DECICCO CARL P
CHERNEY ROBERT J
ARNER ELIZABETH
DEGRADO WILLIAM F
DUAN JINGWU
HE XIAOHUA
JACOBSON IRINA CIPORA
MAGOLDA RONALD L
NELSON DAVID
| WO1992013831A1 | 1992-08-20 | |||
| WO1997018207A2 | 1997-05-22 |
| 1. | A compound, and pharmaceutically acceptable salt forms thereof, selected from: 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[glycine npentyl ester] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N4 phenyl1butylamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[5 methOxytryptamine]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[1(2,5 dimethoxyphenyl)2glycine amidoethanol]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[glycine tbutyl ester] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L glutamic acida, g ditbutyl ester]cyclopentadecane13N hydroxycarboxamide; 2S, 135, 14R1, 7diaza8, 15dioxo9oxa14isobutyl 2 [glycine] cyclopentadecane13Nhydroxycarboxamide; 2S, 135, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N2 <BR> <BR> <BR> phenyl1butylamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[2(2 aminoethyl) 1methylpyrrole] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[2(2 aminoethyl)benzenesulphonamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L glutamic acidgcyclohexyl esterNmethyl amide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L phenylalaninepfluoroNmethylamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L phenylalaninepmethoxyN(S)amethylbenzylamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N cyclohehylmethyl amide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N3 phenyl1propyl amide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N3,3 diphenylpropyl amide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[N(2 aminoethylamino) ethyl pyrrolidine]cyclopentadecane13N hydroxycarboxamide; 25, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L3(2' naphthyl)alanineNmethyl amide]cyclopentadecane13N hydroxycarboxamide; 25, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[ethyl4 aminolpiperidine carboxylate]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[5methyl tryptamine]cyclopentadecane13Nhydroxycarboxamide; S, 135, 14Rl, 7diaza8, 15dioxo9oxa14isobutyl2[N4 trifluoromethylbenzyl amide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[L glutamic acid] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[2 (diethylamino)ethyl4amino benzoate]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[6 fluorotryptamine]cyclopentadecane13NhydroxyCarboxamide; 25, 135, 14R1, 7diaza8, 15dioxo9oxa14isobutyl2[6 methoxy tryptamine]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1, 7diaza8, 15dioxo9oxa14isobutyl 2[tryptamine]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4methylpiperazinamide)carboxamide] cyclopentadecane 1 3Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(L alanineNmorpholinamide)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(L valineNmorpholinamide)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(L tertbutylglycineNmorpholinamide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(b alanineNmorpholinamide)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (ethoxycarbonylNmorpholinamide) carboxamide] cyclopentadecane 13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(2 hydroxy2phenylethyl)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4benzylpiperazinamide)carboxamide] cyclopentadecane 1 3Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4phenylpiperazinamide) carboxamide] cyclopentadecane 1 3Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4(2pyridyl)piperazinamide) carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(a cyclopropaneethyloxycarboxamidebalanine)carboxamide] cyclopentadecane 13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2{N [glycineN4(1piperidinyl)piperidinamide]carboxamide} cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(R isopropyloxycarbonylNmorpholinamide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(S isopropyloxycarbonylNmorpholinamide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(2 hiazole4acetic acid)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(a yclopropaneethyloxycarboxamidebalanineN dimethylamide)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(a cyclopropaneethyloxycarboxamidebalanineN morpholinamide)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(2 thiazole4acetylNmorpholinamide)carboxamide] cyclopentadecane1 3Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(L <BR> <BR> <BR> serineNmorpholinamide) carboxamide] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineNpiperidinamide3carboxylic acid)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN2, 6dimethylmorpholinamide) carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4ethoxycarbonylpiperazinamide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineN4ethoxycarbonylpiperidinamide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2{N[4(1 morpholinyl)phenyl]carboxamide}cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2{N [glycineN(4(1morpholinyl)anilide)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N (glycineNpiperidinamide4carboxylic acid)carboxamide] cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N methylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[alanine Nmethylamide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2 [methylcarboxy]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[glycine Nmethylamide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[2N morpholinoethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[3N morpholinopropylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2 [pheylalanineNmethylamide] cyclopentadecane13N hydroxycarboxamide; 25, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[leucine Nmethylamide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N4 pyridylmethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(R,S) <BR> <BR> <BR> furfurylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N phenylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[t butylglycineNmethylamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N benzylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[3N(2 oxopyrrolidino) propylcarboxamide] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[2N ethylpyrrolidinocarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N3 pyridylmethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N2 (l,l,ltrifluoroethyl)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N2(2 pyridyl)ethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(R,Sl methyl 3pheylpropyl)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[3N imidazoylpropylcarboxamide] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[eNt butyloxycarbonyllysineNmethylamide] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[lysineN methylamide]cyclopentadecane13Nhydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N2 pyridylmethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 22S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[NN morpholinocarboxyamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(R) <BR> <BR> <BR> furfurylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N2(4 imidazoyl)ethylcarboxyamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[NR(2R hydroxyindane)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[NS(2S hydroxyindane)carboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N4 aminobenzylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[2N piperazinoethylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N4 methylpiperinocarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[3N(2 <BR> <BR> <BR> R,Smethylpiperidino)propylcarboxamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N(S) <BR> <BR> <BR> furfurylcarboxamide]cyclopentadecane13NhydroxyCarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2 [aspartate(Otbutyl)Nmethylamide]cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2 [aspartateNmethylamide] cyclopentadecane13N hydroxycarboxamide; 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[3 azaphenylalanineNmethylamide] cyclopentadecane13N hydroxycarboxamide; and 2S, 13S, 14R1,7diaza8,15dioxo9oxa14isobutyl2[N <BR> <BR> <BR> benzhydrylcarboxamide]cyclopentadecane13NhydroxyCarboxamide. |
| 2. | A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1. |
| 3. | A method of treating an inflammatory disease in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. |
| 4. | A method of treating a condition or disease mediated by MMPs and/or TNF and/or aggrecanase in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. |
| 5. | A method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. |
| 6. | A method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. |
| 7. | An assay for detecting inhibitors of aggrecanase, which comprises: (a) generating soluble aggrecanase, by stimulation of cartilage slices; (b) detecting aggrecanase enzymatic activity by using the soluble aggrecanase generated in (a) and monitoring production of aggrecan fragments containing the end terminus ARGSVIL; (c) evaluating inhibition of aggrecanase by comparing the amount of product produced in the presence versus absence of compound. |
BACKGROUND OF THE INVENTION There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease.
Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP's.
Osteo- and rheumatoid arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L.S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
This invention describes macrocyclic molecules that inhibit aggrecanase and other metalloproteinases. These novel molecules are provided as cartilage protecting therapeutics. The inhibiton of aggrecanase and other metalloproteinases by these novel molecules prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26kd precursor form to a 17kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock.
Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non- insulin dependent diabetes melitus. (Lohmander L.S. et al.
Arthritis Rheum. 36, 1993, 1214-22) and Crohn's disease (Macdonald T. et al. Clin. Exp. Immunol. 81, 1990, 301) Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP's are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes macrocyclic molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF product ion may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
PCT International Publication No. WO 92/213260 describes N- carboxyalkylpeptidyl compounds of general formula: wherein AA is an amino acid, as inhibitors of matrix metallproteinase mediated diseases.
PCT International Publication No. WO 90/05716 discloses hydroxamic acid based collagenase inhibitors having the general formula: PCT International Publication No. WO 92/13831 describes related hydroxamic acids having collagenase inhibiting activity with the general formula: PCT International Publication No. WO 94/02446 discloses metalloproteinase inhibitors which are natural amino acid derivatives of general formula: W095/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production.
