CA2102890A1 - Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents - Google Patents
Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agentsInfo
- Publication number
- CA2102890A1 CA2102890A1 CA002102890A CA2102890A CA2102890A1 CA 2102890 A1 CA2102890 A1 CA 2102890A1 CA 002102890 A CA002102890 A CA 002102890A CA 2102890 A CA2102890 A CA 2102890A CA 2102890 A1 CA2102890 A1 CA 2102890A1
- Authority
- CA
- Canada
- Prior art keywords
- ethyl
- carboxy
- glycine
- phenyl
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Novel N-carboxyalkylpeptidyl compounds of formula (I) are found to be useful inhibitors of matrix metalloendoproteinase-mediated diseases including osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture. The matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major components of articular cartilage and basement membranes.
The inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
The inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
Description
WO 92/21360 PCr/US92/03X09 . , . . ~ ` ` . .
.
TITLE OF THE INVENTION
SUBSTITUTED N-CARBOXYALKYLPEPTIDYL DERIVATIVES AS
ANTIDEGENERATIVE ACTIVE AGENTS
BACKGROUND OF THE INVENllO~l Novel N-carboxyalkylpeptidyl compounds of formula I ~-`
are found to be useful inhibitors of matrix 15 metalloendoproteinase-mediated diseases including osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture. The matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major cnmponents of articular cartilage and basement membranes. The inhibitors claimed herein may also be useful in 25 preventing the pathological sequeiae following a traurnatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
.
R1 NH~ X
~(~
L
suesTl I UTE SHEET
WO 92/21360 PCl /US92/03~1)9 :. I . ' - 2 The disability observed in osteoarthritis (OA) and rheumatoid arthritis (RA) is largely due to the loss of articular cartilage. No therapeutic agent in the prior art is known to prevent the attrition of articular cartilage in these diseases.
"Disease modifying antirheumatic drugs" (DMARD), i.e., 5 agents capable of preventing or slowing the ultimate loss of joint function in OA and RA are widely sought. Generic nonsteroidal antiinflammatory drugs (NSAlDs) may be combined with such agents to provide some relief from pain and swelling.
S t r o m e I y s i n (aka. proteoglycanase, matrix metalloproteinase-3, MMP-3, procollagenase activator, "transin"), - c o l l a ~ e n a s e (aka. interstitial collagenase, matrix meta!loproteinase-1), and g~l~i~a~ (aka. type IV collagenase, matrix metalloproteinase-2, MMP-2, 72kDa-gelatinase or type V
collagenase, matrix metalloproteinase-9, MMP-9, 95kDa-ge~latinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. Elevated levels of both enzymes have been detected in joints of arthritic humans and animals: K.A. Hasty, R.A. Reife, 20 A.H. Kang, J.M. Stuart, "The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis", Arthr.
Rheum., 33, 388-97 (1990); S.M. Krane, E.P. Amento, M.B. Goldring, S.R. Goldring, and M.L. Stephenson, "Modulation of matrix synthesis and degradation in joint inflammation", The Control of Tissue 25 Damagen, A.B. Glauert (ed.), Elsevier Sci. Publ., Amsterdam, 1988, Ch. 14, pp 179-95; A. Blanckaert, B. Mazieres, Y. Eeckhout, G. Vaes, "Direct extraction and assay of collagenase from human osteoarthrtic cartilage", Clin. Chim. Acta, 185 73-80 (1989).
Each enzyme is secreted from these cells as an inactive 30 proenzyme which is subsequently activated. There is evidence that stromelysin may be the in ~ LQ activator for collagenase, implyin~g a cascade for degradative enzyme activity: A. Ho, H.
Nagase, nEviden~e that human rheumatoid synovial matrix metalloproteinase 3 i s an endogenous activator of ~ , SU~STITUTE SHEET
., .
WO 92/21360 PCI/US92/03809 `
procollagenase", Arch Biochem Biophys., 267, 211-16 (1988); G.
