing a compound of formula I as claimed in claim 1, which comprises one of the following: : a) reacting a compound of formula R - Rs Re Re LL
Y. Pa “2X rd oH ‘ In Ry / \, Rio » : wherein n, X, Y, A, R,, R,, R,, R;, R,, R,, and R,, are as defined in claim 1 or a reactive derivative thereof, with a compound of formula oo AMENDED SHEET
ZA200105222A 1999-01-27 2001-06-25 Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (MMP) inhibitors/TNF-alpha converting enzyme (TACE) inhibitors. ZA200105222B (en)

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