European Patent Application Publication No. 574,758 Al, discloses hydroxamic acid derivatives as collagenase inhibitors having the general formula: GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
The compounds of the current invention act as inhibitors of MMPs, in particular aggrecanase and TNF-C, thereby preventing cartilage loss and destruction and inflammatory disorders involving TNF. The hydroxamic and carboxylic acids and derivatives are cyclic, and thus non-peptide in nature, which offers a distinct advantage over existing inhibitors because they have superior pharmacokinetic parameters. A selection of these molecules are water soluble and are orally bioavailable.
SUMMARY OF THE INVENTION This invention provides novel hydroxamic acids and carboxylic acids (described below) which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C.
The present invention also includes pharmaceutical compositions comprising such compounds and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previously, in a patient.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of the present invention (described below) for the treatment of arthritis and other inflammatory disorders as described previously.
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and TNF-C, and for the treatment of arthritis by administering a compound of the present invention in combination with one or more second therapeutic agents selected from other inhibitors of metalloproteinases, such as aggrecanase and TNF-C and/or therapeutic agents for the treatment of arthritis and inflammation.
DETAILED DESCRIPTION OF THE INVENTION This invention provides novel compounds which are useful as inhibitors of metalloproteinases, such as aggrecanase and TNF-C.
The present invention also includes pharmaceutical compositions comprising such compounds and methods of using such compounds for the treatment of arthritis and other inflammatory disorders as described previously, in a patient.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of the present invention, for the treatment of arthritis and other inflammatory disorders as described previously.
The present invention also includes methods of inhibiting metalloproteinases, such as aggrecanase and tumor necrosis factor alpha, and for the treatment of arthritis by administering a compound of the present invention in combination with one or more second therapeutic agents selected from other inhibitors of metalloproteinases, such as aggrecanase and tumor necrosis factor alpha and/or therapeutic agents for the treatment of arthritis and inflammation.
The compounds of the present invention include the following compounds, or a pharmaceutically acceptable salt or prodrug form thereof: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[glycine- n-pentyl ester] -cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N-4- <BR> <BR> phenyl-1-butylamide]-cyclopentadecane-13-N-hydroxyCarboxamid e; 2S, '3S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[5- methoxytryptamine]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[1-(2,5- dimethoxyphenyl)-2-glycine amidoethanol]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, i3S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2 [glycine- t-butyl ester] -cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L- glutamic acid-a, g -di-t-butyl ester]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl- 2 [glycine] -cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N-2- phenyl-1-butylamide]-cyclopentadecane-13-N-hydroxyCarboxamid e 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[2-(2- aminoethyl) -1-methylpyrrole] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[2-(2- aminoethyl)benzenesulphonamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L- glutamic acid-g-cyclohexyl ester-N-methyl amide]- cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L- phenylalanine-p-fluoro-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 135, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L- phenylalanine-p-methoxy-N-(S)-a-methylbenzylamide]- cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N- cyclohehylmethyl amide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2 [N-3- phenyl-1-propyl amide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N-3,3- diphenylpropyl amide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 135, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N-(2- aminoethylamino) ethyl pyrrolidine]-cyclopentadecane-13-N- hydroxycarboxamide; 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L-3(2'- naphthyl)alanine-N-methyl amide]-cyclopentadecane-13-N- hydroxycarboxamide; 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[ethyl-4- amino-1-piperidine carboxylate]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[5-methyl tryptamine]-cyclopentadecane-13-N-hydroxycarboxamide; 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[N-4- trifluoromethylbenzyl amide]-cyclopentadecane-13-N- hydroxycarboxamide; 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[L- glutamic acid] -cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[2- (diethylamino)ethyl-4-amino benzoate]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[6- fluorotryptamine]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 135, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl-2[6- methoxy tryptamine]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14-isobutyl- 2[tryptamine]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- <BR> <BR> <BR> (glycine-N-4-methylpiperazinamide)carboxamide]cyclopentadeca ne- 13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(L- alanine-N-morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(L- valine-N-morpholinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(L- tert-butylglycine-N-morpholinamide)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(b- alanine-N-morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (ethoxycarbonyl-N-morpholinamide) carboxamide] cyclopentadecane- 13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(2- hydroxy-2-phenylethyl)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-4-benzylpiperazinamide)carboxamide] cyclopentadecane- 1 3-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-4-phenylpiperazinamide)carboxamide] cyclopentadecane- 13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-4-(2-pyridyl)piperazinamide)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(a- cyclopropaneethyloxycarboxamide-b-alanine)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-{N- [glycine-N-4-(1-piperidinyl)piperidinamide]carboxamide} cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(R- isopropyloxycarbonyl-N-morpholinamide)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(S- isopropyloxycarbonyl-N-morpholinamide)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(2- thiazole-4-acetic acid)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-lsobutyl-2-[N-(a- cyclopropaneethyloxycarboxamide-b-alanine-N- dimethylamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(a- cyclopropaneethyloxycarboxamide-b-alanine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(2- thiazole-4-acetyl-N-morpholinamide)carboxamide]cyclopentadec ane- 1 3-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(L- serine-N-morpholinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-piperidinamide-3-carboxylic acid)carboxamide]cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-2,6- dimethylmorpholinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-4- ethoxycarbonylpiperazinamide)carboxamide]cyclopentadecane-13 -N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-4 -ethoxycarbonylpiperidinamide) carboxamide]cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-{N-[4-(1- morpholinyl)phenyl]carboxamideXcyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-{N- [glycine-N-(4-(1-morpholinyl)anilide)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- (glycine-N-piperidinamide-4-carboxylic acid)carboxamide] cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- methylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[alanine- N-methylamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2- [methylcarboxy]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[glycine- N-methylamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[2-N- morpholinoethylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[3-N- morpholinopropylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2- [pheylalanine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, ;4R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[leucine- N-methylamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-4- pyridylmethylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(R,S)- <BR> <BR> furfurylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamid e; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N phenylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[t- butylglycine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N benzylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[3-N-(2- oxo-pyrrolidino) propylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[2-N- ethylpyrrolidinocarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-3- pyridylmethylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-2- (1,1,1-trifluoroethyl)carboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-2-(2- pyridyl)ethylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(R,S-1- methyl -3-pheylpropyl)carboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[3-N- imidazoylpropylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[e-N-t butyloxycarbonyllysine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[lysine-N- methylamide]-cyclopentadecane-13-N-hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-2- pyridylmethylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 22S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-N- morpholinocarboxyamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(R)- <BR> <BR> <BR> furfurylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamid e; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-2(4- imidazoyl)ethylcarboxyamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-R-(2-R- hydroxyindane)carboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-S-(2-S- hydroxyindane)carboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-4- aminobenzylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[2-N- piperazinoethylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-4- methylpiperinocarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[3-N-(2- <BR> <BR> <BR> R,S-methyl-piperidino)propylcarboxamide]-cyclopentadecane-13 -N- hydroxycarboxamide 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N-(S)- furfurylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxamid e 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2- [aspartate(O-t-butyl)-N-methylamide]-cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2- [aspartate-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[3- azaphenylalanine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide; 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl-2-[N- <BR> <BR> <BR> benzhydrylcarboxamide]-cyclopentadecane-13-N-hydroxyCarboxam ide.
In the present invention it has been discovered that the compounds above are useful as inhibitors of metalloproteinases, including aggrecanase and TNF-C, and are useful for the treatment of rheumatoid arthritis, osteoarthritis and related inflammatory disorders, as described previously. These compounds inhibit the production of TNF in animal models and are useful for the treatment of diseases mediated by TNF.
The present invention also provides methods for the treatment of osteo- and rheumatoid arthritis and related disorders as described previously, by administering to a host a pharmaceutically or therapeutically effective or acceptable amount of a compound of the present invention as described above. By therapeutically effective amount, it is meant an amount of a compound of the present invention effective to inhibit the target enzyme or to treat the symptoms of osteo- or rheumatoid arthritis or related disorder, in a host.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents. Administration of the compounds of the present invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
By "therapeutically effective amount" it is meant an amount of a compound of the present invention that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to inhibit the target enzyme so as to prevent or ameliorate the inflamatory disease condition or the progression of the disease.