Murphy, M.l. Crockett, P.E. Stephens, B.J. Smith, A.J.P. Docherty, "Stromelysin is an activator of procollagenase", Biochem. J., 248, 265-8 (1987). Inhibiting stromelysin could limit the activation of collagenase as well as prevent the degradation of proteoglycan.
That stromelysin inhibition may be effective in preventing articular cartilage degradation has been demonstrated in vitro by measuring the effect of matrix metalloendoproteinase inhibitors on proteoglycan release from rabbit cartilage explants:
C.B. Caputo, L.A. Sygowski, S.P. Patton, D.J. Wolanin, A. Shaw, R.A.
Roberts, G. DiPasquale, J. Orthopaedic Res., 6, 103-8 (1988).
There is an extensive literature on the involvement of these metalloproteinases in arthritis, but there is very little to guide one in developing a specific inhibitor for each enzyme.
In preliminary studies of rabbit proteoglycanase with - 15 substrates ~ and inhibitors, little was found to indicate the enzyme's requirements for hydrolysis or inhibition beyond a preference for hydrophobic residues at the P1' position: A. Shaw, R.A. Roberts, D.J. Wolanin, "Small substrates and inhibitors of the metalloproteoglycanase of rabbit articular chondrocytes", Adv.
~` 20 Inflam. Res., 12, 67-79 ~1988). More extensive studies with a series of substrates revealed that stromelysin will tolerate nearly every amino acid residue around the scissile bond: G.B.
Fields, H. Brikedal-Hansen, H.E. Van Wart, unpublished results presented at the Matrix Metalloproteinase Conference, Sept. 1989, Sandestin Fla.
Human rheumatoid synovial collagenase has been shown to share ~ 50% homology with human stromelysin: S.E.
Whitham, G. Murphy, P. Angel, H.J. Rahmsdorf, B.J. Smith, A. Lyons, T.J.R. Harris, J.J. Reynolds, P. Herrlich, A.J.P.~ Docherty, ~o "Comparison of human stromelysin and collagenase by cloning and sequence analysis", Biochem. J., 240, 913-6 (1986). Many collagenase inhibitors have been designed around the cleavage site of the a-chain sequence of Type !I collagen: W.H. Johnson, N.A.
Roberts, N. Brokakoti, "Collagenase inhibitors: their design and ~ ~ SUBSTI~E SHEE~
,, `1 ` ,:, ~ , - 4 -. ' ~ ! , '; ., _.
potential therapeutic use", J. Enzyme Inhib., 2, 1 -22 ( 1987) . One such inhibitor, N-[3-(benzyloxycarbonyl)amino-1-carboxy-n-propyl]-L~leucyl-O-methyl-L-tyrosine, N-methylamide, prepared at G.D. Searle, Inc., and shown to be a potent inhibitor of human rheumatoid synovial collagenase (ICso = 0.8 ~M), was also found 5 to inhibit rab~it bone proteoglycanase (ICso = 0.5 ~lM): J.-M.
Delaisse, Y. Eeckhout, C.Sear, A. Galloway, K. McCullagh, G. Vaes, "A new synthetic inhibitor of mammalian tissue collagenase inhibits bone resorption in culture", Biochem. Biophys. Res.
Commun., 183, 483-90 (1985).
Gelatinase (MR ~ 72,000) has been isolated from rheumatoid fibroblasts: Y. Okada, T. Morodomi, J. J. Enghild, K.
Suzuki, A. Yasui, I. Nakanishi, G. Salvesen, H. Nagase, "Matrix metalloproteinase 2 from human rheumatoid synovial ~ibroblasts", Eur. J., Biochem., 194, 721-~0 (1990). The synthesis 15 of the proenzyme is not coordinately regulated with the other two metalloproteinases and its activation may also be different. The role of geiatinase in the tissue destruction of articular cartilage appears different from the other two enzymes and, therefore, its inhibition may provide additional protection ~rom degradation. A
20 higher molecular weight gelatinase (MR ~~5,000; aka. type-V
collagenase, matrix metalloproteinase-9, MMP-9) is also secreted by ~ibroblasts and monocytes and may be involved in cartilage degradation.