By "administered in combination" or "combination therapy" it is meant that a compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds herein described may have asymmetric centers.
Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention may contain asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of the present invention then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =0), then 2 hydrogens on the atom are replaced.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "Cl-Cl 0" denotes alkyl having 1 to 10 carbon atoms); in addition lower alkyl defines branched and/or unbranched alkyl chain of from 1 to 8 C atoms; "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v = 1 to 3 and w = 1 to (2v+1) ) ; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
"Alkylcarbonyl" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location.
"Alkylcarbonylamino" is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to an amino bridge, where the bridge is attached to the residue of the compound at the designated location.
"Alkylcarbonyloxy" is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
The terms "alkylene", "alkenylene", "phenylene", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of the present invention-III. Such "alkylene", "alkenylene", "phenylene", and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", "-(alkyenyl)-" and "-(phenyl)-", and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of the present invention wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the compounds of the present invention and the like.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of of the present invention is modified by making acid or base salts of the compound of the present invention.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids and the like.
The pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of the present invention formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of list with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
SYNTHESIS The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
The compounds of the present invention may be prepared by the methods outlined in the Schemes below. A diprotected 2,3- diaminopropionic acid, 2,4-diaminobutyric acid, ornithine or lysine (compound 1, Scheme 1) is converted to its corresponding amide 2 using a coupling agent such as BOP. Coupling of 1 with a diaminobenzene followed by reaction in acetic acid at 60 C produces a benzimidazole analog 3. 1 can also be converted to an aldehyde 4 which is reacted with ammonia and glyoxal trimer to give an imidazole analog 5. Deprotection of the Na-Boc group of 2, 3 and 5 using an acid such as 4 N HCl in dioxane gave compound 6. Removal of the side chain protecting group of 2, 3 and 5 using hydrogenation afforded compound 7.
Scheme 1 A. 0 0 BocHN = OH HNR5R6/BOP BocHN, NR5R6 )n>n NHCbz NHCbz 1 n=0-4 2 \. NHCH30CH3/BOP/ DIENDMF 2.LiAIHITHF H2N I-R BocHN H2N (¼)n BOP/DliNDMF NHCbz 2. AcOH/GOOC 4 V t | NH3/glyoxal trimer N < s MeOH BocHN Nw;AR ¼Nij) N N BocHN ()n H NHCbz NHCbz 3 5 B. 2,3,5 4 N HCI/dioxi \ /Pd/C/MeOH H2NR2 BocHN R2 ())n ( \)n NHCbz NH2 6 7 The synthesis of the 2,3-disubstituted succinic acid portion is described in Scheme 2 below. The acid chloride 8 (X = Cl) is converted to its oxazolidinone derivative 10 using n-butyl lithium. An asymmetric alkylation (JACS, 1982, 104, 1737) followed by removal of the chiral auxiliary converts 10 to the acid 11. A second alkylation gives compound 12. This can be epimerized with LDA and Et2AlCl to give compound 13. The benzyl ester 14 is then made by standard methods. When 14 contains R as an olefin, it can be converted to the alcohol 15 via hydroboration.
Scheme 2 0 0 I)LDA, THF, -780C ° XtX n-BuLi I)LDA, 1N x HN0 0 tB$;0;¼Br -780C \x HN -780 R R1 Brl Bn LiOH 8 9 10 0 R2 LDA LDA, THF, -7S°C 9> tBu02C - OH Ri Br Bur 11 12 R2 R2 LDA, Et2AICI 9 X BnBr ,C028zl THE -78° C ' tBuO2C - OH ' tBuO2C DBU 2) MeOH R PhH R1 13 14 rOH 9-BBN OH I H202, NaOAc J\/CO2BZI tBuO2C R1 15 Compounds of formula 118, where R2 is an amide or other functionality, can be prepared by the route shown in Scheme 24.
The succinate 109 can be converted to the carbonate 110 by 4- nitrophenyl chloroformate. This carbonate 110 reacts with a lysine derivative to yield the carbamate 111. Hydrogenation gives the amino acid 112, which is cyclized to give the macrscycle 113. The t-butyl ester is converted to the acid 114 using TFA. This material is converted to the O-benzyl hydroxamate 115 via a standard coupling reaction. The methyl ester can be hydrolyzed to the acid and then converted to the desired R2 group to give 117. This material is hydrogenated to give the final desired hydroxamate 118.
Scheme 24 O R1 0 R1 t-BuO CO2BzI chlOrOfOhrenntye t-BuO<CO2Bzl NOz 109 OH NMMITHF 110 Q XO)4] \ OH O/ CO2Me ° R1OR1 CbzHN 9 NHR6 t-BuO v CO2BZI NHCbz H2/Pd-C/MeOH K2C03/DMF 111 s CO2Me 0 N R6 0 R1 t. ¼ t-BuO N CO2Me t-BuO : CO2H N:H2 BOP/NMM - - BOP/NMM o R6 CO2Me DMF/CHCI3 </° ) NR6 112 113 O R1 H N / N CO2Me TFA HO : n - O-Benzylhydroxylamine Hydrochloride CH2C12 O ° )n BOP/NMM/DMF 0 NR6 o 114 O Rl O ° R1 NH H N no CO2Me BziO N jt J CO2H N LiOH/THF N H P H::0 NR6 ½o NR6 115 $ 116 $ O R1 BZION NH R2 N s N ) 0 " \/ R H2/Pd-C/MeOH t0 Y NR6 o O R1 HOu N JU R2 H j n=1-3 40 )S NR6 o The substituents in the above schemes are defined as follows: Rl is isobutyl; R2 is defined in Table 32 below; and R5 and R6 are hydrogen.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Not all compounds of the present invention falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Examples Abbreviations used in the Examples are defined as follows: "1X" for once, "2X" for twice, "3X" for thrice, "bs" for broad singlet, ""C" for degrees Celsius, "Cbz" for benzyloxycarbonyl, "d" for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, ''1H'' for proton, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "mp" for melting point range, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "tlc" for thin layer chromatography, "v/v" for volume to volume ratio. "a", "b", "R" and "S" are stereochemical designations familiar to those skilled in the art. l(a) 3R-Allyl-3-t-Butoxycarbonyl-2 (R)-isobutyl propanoic acid: To a stirred cooled(-78 "C) solution of 20 grams (87 mmol) of 3-t-Butoxycarbonyl-2(R)-isobutylpropanoic acid (1.15 g, 5 mmol) (previously aziotroped with toluene) in 400 mL of anhydrous THF, was added 180 mmol of LDA via cannula over 30 minutes. After stirring for 1 hour, 8.3 mL (96 mmol) of allyl bromide was added dropwise. The reaction was allowed to slowly warm to room temperature while stirring overnight. The reaction was quenched with 10% aqueous citric acid followed by removal of the volatiles under reduced pressure. The remaining material was taken into ethyl acetate and washed with H2O. The aqueous phase was then extracted 3 times with ethyl acetate and the combined organic fractions were washed with 10% citric acid, saturated NaHCO3 (2x), H2O (2x), and brine then dried over MgSO4. The solvent was removed under reduced pressure obtaining 23.3 grams (99% yield) which was carried on without purification. MS (M+Na)+ = 293 l(b) 3S-Allyl-3-t-butoxycarbonyl-2(R)-isobutyl propanoic acid: To a stirred, cooled (-78 OC) solution of 2 grams of acid l(a) (previously aziotroped 2 times with benzene) in 25 ml of anhydrous THF, was added 16.3 mmol of LDA via cannule over 15 minutes. The reaction was stirred 15 minutes at -78 "C and then for 15 minutes in a room temperature (24 ~C) water bath. The reaction was then cooled to -78 "C for 15 minutes, followed by the addition of 15.6 ml of 1 M diethylalluminum chloride (hexane). The reaction was stirred 10 minutes at -78 OC, 15 minutes in a room temperature water bath, then for 15 minutes at -78°C again, followed by quench with the rapid addition of methanol. The reaction mixture was concentrated to 1/4 its origional volume under reduced pressure and the resulting material was dissolved in 200 ml of ethyl acetate and washed with a mixture of 70 mL of 1N HCl and 100 grams of ice. The aqueous was extracted 2 times with ethyl acetate. The combined organic fractions were washed with a solution of 3.5 grams of KF dissolved in 100 mL of water and 15 mL of 1 N HCl (pH 3-4). The organic phase was washed with brine, dried with MgSO4, filtered and the solvent was removed under reduced pressure affording a 92% mass recovery. 1H NMR in acetone d-6 indicated an 8:1 anti syn ratio. MS (M+Na)+ = 293 l(c) Benzyl 3S-Allyl-3-t-butoxycarbonyl-2(R)-isobutylpropanOate: To a stirred cooled (0 "C) solution of 20.6 grams(76 mmol; of crude equilibrated acid l(b) (8:1 mixture) in 75 mL of benzene, was added 11.4 mL (76 mmol) of DBU followed by 9.98 mL (84 mmol) of benzyl bromide. After 10 minutes the reaction was refluxed for 4 hours. The reaction was then diluted to 3 times origional volume with ethyl acetate and washed 3 times with 10% aqueous citric acid. The combined aqueous was extracted 3 times with ethyl acetate. The combined organic fractions were then washed with brine, dried over MgSO4 and the volatiles were removed under reduced pressure. The resulting material was chromatographed over silica gel eluting with 2.2 % ethyl acetate/hexanes affording 16.9 grams of benzyl ester (62% yield). MS (M+NH4)+ = 378 l(d) Benzyl 3S-(3-hydroxypropyl)-3-t-butoxycarbonyl-2(R)- isobutylpropanoate: To a stirred, cooled (0 "C) solution of 5.2 grams of olefin l(c) in 100 mL of anhydrous THF, was added 72.2 mL of 0.5M 9-BBN in THF over 1 hour. The reaction was allowed to warm to room temperature while stirring 12 h. The reaction was cooled to 0 "C followed by the addition of 2.9 mL of H2O added (caution foaming) dropwise over 5 minutes. After stirring for an additional 20 minutes, 8 mL of H2O containing 3.21 grams of NaOAc was added simultaneously with 8 mL of 30% H2O2 over 5 minutes. The mixture was stirred 20 additional minutes followed by removal of the volatiles under reduced pressure. The remaining material was dissolved in ethyl acetate and washed with brine. The aqueous phase was extracted 2 times with ethyl acetate. The combined organic fractions were washed with water, brine, dried MgSO4 followed by removal of the volatiles under reduced pressure. The resulting material was chromatographed on silica gel with an eluting gradient from 1:20 to 1:10 to 1:5 ethyl acetate/hexanes affording 3.5 grams (64% yield). MS (M+H)+ = 379 Example 869: 2S,13S,14R-1,7-diaza-8,15-dioxo-9-oxa-14-isobutyl- 7-methyl-2-(N-methylcarboxamido)-cyclopentadecane-13-N- hydroxycarboxamide 869(a). To a solution of the alcohol intermediate l(d) 11.4 33.1 mmol) and 4-nitrophenyl chloroformate (10.0 g, 50 mmol) in 50 mL CH2Cl2 cooled in an ice bath was slowly added N- methylmorpholine (4.4 mL, 40 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was taken up in 200 mL EtOAc.The solution was washed with brine 3 times, dried (MgSO4) and concentrated.
Purification on a silica gel column using 10% EtOAc/hexane gave the desired product (15.0 g, 91%) as a pale yellow solid. DCI- MS: calcd (M+NHq)+=561; found 561.
869(b). To a solution of 869(a) (15.20 g, 27.28 mmol) and Na- Cbz-Nd-methyl-L-lysine methyl ester HC1 salt (11.22 g, 32.78 mmol) was added potassium carbonate (15 g, 109 mmol) and the mixture was heated at 50 C for 1 hour. Insoluble material was filtered off and EtOAc was added. The solution was washed with 10% citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 15% EtOAc/hexane gave an oily product (17.0 g, 91%). ESI-MS: calcd M+1=713.5; found 713.7.
869(c). 869(b) (10.0 g, 14.02 mmol) was dissolved in 30 mL MeOH and the solution was hydrogenated for 1 hour under atmospheric pressure using 10% Pd-C (1.0 g) as catalyst. The catalyst was filtered off and the solution was concentrated to give an oily product (6.8 g, 100%). ESI-MS: calcd M+1=489.4; found 489.6.
869(d). To a solution of BOP (9.2 g, 20.8 mmol) and diisopropylethylamine (12 mL, 70 mmol) in 600 mL CHCl3 cooled in an ice bath was dropwise added a solution of 869(c) (6.8 g, 13.9 mmol) in 50 mL CHCl3 over 2 hours and the mixture was stirred at room temperature overnight. CHCl3 was removed in vacuo and EtOAc was added. The solution was washed with 5% citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated. Purification on a silica gel column using 4% MeOH/CH2C12 gave the cyclic product (3.4 g, 46%) as a powder. ESI-MS: calcd M+1=471.4; found 471.5.
869(e). 869(d) (2.6 g, 5.5 mmol) was treated with 20 mL 50% TFA in CH2Cl2 for 1 hour and the solution was concentrated to give an oily product (2.3 g, 100%). ESI-MS: calcd. M+1=415.3; found 415.4.
869(f). To a solution of 869(e) (2.2 g, 5.3 mmol) and 0- benzylhydroxylamine hydrochloride (0.96 g, 6.15 mmol) in 10 mL DMF cooled in an ice bath was added Diisopropylethylamine (4.3 mL, 24.6 mmol) followed by BOP (2.72 g, 6.15 mmol) and the solution was allowed to stir overnight. EtOAc was added and the solution was washed with 5% citric acid, brine, NaHCO3 and brine, dried (MgSO4) and concentrated to give a crude product which was washed with ether to give the desired product as a pure solid (2.9 g, 90%). ESI-MS: calcd. M+1=520.5; found 520.5.
869(g). 869(f) (0.5 g, 0.96 mmol) was treated with 5 mL THF and 4 mL 1 N LiOH for 1 hour and the solution was acidified with TFA and concentrated. EtOAc was added and the solution was washed with brine, dried (MgSO4) and concentrated to give the acid as a solid (0.3 g, 63%). ESI-MS: calcd M+1=506.5; found 506.5.
869(h) To a solution of 869(g) (0.2 g, 0.396 mmol) and methylamine hydrochloride (0.11 g, 1.58 mmol) in 2 mL DMF cooled in an ice bath was added BOP (0.18 g, 0.4 mmol) followed by diisopropylethylamine (0.52 mL, 3 mmcl) . The mixture was allowed to stir at room temperature for 2 hours. EtOAc was added and the product precipitated out. The precipitate was filtered and washed with EtOAc and water to give the title compound as a solid (0.15 g, 73%). ESI-MS: calcd M+1=519.4; found 519.5.
Example 869: 869(h) (120 mg, 0.23 mmol) in 5 mL MeOH was hydrogenated for 30 min at atmospheric pressure using 10% Pd-C (40 mg) as catalyst. The catalyst was filtered off and the solution was concentrated. Purification on reversed phase HPLC afforded the final product as a powder (81 mg, 82%). ESI-MS: calcd M+1=429.3; found 429.4.