As appreciated by those of skili in the art, the 25 significant proportion of homology between human` fibroblast collagenase, stromelysin, and geiatinase leads to the possibility that a compound that inhibits one enzyme may to some degree inhibit all of them.
Compounds that inhibit collagenase, which possess 30 structural portions akin to those of the instant invention include those encompassed by U.S.4,511,504 issued Apr. 16, 1985; U.S.
4,568,666, issued Feb 4, 1986.
SU~STI, UTE SHEET
WO 92/21360 PCr~US92/03809 Compounds of related structure that are ciaimed to inhibit stromelysin (proteoglycanase) are encompassed by U.S.
4,771,037, issued Sept. 13, 1988.
The applicants believe that stromelysin and collagenase inhibitors have utility in preventing articular cartilage damage associated with septic arthritis. Bacterial infections of the joints can elicit an inflammatory response that may then be perpetuated beyond what is needed for removal of the infective agent resulting in permanent damage to structural components. Bacterial agents have been used in animal models to elicit an arthritic response with the appearance of proteolytic activities. See J.P. Case, J. Sano, R. Lafyatis, E.F. Remmers, G.K.
Kumkumiàn, R.L. Wilder, "Transin/stromelysin expression in the synovium of rats with experimental erosive arhtritis", J. Clin Invest., 84, 1731-40 (1989); R J. Williams, R.L. S;mith, D.~).
Schurman, nSeptic Arthritis: Staphylococcal induction of chondrocyte proteolytic activityn, Arthr. Rheum., 33, 533-4t (1 990~.
The applicants also believe that inhibitors of ~tromelysin, collagenase, and gelatinase will be useful to control ~: - 20 tumor metastasis, optionally in combination with current chemotherapy and/or radiation. See L.M. Matrisian, G.T. Bowden, P.
Krieg, G. Furstenberger, J;P. Briand, P. Leroy? R. E3reathnach, "The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors", Proc. Natl. Acad.
Sci., USA, 83, 9413-7 (1986); S.M. Wilhelm, I.E. Collier, A.
Kronberger, A.Z. Eisen, B.L. Marmer, G.A. Grant, E.A. Bauer, G. I.
Goldberg, "Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells", Ibid., 84, 6725-29 (1987); Z.
Werb et al., Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression, J. Cell Biol., 109, 872-889 (1`989); L.A. Liotta, C.N. Rao, S.H. Barsky, "Tumor invasion: and~the extracellular matrixn, Lab. Invest., 49, 636-649 (1983); R. Reich, B.~Stratford, K. Klein, G. R. Martin, R. A. Mueller, ;UBSTITUTE SHEET
~I t~ ~S` ~ , - 6 -G. C. Fuller, "Inhibitors of collagenase IV and cell adhesion reduce the invasive activity of malignant tumor cells", in Metastasis:
Ciba Foundation Symposium; Wiley, Chichester, 1988, pp. 193-210.
Secreted proteinases such as stromelysin, collagenase, and gelatinase play an important role in processes involved in the movement of cells during metastasic tumor invasion. Indeed, there is also evidence that the matrix metalloproteinases are overexpressed in certain metastatic tumor cell lines. In this context, the enzyme functions to 0 penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation. - After adhering to blood vessel walls, the tumor cells use these same metalloendoproteinases to pierce underlying basement membranes and penetrate other tissues, thereby leading 15 to tumor metastasis. Inhibition of this process would prevent -` metastasis and improve the efficacy of current treatments with chemotherapeutics and/or radiation.
These inhibitors should also be useful for controlling periodontal diseases, such as gingivitis. Both collagenase and 20 stromelysin activities have been isolated~ from fibroblasts isolated from inflammed gingiva: V.J. Uitto, R. Applegren, P.J.