Example 2934: 2S, 13S, 14R-117-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-4- methylpiperazinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 541.3 Example 2935: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2- [N- (L-alanine-N- <BR> <BR> <BR> <BR> <BR> morpholinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 564.3 (M+Na) Example 2936: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N- (L-valine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 592.2 (M+Na) Example 2937: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N- (L-tert-butylglycine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 606.4 (M+Na) Example 2938: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(b-alanine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 564.3 (M+Na) Example 2939: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N- (ethoxycarbonyl-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 580.3 (M+Na) Example 2940: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N- (2-hydroxy-2- phenylethyl)carboxamide]cyclopentadecane-13-N-hydroxycarboxa mide This compound was prepared using the procedures analogous to those above. ESI-MS: 543.3 (M+Na) Example 2941: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-4- benzylpiperazinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 617.3 (M+1) Example 2942: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-4- phenylpiperazinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 616.7 (M+1) Example 2943: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2- [N- (glycine-N-4-(2- <BR> <BR> <BR> pyridyl) piperazinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 604.4(M+1) Example 2944: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> <BR> isobutyl-2-[N-(α-cyclopropanethyloxycarboxamide- -<BR> <BR> <BR> <BR> <BR> alanine)carboxamidejcyclopentadecane-13-N-hydroxyCarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 600.3(M+1) Example 2945: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> <BR> isobutyl-2-(N- [glycine-N-4- (1- <BR> <BR> <BR> <BR> <BR> miperidinyl)piperidinamide]carboxamideNcyclopentadecane-13-N - hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 609.4(M+1) Example 2946: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(R-isopropyloxycarbonyl-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 572.3(M+1) Example 2947: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(S-isopropyloxycarbonyl-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 572.3(M+1) Example 2948: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(2-thiazole-4-acetic acid)carboxamide]cyclopentadecane-13-N-hydroxyCarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 564.2(M+Na) Example 2949: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(a-cyclopropaneethyloxycarboxamide-b-alanine-N - dimethylamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 627.3(M+1) Example 2950: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[N-(a-cyclopropaneethyloxycarboxamide- -alanine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 627.3(M+1) Example 2951: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(2-thiazole-4-acetyl-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 611.2(M+1) Example 2952: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- lsobutyl-2-[N-(L-serine-N- morpholinamide)carboxamide]cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 558.2(M+1) Example 2953: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2- [N- (glycine-N-piperidinamide-3-carboxylic <BR> <BR> <BR> <BR> acid) carboxamide] cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 592.2(M+Na) Example 2954: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-2,6- dimethylmorpholinamide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 556.4(M+1) Example 2955: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-4- ethoxycarbonylpiperazinamide)carboxamide]cyclopentadecane-13 -N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 599.4(M+1) Example 2956: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(glycine-N-4- ethoxycarbonylpiperazinamide)carboxamide]cyclopentadecane-13 -N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 598.4(M+1) Example 2957: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-{N-[4-(1- morpholinyl)phenyl]carboxamide}cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 562.3(M+1) Example 2958: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-{N-[glycine-N-(4-(1- <BR> <BR> <BR> <BR> <BR> morpholinyl) anilide) carboxamide] cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 619.4(M+1) Example 2959: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2- [N- (glycine-N-piperidinamide-4-carboxylic <BR> <BR> <BR> <BR> <BR> acid)carboxamide]cyclopentadecane-13-N-hydroxyCarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 592.3(M+Na) Example 2960: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N-methylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 437(M+Na) Example 2961: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[alanine-N-methylamide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 508(M+Na) Example 2962: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [methylcarboxy] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 438(M+Na) Example 2963: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[glycine-N-methylamide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 494(M+Na) Example 2964: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[2-N-morpholinoethylcarboxamidej-cyclopentadecane -13- N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 514(M+H) Example 2965: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[3-N-morpholinopropylcarboxamide]-cyclopentadecan e- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 528(M+H) Example 2966: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2- [pheylalanine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 584(M+Na) Example 2967: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [leucine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 550(M+Na) Example 2968: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[N-4-pyridylmethylcarboxamide]-cyclopentadecane-1 3-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 492(M+H) Example 2969: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(R,S)-furfurylcarboxamide]-cyclopentadecane-13 -N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 507(M+Na) Example 2970: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-phenylcarboxamide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 499(M+Na) Example 2971: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> lsobutyl-2-[t-butylglycine-N-methylamide]-cyclopentadecane-1 3-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 550(M+Na) Example 2972: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N-benzylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 513(M+Na) Example 2973: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[3-N-(2-oxo-pyrrolidino)propylcarboxamide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 548(M+Na) Example 2974: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[2-N-ethylpyrrolidinocarboxamide]-cyclopentadecan e- 13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 498(M+H) Example 2975: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[N-3-pyridylmethylcarboxamide]-cyclopentadecane-1 3-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 492(M+H) Example 2976: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N-2- (1,1, 1-trifluoroethyl) carboxamide] - cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 505(M+Na) Example 2977: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-2-(2-pyridyl)ethylcarboxamide]-cyclopentadecan e- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 506(M+H) Example 2978: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(R,S-l-methyl-3-pheylpropyl)carboxamide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 555(M+Na) Example 2979: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[3-N-imidazoylpropylcarboxamide]-cyclopentadecane -13- N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 509(M+H) Example 2980: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[e-N-t-butyloxycarbonyllysine-N-methylamide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 665(M+H) Example 2981: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [lysine-N-methylamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 543(M+H) Example 2982: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[N-2-pyridylmethylcarboxamide]-cyclopentadecane-1 3-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 492(M+H) Example 2983: 22S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-N-morpholinocarboxyamide]-cyclopentadecane-13- N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 508(M+Na) Example 2984: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- lsobutyl-2-[N-(R)-furfurylcarboxamide]-cyclopentadecane-13-N - hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 507(M+Na) Example 2985: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[N-2(4-imidazoyl)ethylcarboxyamide]-cyclopentadec ane- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 495(M+H) Example 2986: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-R-(2-R-hydroxyindane)carboxamide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 555(M+Na) Example 2987: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-S-(2-S-hydroxyindane)carboxamide]- cyclopentadecane-1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 555(M+Na) Example 2988: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-4-aminobenzylcarboxamide]-cyclopentadecane-13- N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 