Robinson, 'iCollagenase and neutral metalloproteinase activity in extracts of inflamed human gingiva", J. Periodontal Res., 16, 417-424(1981). Enzyme levels have been correlated to the severity of 25 gum disease: C.M. Overali, O.W. Wiebkin, J.C. Thonard, "Demonstration of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva", J.
Periodontal Res., 22, 81-88 (1987).
; ~ Proteolytic processes have also been observed in the 30 ulceration of the cornea following alkali burns: S.l. Brown, C.A.
Weller, H.E. Wasserman, "Collagenolytic activity of alkali-burned corneasN, Arch. Opthalmol., 81, 370-373 ~1969). Mercapto-containing pep~ides do inhibit the collagenase isolated from alkali-burned rabbit cornsa:~F.R. Burns, M.S. Stack, R.D. Gray, C.A.
S~BSTITUTE SHEET
WO 92/21360 PCI/I)S92/03809 Paterson, Invest. Opthalmol., 30, 1569-1575 (1989). Treatment of alkali-burned eyes or eyes exhibiting corneal ulceration as a result of infection with inhibitors of these metalloendoproteinases in combination with sodium citrate or sodium ascorbate and/or antimicrobials may be effective in preventing developing corneal degradation.
Stromelysin has been implicated in the degradation of structural components of the glomerular basement membrane (GBM) of the kidney, the major function of which is to restrict passage of plasma proteins into the urine; W.H. Baricos, G. Murphy, Y. Zhou, H.H. Nguyen, S.V. Shah, "Degradation of glomerular basement membrane by purified mammalian meta!loproteinasesn, Biochem. J., 254, 609-612 ~1988). Proteinuria, a result of glomerular disease, is excess protein in the urine caused by increased permeability of the GBM to plasma proteins. The underlying causes of this increased GBM permeability are unknown, but proteinases including stromelysin may play an important role in glomerular diseases. Inhibition of this enzyme may alleviate the proteinura associated with kidney malfunction.
It is suggested that inhibition of stromelysir. activity may prevent the rupturing of atherosclerotic plaques leading to coronary thrombosis. The tearing or rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
Destabilization and degradation of the connective tissue matrix surrounding these plaques by proteolytic enzymes or cytokines released by infiltrating inflammatory cells has been proposed as a cause of plaque fissuring. Such tearing ot these plaques can cause an acute thrombolytic event as blood rapidly flows out of the blood vessel. High levels of stromelysin RNA message have been fqund to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery: A. M. Henney, P. R. Wakeley, M. J. Davies, K. Foster, R.
Hembry, G. Murphy, S. Humphries, "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad. Sci. USA, 88, 8154 8158 SUBS~TUT~ Sl IEE~
: ~ `
WO 92/21360 PCl/US92/03809 . . ,, , . (,j I ., (1991). Inhibition of stromelysin by these compounds may aid in preventing or delaying the degradation of the connective tissue matrix that stabilizes the atherosclerotic plaques, thereby preventing events leading to acute coronary thrombosis.
It is also believed that specific inhibitors of 5 stromelysin and collagenase should be useful as birth control agents. There is evidence that expression of metalloendoproteinases, including stromelysin and collagenase, is observed in unfertilized eggs and zygotes and at further cleavage stages and increased at the blastocyst stage of fetal development and with endoderm differentiation: C.A. Brenner, R.R.
- Adler, D.A. Rappolee, R.A. Pedersen, Z. Werb, "Genes for extracellular matrix-degrading metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development", Genes 8~ Develop., 3, 848-59 (1989). By;analogy to tumor invasion, a blastocyst may express metalloproteinases in order to penetrate the extracellular matrix of the uterine wall dari;n g implantation. Inhibition of stromelysin and collagenase during these early developmental processes should presumably prevent normal embryonic development and/or implantation in the 20 uterus. Such intervention would constitute a novel method of ; birth control. In addition there is evidence that collagenase is important in ovulation processes. In this example, a covering of coilagen over the apical region of the follicle must be penetrated in order for the ovum to escape. Collagenase has been detected 25 during this process and an inhibitor has been shown to be effective in preventing ovulation: J.F. Woessner, N. Morioka, C.
Zhu, T. Mukaida, T. Butler, W.J. LeMaire "Connective tissue breakdown in ovulationn, Steroids, 54, 491-499 (1989). There may also be a role for stromelysin activity during ovuiation: C.K.L.
3-o ~OO, G.D. Bryant-Greenwood, F.C. Greenwood, "Relaxin increases the release of plasminogen activator, collagenase, and proteo-glycanase from rat granulosa cells in vitron, Endocrin., 11 5, 1043-1 D50 (1984).
;~ SUBSTITUTE SHEET
~ .
W O 92/21360 P ~ /US92/03X09 . ~; ~ ., - 9 , i~ . . i . j Collagenolytic and stromelysin activity have also been observed in dystrophobic epidermolysis bullosa: A. Kronberger, K.J. Valle, A.Z. Eisen, E.A. Bauer, J. Invest. Dermatol., 79 208-211 (1982); D. Sawamura, T. Sugawara, I. Hashimoto, L. Bruckmer-Tuderman, D. Fujimoto, Y. Okada, N. Utsumi, H. Shikata, Biochem.
Biophys. Res. Commun., 174, 1003-8 (1991). Inhibition of metalloendoproteinases should limit the rapid destruction of connective components of the skin.
In addition to extracellular matrix comprising structural components, stromelysin can degrade other in vivo - l0 substrates including the inhibitors a 1 -proteinase inhibitor and may therefore influence the activities of other proteinases such as elastase: P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W.
Carrell, G. Murphy, "Proteolytic inactivation of human a 1 -antitrypsin by human stromelysin", FEBS Letts., 279,; 1, 91-94 :: 15 :(1991). Inhibition of the matrix metalloendoproteinases may potentiate the antiproteinase activity of these endogenous inhibitors.
SUMMARY OF THE INVENTION
The invention encompasses novel N-carboxy-alkylpeptidyl compounds of formula I which are useful inhibitors of matrix metalloendoproteinase-mediated diseases including degenerative diseases (such as defined abo~re) and certain cancers.
R /~NH~Il[ ]X
) J ~ (~.) L
DETAILED DESCRIPTION OF THE INVENTION
, "
BSTITUrE SHEET
WO 92/21360 P~/US92/03809 -., i i . (~ .J ;J
The invention encompasses compounds of formula 1.
~ ~_ (~ (~,~) ' o or a pharmaceutically acceptable salt thereof wherein: :
R 1 is substituted C1 6alkyl, wherein the substituent is selected from the group consisting of:
(a) hydrogen, ~- 15 (b) carboxy, ,; ; ~ , ;
,: ~
~ ~ SU~STlT~)Tt SH~ET
:
_ __ _ _ _ _ _ _ __ _ __ _ . _ _ _ .. _ _. __ .. _ . _.. _ .. :.. : .. ' ~ .-- I--~'F ~.' '-- ' --WO 92/21360 PCI /US~2/03809 (c) -CNH2, (d) C 6 1 oaryl wherein the aryl group is selected from the group consisting of -(1 ) phenyl, (2) naphthyl, ~:
.
TITLE OF THE INVENTION
SUBSTITUTED N-CARBOXYALKYLPEPTIDYL DERIVATIVES AS
ANTIDEGENERATIVE ACTIVE AGENTS
BACKGROUND OF THE INVENllO~l Novel N-carboxyalkylpeptidyl compounds of formula I ~-`
are found to be useful inhibitors of matrix 15 metalloendoproteinase-mediated diseases including osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture. The matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major cnmponents of articular cartilage and basement membranes. The inhibitors claimed herein may also be useful in 25 preventing the pathological sequeiae following a traurnatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
.