504(M-H) Example 2989: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[2-N-piperazinoethylcarboxamide]-cyclopentadecane -13- N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 513(M+H) Example 2990: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-EN-4-methylpiperinocarboxamide]-cyclopentadecane- 13- N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 498(M+H) Example 2991: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[3-N-(2-R,S-methyl-piperidino)propylcarboxamide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 540(M+H) Example 2992: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[N-(S)-furfurylcarboxamide]-cyclopentadecane-13-N - hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 507(M+Na) Example 2993: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [aspartate (O-t-butyl) -N-methylamide] - cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 608(M+Na) Example 2994: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2-[aspartate-N-methylamide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 552(M+Na) Example 2995: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2-[3-azaphenylalanine-N-methylamide]-cyclopentadeca ne- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 563(M+H) Example 2996: 2S, 13S, 14R-1,7-diaza-8,15-dioxo-9-oxa-14- isobutyl-2- [N-benzhydrylcarboxamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 589(M+Na) Example 2997: 2S, 135, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[glycine-n-pentyl ester]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 528.6 Example 2998: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[N-4-phenyl-1-butylamide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 532.7 Example 2999: 2S, 135, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[5-methoxytryptamine]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 573.7 Example 3000: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2 [1- (2, 5-dimethoxyphenyl) -2-glycine amidoethanol]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 637.7 Example 3001: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[glycine-t-butyl ester]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 514.6 Example 3002: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[L-glutamic acid-a, g -di-t-butyl ester]- cyclopentadecane- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 658.8 Example 3003: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[glycine]-cyclopentadecane-13-N-hydroxyCarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 458.5 Example 3004: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [N-2-phenyl-1-butylamide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 519.7 Example 3005: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[2-(2-aminoethyl)-1-methylpyrrole]-cyclopentadecan e- 13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 507.6 Example 3006: 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2[2-(2-aminoethyl)benzenesulfonamide]-cyclopentadec ane- 1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 583.7 Example 3007: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [L-glutamic acid-g-cyclohexyl ester-N-methyl amide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 611.7 Example 3008: 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[L-phenylalanine-p-fluoro-N-methylamide]- cyclopentadecane-13-N-hydroxycarboxamide his compound was prepared using the procedures analogous to those above. ESI-MS: 579.7 Example 3009: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- <BR> <BR> <BR> <BR> isobutyl-2[L-phenylalanine-p-methoxy-N-(S)-a-methylbenzylami de]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 681.8 Example 3010: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[N-cyclohehylmethyl amide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 496.7 Example 3011: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [N-3-phenyl-1-propyl amide] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 518.7 Example 3012: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[N-3,3-diphenylpropyl amide]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 594.8 Example 3013: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[N-(2-aminoethylamino)ethyl pyrrolidine] - cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 654.7 Example 3014: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[L-3(2'-naphthyl)alanine-N-methyl amide]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 611.7 Example 3015: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [ethyl-4-amino-1-piperidine carboxylate]- cyclopentadecane-1 3-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 555.7 Example 3016: 25, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[5-methyl tryptamine]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 557.7 Example 3017: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[N-4-trifluoromethylbenzyl amide]-cyclopentadecane-13- N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 558.6 Example 3018: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [L-glutamic acid]-cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 546.6 Example 3019: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[2-(diethylamino)ethyl-4-amino benzoate]- cyclopentadecane-13-N-hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 733.8 Example 3020: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2 [6-fluorotryptamine] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 561.7 Example 3021: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- isobutyl-2[6-methoxy tryptamine] -cyclopentadecane-13-N- hydroxycarboxamide This compound was prepared using the procedures analogous to those above. ESI-MS: 573.7 Example 3022: 2S, 13S, 14R-1, 7-diaza-8, 15-dioxo-9-oxa-14- <BR> <BR> <BR> isobutyl-2[tryptamine]-cyclopentadecane-13-N-hydroxyCarboxam ide This compound was prepared using the procedures analogous to those above. ESI-MS: 543.7 TABLE 32 Ex R2 MS (ESI) 2930 COHCH2CON-morphlino 527.6 2931 | CONHCH2CO[N-hydroxypiperidine] 541.7 2934 CONHCH2CON-(4-methylpiperazino) 541.3 (M+1) 2935 CONHCH(CH3)CON-morpholino 564.3 (M+l+Na) 2936 CONHCH(isopropyl)CON-morpholino 592.2 (M+1+Na) 2937 CONHCH(tert-butyl)CON- 606.4 (M+1+Na) morpholino 2938 CONHCH2CH2CON-morpholino 564.3 (M+1+Na) 2939 CONHCH2CH2OCON-morpholino 580.3 (M+1+Na) 2940 CONHCH2CH(OH)Ph 543.3 (M+1+Na) 2941 CONHCH2CON-(4-benzylpiperazino) 617.3 (M+1) 2942 CONHCH2CON-(4-phenylpiperazino) 603.3 (M+1) 2943 CONHCH2CON-[4-(2- 604.4 (M+1) pyridyl)morpholino] 2944 CONHCH2CH(S-NHCOOCH2CH2- 600.3 (M+1) cyclopropane)COOH 2945 CONHCH2CON-[4-(1- 609.4 (M+1) piperidinyl)piperidino] 2946 CONHCH2CH(R-CH3)0CON-morpholino 572.3 (M+1) 2947 CONHCH2CH(S-CH3)0CON-morpholino 572.3 (M+1) 2948 CONH-2-thiazole-4-acetic acid 564.2 (M+1+Na) 2949 CONHCH2CH(S-NHCOOCH2CH2- 627.3 (M+1) cyclopropane) coN (cH3) 2 2950 CONHCH2CH(S-NHCOOCH2CH2- 669.3 (M+1) cyclopropane)CON-morpholino 2951 CONH-2-thiazole-4-CH2CON- 611.2 (M+1) morpholino 2952 CONHCH (CH2OH) CON-morpholino 558.2 (M+1) 2953 CONHCH2CON-morpholino-3- 592.2 (M+1+Na) carboxylic acid 2954 CONHCH2CON-(2,6- 556.4 (M+1) dimethylmorpholino) 2955 CONHCH2CON- (4- 599.4 (M+1) ethoxycarbonylpiperazino) 2956 CONHCH2CON-(4- 598.4 (M+1) ethoxycarbonylpiperidino) 2957 CONH-[4-(4-morpholinyl)Ph] 562.3 (M+1) 2958 CONHCH2CONH-[4-(4- 619.4 (M+1) morpholinyl)Ph] 2959 CONHCH2CON-piperidine-4- 592.3 (M+1+Na) carboxylic acid 2960 CONHCH3 [M+Na]+=437 2961 CONH-Ala-NHCH3 [M+Na]+=508 2962 C02CH3 [M+Na]+=438 2963 CONHCH2CONHCH3 [M+Na]+=494 2964 A [M+H]+=514 CONH(CH2)2 - Nx O 2965 /m [M+H]+=528 CONH(CH2)3 N O 2966 CONH-Phe-NHCH3 [M+Na]+=584 2967 CONH-Leu-NHCH3 [M+Na]+=550 2968 CONHCH2-4-pyridyl [M+H]+=492 2969 /> [M+Na]+=507 CONHCH2 MoJ 2970 CONHC6H5 [M+Na]+=499 2971 CONH-t-butylglycine-NHCH3 [M+Na]+=550 2972 CONHCH2C6H5 [M+Na]+=513 2973 - no [M+Na]+=548 CONH(CH2)3 9 n 2974 [M+H]+=498 CONH (CH2)2 --N\I 2975 CONHCH2-3-pyridyl [M+H]+=492 2976 CONHCH2CF3 [M+Na]+=505 2977 CONH(CH2)2-2-pyridyl [M+H]+=506 2978 CONH(~)CH(CH3)CH2CH2C6H5 [M+Na]+=555 2979 eN [M+H]+=509 CONH(CH2)3 - NW 2980 CONH-Lys(Boc)-NHCH3 [M+H]+=665 2981 CONH-Lys-NHCH3 1 [M+H]+=543 2982 CONHCH2-2-pyridyl [M+H]+=492 2983 A [M+Na]+=508 C0NH -N 0 2984 < [M+Na]+=507 CONHCH2 OJ 2985 h~4, [M+H]+=495 CONH(CH; 2986 xc, [M+Na] +=555 CONH O 2987 [M+Na]+=555 CONH 4 D 2988 cONHcH2-Ph-4-NH2 [M-H]-=504 2989 /-7 [M+H]+=513 CONH(CH2)2 -NX 2990 7 [M+H]+=498 CONHCH2NH 2991 ~N< [M+H]+=540 CONH(CH2)3 H 2992 00 [M+Na]+=507 CONHCH2 2993 CONH-Asp(t-Bu)-NHCH3 [M+Na) +-608 2994 CONH-Asp-NHCH3 [M+Nal+=552 2995 g [M+H]+=563 N CONH l CONHCH3 2996 CONHCH(C6H5)2 [M+Na]+=589 2997 CONHCH2C02C5H11 528.6 2998 CONH(Ch2)4Ph 532.7 2999 CONH(CH2)2-5-methoxy indole 573.7 3000 CONHCH2CONHCH2CH(OH)-2,5- 637.7 dimethoxyphenyl 3001 CONHCH2CO2tBU X 0 514.6 3002 CONHCH(S) (CH2)2C02tBU(C02tBu) 658.8 3003 CONHCH2C02H 458.5 3004 CONH(CH2)2Ph ~ 519.7 3005 CONH(CH2)2-1-methylpyrrole 507.6 3006 CONH(CH2)2NHSO2Ph 583.7 3007 CONHCH(S)CH2CO2C6Hll(CONHCH3) 611.7 3008 CONHCH(S)CH2-p-fluoro- 579.7 phenyl(CONHCH3) 3009 CONHCH(S)CH2-p-methoxy Ph(CONHCH(S- 681.8 CH3) Ph) 3010 CONHCH2C6Hll 496.7 3011 CONH(CH2)3Ph 518.7 3012 CONH(CH2)2CH(Ph)2 594.8 3013 CONH(CH2)2NH(CH2)2-pyrrolidine 654.7 3014 CONHCH(S)CH2-2'-naphthyl(CONHCH3) 611.7 3015 0 CONH-piperidine-4-N-C02CH2CH3 555.7 3016 CONH(CH2)2-5-methylindole 557.7 3017 CONHCH2-p-CF3-phenyl 558.6 3018 CONHCH (S) (CH2) 2C02H (C02H) 546.6 3019 CONH-p-Ph-C02CH2CH2N (C2Hg)2 733.8 3020 CONH(CH2)2-6-fluoroindole 561.7 3021 CONH (CH2) -6-methoxyindo1e 573.7 3022 CONH(CH2)2-indole 543.7 UTILITY The compounds of the present invention possess metalloproteinase and aggrecanase and TNF inhibitory activity.
The MMP-3 inhibitory activity of the compounds of the present invention is demonstrated using assays of MMP-3 activity, for example, using the assay described below for assaying inhibitors of MMP-3 activity. The compounds of the present invention are bioavailable in vivo as demonstrated, for example, using the ex vivo assay described below. The compounds of the present invention have the ability to suppress/inhibit cartilage degradation in vivo, for example, as demonstrated using the animal model of acute cartilage degradation described below.
The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit MPs. These would be provided in commercial kits comprising a compound of this invention.
Metalloproteinases have also been implicated in the degradation of basement membrances to allow infiltration of cancer cells into the circulation and subsequent penetration into other tissues leading to tumor metastasis. (Stetler- Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990.) The compounds of the present invention should be useful for the prevention and treatment of invasive tumors by inhibition of this aspect of metastasis.
The compounds of the present invention would also have utility for the prevention and treatment of osteopenia associated with matrixmetalloproteinase-mediated breakdown of cartilage and bone which occurs in osteoporosis patients.
Compounds which inhibit the production or action of TNF and/or Aggrecanase and/or MP's are potentially useful for the treatment or prophylaxis of various inflammatory, infectious, immunological or malignant diseases. These include, but are not limited to inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, an acute infection, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, periodontits, gingivitis, congestive heart failure, fibrotic disease, cachexia, and aneroxia, graft rejection, cancer, corneal ulceration or tumor invasion by secondary metastases, autoimmune disease, skin inflammatory diseases, multiple osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, HIV, and hyperoxic alveolar injury.
The compounds of the present invention have been shown to inhibit TNF production in lipopolysacharride stimulated mice, for example, using the assay for TNF Induction in Mice and in human whole blood asdescribed below.
The compounds of the present invention have been shown to inhibit aggrecanase a key enzyme in cartilage breakdown as determined by the aggrecanase assay described below.
As used herein "ug" denotes microgram, "mg" denotes milligram, "g" denotes gram, "pL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "uM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma- Aldrich Corp. of St. Louis, MO.
A compound is considered to be active if it has an IC50 or Ki value of less than about 1 mM for the inhibition of MMP-3.
Aggrecanase Enzymatic Assay A novel enzymatic assay was developed to detect potential inhibitors of aggrecanase. The assay uses active aggrecanase accumulated in media from stimulated bovine nasal cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or a fragment thereof as a substrate.
The substrate concentration, amount of aggrecanase time of Incubation and amount of product loaded for Western analysis were optimized for use of this assay in screening putative aggrecanase inhibitors. Aggrecanase is generated by stimulation of cartilage slices with interleukin-l (IL-1), tumor necrosis factor alpha (TNF~) or other stimuli. Matrix metalloproteinases (MMPs) are secreted from cartilage in an inactive, zymogen form following stimulation, although active enzymes are present within the matrix. We have shown that following depletion of the extracellular aggrecan matrix, active MMPs are released into the culture media. (Tortorella, M.D. et. al. Trans. Ortho. Res.
Soc. 20, 341, 1995). Therefore, in order to accumulate BNC aggrecanase in culture media, cartilage is first depleted of endogenous aggrecan by stimulation with 500 ng/ml human recombinant IL- for 6 days with media changes every 2 days.
Cartilage is then stimulated for an additional 8 days without media change to allow accumulation of soluble, active aggrecanase in the culture media. In order to decrease the amounts of other matrix metalloproteinases released into the media during aggrecanase accumulation, agents which inhibit MMP- 1, -2, -3, and -9 biosynthesis are included during stimulation.
This BNC conditioned media, containing aggrecanase activity is then used as the source of aggrecanase for the assay.
Aggrecanase enzymatic activity is detected by monitoring production of aggrecan fragments produced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody, BC-3 (Hughes, CE, et al., Biochem J 306:799-804, 1995). This antibody recognizes aggrecan fragments with the N-terminus, 374ARGSVIL.., generated upon cleavage by aggrecanase. The BC-3 antibody recognizes this neoepitope only when it is at the N- terminus and not when it is present internally within aggrecan fragments or within the aggrecan protein core. Other proteases produced by cartilage in response to IL-1 do not cleave aggrecan at the Glu373-Ala374 aggrecanase site; therefore, only products produced upon cleavage by aggrecanase are detected. Kinetic studies using this assay yield a Km of 1.5 +/- 0.35 uM for aggrecanase.
To evaluate inhibition of aggrecanase, compounds are prepared as 10 mM stocks in DMSO, water or other solvents and diluted to appropriate concentrations in water. Drug (50 ul) is added to 50 ul of aggrecanase-containing media and 50 ul of 2 mg/ml aggrecan substrate and brought to a final volume of 200 ul in 0.2 M Tris, pH 7.6, containing 0.4 M NaCl and 40 mM CaCl2.
The assay is run for 4 hr at 37or, quenched with 20 mM EDTA and analyzed for aggrecanase-generated products. A sample containing enzyme and substrate without drug is included as a positive control and enzyme incubated in the absence of substrate serves as a measure of background.
Removal of the glycosaminoglycan side chains from aggrecan is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core protein. Therefore, for analysis of aggrecan fragments generated by cleavage at the Glu373-Ala374 site, proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 units/l0 ug GAG) for 2 hr at 37OC and then with keratanase (0.1 units/l0 ug GAG) and keratanase II (0.002 units/l0 ug GAG) for 2 hr at 37oC in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5. After digestion, aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in 30 ul of Tris glycine SDS sample buffer (Novex) containing 2.5t beta mercaptoethanol.
Samples are loaded and then separated by SDS-PAGE under reducing conditions with 4-122 gradient gels, transferred to nitrocellulose and immunolocated with 1:500 dilution of antibody BC3. Subsequently, membranes are incubated with a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatase second antibody and aggrecan catabolites visualized by incubation with appropriate substrate for 10-30 minutes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount of product produced in the presence versus absence of compound.
Bisacetylated Substance P / MMP-3 fluorescent Assay A high capacity enzymatic assay was developed to detect potential inhibitors of MMP-3. The assay uses a derivative of a peptide substrate, substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe- Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the glutamine-phenylalanine bond. In order to adapt this assay for high throughput screening, we have developed a fluorimetric method of product detection. The production of the hydrolysis product, substance P 7-11, is measured by reaction with fluorescamine, a fluorogenic compound which reacts with the primary amine of this fragment. The substance P substrate is bisacetylated to block the primary amines of the intact substrate. Thus, the resulting fluorescence represents generation of product (7-11 peptide) formed upon cleavage by MMP-3, and is quantitated using a standard curve prepared with known concentrations of 7-11 peptide. Kinetic studies using the bisacetylated substrate yield the following parameters for MMP- Xm =769 +/- 52 uM; Vmax = 0.090 +/- 0.003 nmoles 7-11 peptide/min.