R1 NH~ X
~(~
L
suesTl I UTE SHEET
WO 92/21360 PCl /US92/03~1)9 :. I . ' - 2 The disability observed in osteoarthritis (OA) and rheumatoid arthritis (RA) is largely due to the loss of articular cartilage. No therapeutic agent in the prior art is known to prevent the attrition of articular cartilage in these diseases.
"Disease modifying antirheumatic drugs" (DMARD), i.e., 5 agents capable of preventing or slowing the ultimate loss of joint function in OA and RA are widely sought. Generic nonsteroidal antiinflammatory drugs (NSAlDs) may be combined with such agents to provide some relief from pain and swelling.
S t r o m e I y s i n (aka. proteoglycanase, matrix metalloproteinase-3, MMP-3, procollagenase activator, "transin"), - c o l l a ~ e n a s e (aka. interstitial collagenase, matrix meta!loproteinase-1), and g~l~i~a~ (aka. type IV collagenase, matrix metalloproteinase-2, MMP-2, 72kDa-gelatinase or type V
collagenase, matrix metalloproteinase-9, MMP-9, 95kDa-ge~latinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. Elevated levels of both enzymes have been detected in joints of arthritic humans and animals: K.A. Hasty, R.A. Reife, 20 A.H. Kang, J.M. Stuart, "The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis", Arthr.
Rheum., 33, 388-97 (1990); S.M. Krane, E.P. Amento, M.B. Goldring, S.R. Goldring, and M.L. Stephenson, "Modulation of matrix synthesis and degradation in joint inflammation", The Control of Tissue 25 Damagen, A.B. Glauert (ed.), Elsevier Sci. Publ., Amsterdam, 1988, Ch. 14, pp 179-95; A. Blanckaert, B. Mazieres, Y. Eeckhout, G. Vaes, "Direct extraction and assay of collagenase from human osteoarthrtic cartilage", Clin. Chim. Acta, 185 73-80 (1989).
Each enzyme is secreted from these cells as an inactive 30 proenzyme which is subsequently activated. There is evidence that stromelysin may be the in ~ LQ activator for collagenase, implyin~g a cascade for degradative enzyme activity: A. Ho, H.
Nagase, nEviden~e that human rheumatoid synovial matrix metalloproteinase 3 i s an endogenous activator of ~ , SU~STITUTE SHEET
., .
WO 92/21360 PCI/US92/03809 `
procollagenase", Arch Biochem Biophys., 267, 211-16 (1988); G.
Murphy, M.l. Crockett, P.E. Stephens, B.J. Smith, A.J.P. Docherty, "Stromelysin is an activator of procollagenase", Biochem. J., 248, 265-8 (1987). Inhibiting stromelysin could limit the activation of collagenase as well as prevent the degradation of proteoglycan.
That stromelysin inhibition may be effective in preventing articular cartilage degradation has been demonstrated in vitro by measuring the effect of matrix metalloendoproteinase inhibitors on proteoglycan release from rabbit cartilage explants:
C.B. Caputo, L.A. Sygowski, S.P. Patton, D.J. Wolanin, A. Shaw, R.A.
Roberts, G. DiPasquale, J. Orthopaedic Res., 6, 103-8 (1988).
There is an extensive literature on the involvement of these metalloproteinases in arthritis, but there is very little to guide one in developing a specific inhibitor for each enzyme.
In preliminary studies of rabbit proteoglycanase with - 15 substrates ~ and inhibitors, little was found to indicate the enzyme's requirements for hydrolysis or inhibition beyond a preference for hydrophobic residues at the P1' position: A. Shaw, R.A. Roberts, D.J. Wolanin, "Small substrates and inhibitors of the metalloproteoglycanase of rabbit articular chondrocytes", Adv.