To evaluate inhibition of MMP-3, compounds were prepared at a concentration of 10 mM in 100% methanol, and then further diluted to a 20X molar stock. Five microliters of each drug stock was added to the assay in the presence of 20 nM truncated MMP-3 in 67.5 mM tricine (pH 7.5), 10 mM CaCl2, 40 mM NaCl, and 0.005% Brij 35 in a final volume of 100 microliters.
Bisacetylated substance P (1000 mM) was added, and the assay was run for 1 hour at 250C. The reaction was quenched with EDTA (20 mM) and product was detected fluorometrically following addition of fluorescamine (0.075 mg/ml). Fluorescence of each sample was converted to an amount of product formed using a substance P 7- 11 standard curve. Under these conditions, the assay is linear with respect to MMP-3 amount up to 10 pmoles. Inhibition of MMP-3 was determined by comparing the amount of product generated in the presence and absence of compound.
Selected compounds of the present invention were tested and shown to have activity in the above assay.
Ex vivo assay for bioavailability of MMP-3 inhibitors Blood was collected by cardiac puncture from rats at different times after dosing I.V., I.P., or P.O. with compound in order to determine the levels of inhibitor present. Plasma was extracted with 10% TCA in 95% methanol, and placed on ice for 10 minutes. The plasma was then centrifuged for 15 minutes at 14,000 rpm in an Eppendorf microcentrifuge. The supernatant was removed, recentrifuged, and the resulting supernatant was diluted 1:10 in 50 mM tricine, pH 8.5. The pH of the sample was adjusted to 7.5, and then assayed in the MMP-3 substance P fluorescent enzymatic assay. Plasma from naive rats was extracted by the same method and used as a negative control.
This plasma was also used to prepare a spiked plasma curve of the compound of interest. Known concentrations of the compound were added to control plasma, the plasma was extracted by the same method, and then assayed in the MMP-3 enzymatic assay. A standard curve was prepared that related percent inhbition in the MMP-3 assay to the concentration of drug added in the spiked samples. Based on the percent inhibition in the presence of plasma from dosed rats, the concentration of compound was determined using the standard curve.
Acute Cartilage Degradation Rat Model A novel in vivo model of acute cartilage degradation in rats has been characterized as a method to determine the proteoglycan content in the synovial fluid after the induction of cartilage degradation. Experimental groups exhibit increased levels of proteoglycan content in their synovial fluid versus control rats. The criteria to demonstrate a compound's activity in this model, is the ability to inhibit the demonstration of cartilage degradation, as measured by increased proteoglycan content in the synovial fluid of rats after compound administration. Indomethacin, a non-steroidal anti-inflammatory drug is inactive in this model. Indomethacin administration does not inhibit the demonstration of cartilage degradation in experimental animals. In contrast, administration of a compound of this invention significantly inhibited the demonstration of cartilage degradation in this model.
TNF Human Whole Blood Assay Blood is drawn from normal donors into tubes containing 143 USP units of heparin/l0ml. 225u1 of blood is plated directly into sterile polypropylene tubes. Compounds are diluted in DMSO/serum free media and added to the blood samples so the final concentration of compounds are 50,10,5,1,.5,.1, and .OluM.
The final concentration of DMSO does not exceed .5%. Compounds are preincubated for 15 minutes before the addition of 100ng/ml LPS. Plates are incubated for 5 hours in an atmosphere of 5% C02 in air. At the end of 5 hours, 750ul of serum free media is added to each tube and the samples are spun at 1200RPM for 10 minutes. The supernatant is collected off the top and assayed for TNF-alpha production by a standard sandwich ELISA. The ability of compounds to inhibit TNF-alpha production by 50% compared to DMSO treated cultures is given by the IC50 value.
TNF Induction In Mice Test compounds are administered to mice either I.P. or P.O. at time zero. Immediately following compound administration, mice receive an I.P. injection of 20 mg of D-galactosamine plus 10 pg of lipopolysaccharide. One hour later, animals are anesthetized and bled by cardiac puncture. Blood plasma is evaluated for TNF levels by an ELISA specific for mouse TNF.
Administration of representative compounds of the present invention to mice results in a dose-dependent suppression of plasma TNF levels at one hour in the above assay.
Dosage and Formulation The compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an antiinflammatory and antiarthritic agent.
The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, MMP-3, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70 kg of body weight, this translates into a dosage of 70 to 1400 mg/day.
Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon aprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules Capsules are prepared by conventional procedures so that the dosage unit is 500 milligrams of active ingredient, 100 milligrams of cellulose and 10 milligrams of magnesium stearate.
A large number of unit capsules may also prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Syrup Wt. 96 Active Ingredient 10 Liquid Sugar 50 Sorbitol 20 Glycerine 5 Flavor, Colorant and as required Preservative Water as required The final volume is brought up to 100% by the addition of distilled water.
Aqueous Suspension Wt. % Active Ingredient 10 Sodium Saccharin 0.01 KeltrolB (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5 Flavor, Colorant and as required Preservative Water as required Xanthan gum is slowly added into distilled water before adding the active ingredient and the rest of the formulation ingredients. The final suspension is passed through a homogenizer to assure the elegance of the final products.
Resuspendable Powder Wt. % Active Ingredient 50.0 Lactose 35.0 Sugar 10.0 Acacia 4.7 Sodium Carboxylmethylcellulose 0.3 Each ingredient is finely pulverized and then uniformly mixed together. Alternatively, the powder can be prepared as a suspension and then spray dried.
Semi-Solid Gel Wt. % Active Ingredient 10 Sodium Saccharin 0.02 Gelatin 2 Flavor, Colorant and as required Preservative Water as required Gelatin is prepared in hot water. The finely pulverized active ingredient is suspended in the gelatin solution and then the rest of the ingredients are mixed in. The suspension is filled into a suitable packaging container and cooled down to form the gel.
Semi-Solid Paste Wt. % Active Ingredient 10 GelcarinX (Carrageenin gum) 1 Sodium Saccharin 0.01 Gelatin 2 Flavor, Colorant and as required Preservative Water as required GelcarinB is dissolved in hot water (around 800C) and then the fine-powder active ingredient is suspended in this solution. Sodium saccharin and the rest of the formulation ingredients are added to the suspension while it is still warm. The suspension is homogenized and then filled into suitable containers.
Emulsifiable Paste Wt. % Active Ingredient 30 Tweeny 80 and Spans 80 6 KeltrolB 0.5 Mineral Oil 63.5 All the ingredients are carefully mixed together to make a homogenous paste.
Soft Gelatin Capsules A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets Tablets may be prepared by conventional procedures so that the dosage unit is 500 milligrams of active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose and 10 milligrams of magnesium stearate.
A large number of tablets may also be prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ngredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.
The compounds of the present invention may be administered in combination with a second therapeutic agent, especially non- steroidal anti-inflammatory drugs (NSAID's). The compound of the present invention and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.
The compound of the present invention may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of the present invention and the second therapeutic agent are not formulated together in a single dosage unit, the compound of the present invention and the second therapeutic agent may be administered essentially at the same time, or in any order; for example the compound of the present invention may be administered first, followed by administration of the second agent. When not administered at the same time, preferably the administration of the compound of the present invention and the second therapeutic agent occurs less than about one hour apart, more preferably less than about 5 to 30 minutes apart.
Preferably the route of administration of the compound of the present invention is oral. Although it is preferable that the compound of the present invention and the second therapeutic agent are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).
The dosage of the compound of the present invention when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of osteoarthritls or rheumatoid arthritis, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.
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