~` 20 Inflam. Res., 12, 67-79 ~1988). More extensive studies with a series of substrates revealed that stromelysin will tolerate nearly every amino acid residue around the scissile bond: G.B.
Fields, H. Brikedal-Hansen, H.E. Van Wart, unpublished results presented at the Matrix Metalloproteinase Conference, Sept. 1989, Sandestin Fla.
Human rheumatoid synovial collagenase has been shown to share ~ 50% homology with human stromelysin: S.E.
Whitham, G. Murphy, P. Angel, H.J. Rahmsdorf, B.J. Smith, A. Lyons, T.J.R. Harris, J.J. Reynolds, P. Herrlich, A.J.P.~ Docherty, ~o "Comparison of human stromelysin and collagenase by cloning and sequence analysis", Biochem. J., 240, 913-6 (1986). Many collagenase inhibitors have been designed around the cleavage site of the a-chain sequence of Type !I collagen: W.H. Johnson, N.A.
Roberts, N. Brokakoti, "Collagenase inhibitors: their design and ~ ~ SUBSTI~E SHEE~
,, `1 ` ,:, ~ , - 4 -. ' ~ ! , '; ., _.
potential therapeutic use", J. Enzyme Inhib., 2, 1 -22 ( 1987) . One such inhibitor, N-[3-(benzyloxycarbonyl)amino-1-carboxy-n-propyl]-L~leucyl-O-methyl-L-tyrosine, N-methylamide, prepared at G.D. Searle, Inc., and shown to be a potent inhibitor of human rheumatoid synovial collagenase (ICso = 0.8 ~M), was also found 5 to inhibit rab~it bone proteoglycanase (ICso = 0.5 ~lM): J.-M.
Delaisse, Y. Eeckhout, C.Sear, A. Galloway, K. McCullagh, G. Vaes, "A new synthetic inhibitor of mammalian tissue collagenase inhibits bone resorption in culture", Biochem. Biophys. Res.
Commun., 183, 483-90 (1985).
Gelatinase (MR ~ 72,000) has been isolated from rheumatoid fibroblasts: Y. Okada, T. Morodomi, J. J. Enghild, K.
Suzuki, A. Yasui, I. Nakanishi, G. Salvesen, H. Nagase, "Matrix metalloproteinase 2 from human rheumatoid synovial ~ibroblasts", Eur. J., Biochem., 194, 721-~0 (1990). The synthesis 15 of the proenzyme is not coordinately regulated with the other two metalloproteinases and its activation may also be different. The role of geiatinase in the tissue destruction of articular cartilage appears different from the other two enzymes and, therefore, its inhibition may provide additional protection ~rom degradation. A
20 higher molecular weight gelatinase (MR ~~5,000; aka. type-V
collagenase, matrix metalloproteinase-9, MMP-9) is also secreted by ~ibroblasts and monocytes and may be involved in cartilage degradation.
As appreciated by those of skili in the art, the 25 significant proportion of homology between human` fibroblast collagenase, stromelysin, and geiatinase leads to the possibility that a compound that inhibits one enzyme may to some degree inhibit all of them.
Compounds that inhibit collagenase, which possess 30 structural portions akin to those of the instant invention include those encompassed by U.S.4,511,504 issued Apr. 16, 1985; U.S.
4,568,666, issued Feb 4, 1986.
SU~STI, UTE SHEET
WO 92/21360 PCr~US92/03809 Compounds of related structure that are ciaimed to inhibit stromelysin (proteoglycanase) are encompassed by U.S.
4,771,037, issued Sept. 13, 1988.
The applicants believe that stromelysin and collagenase inhibitors have utility in preventing articular cartilage damage associated with septic arthritis. Bacterial infections of the joints can elicit an inflammatory response that may then be perpetuated beyond what is needed for removal of the infective agent resulting in permanent damage to structural components. Bacterial agents have been used in animal models to elicit an arthritic response with the appearance of proteolytic activities. See J.P. Case, J. Sano, R. Lafyatis, E.F. Remmers, G.K.
Kumkumiàn, R.L. Wilder, "Transin/stromelysin expression in the synovium of rats with experimental erosive arhtritis", J. Clin Invest., 84, 1731-40 (1989); R J. Williams, R.L. S;mith, D.~).
Schurman, nSeptic Arthritis: Staphylococcal induction of chondrocyte proteolytic activityn, Arthr. Rheum., 33, 533-4t (1 990~.
The applicants also believe that inhibitors of ~tromelysin, collagenase, and gelatinase will be useful to control ~: - 20 tumor metastasis, optionally in combination with current chemotherapy and/or radiation. See L.M. Matrisian, G.T. Bowden, P.
Krieg, G. Furstenberger, J;P. Briand, P. Leroy? R. E3reathnach, "The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors", Proc. Natl. Acad.
Sci., USA, 83, 9413-7 (1986); S.M. Wilhelm, I.E. Collier, A.
Kronberger, A.Z. Eisen, B.L. Marmer, G.A. Grant, E.A. Bauer, G. I.
Goldberg, "Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells", Ibid., 84, 6725-29 (1987); Z.
Werb et al., Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression, J. Cell Biol., 109, 872-889 (1`989); L.A. Liotta, C.N. Rao, S.H. Barsky, "Tumor invasion: and~the extracellular matrixn, Lab. Invest., 49, 636-649 (1983); R. Reich, B.~Stratford, K. Klein, G. R. Martin, R. A. Mueller, ;UBSTITUTE SHEET
~I t~ ~S` ~ , - 6 -G. C. Fuller, "Inhibitors of collagenase IV and cell adhesion reduce the invasive activity of malignant tumor cells", in Metastasis:
Ciba Foundation Symposium; Wiley, Chichester, 1988, pp. 193-210.
Secreted proteinases such as stromelysin, collagenase, and gelatinase play an important role in processes involved in the movement of cells during metastasic tumor invasion. Indeed, there is also evidence that the matrix metalloproteinases are overexpressed in certain metastatic tumor cell lines. In this context, the enzyme functions to 0 penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation. - After adhering to blood vessel walls, the tumor cells use these same metalloendoproteinases to pierce underlying basement membranes and penetrate other tissues, thereby leading 15 to tumor metastasis. Inhibition of this process would prevent -` metastasis and improve the efficacy of current treatments with chemotherapeutics and/or radiation.
These inhibitors should also be useful for controlling periodontal diseases, such as gingivitis. Both collagenase and 20 stromelysin activities have been isolated~ from fibroblasts isolated from inflammed gingiva: V.J. Uitto, R. Applegren, P.J.
Robinson, 'iCollagenase and neutral metalloproteinase activity in extracts of inflamed human gingiva", J. Periodontal Res., 16, 417-424(1981). Enzyme levels have been correlated to the severity of 25 gum disease: C.M. Overali, O.W. Wiebkin, J.C. Thonard, "Demonstration of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva", J.
Periodontal Res., 22, 81-88 (1987).
; ~ Proteolytic processes have also been observed in the 30 ulceration of the cornea following alkali burns: S.l. Brown, C.A.
Weller, H.E. Wasserman, "Collagenolytic activity of alkali-burned corneasN, Arch. Opthalmol., 81, 370-373 ~1969). Mercapto-containing pep~ides do inhibit the collagenase isolated from alkali-burned rabbit cornsa:~F.R. Burns, M.S. Stack, R.D. Gray, C.A.
S~BSTITUTE SHEET
WO 92/21360 PCI/I)S92/03809 Paterson, Invest. Opthalmol., 30, 1569-1575 (1989). Treatment of alkali-burned eyes or eyes exhibiting corneal ulceration as a result of infection with inhibitors of these metalloendoproteinases in combination with sodium citrate or sodium ascorbate and/or antimicrobials may be effective in preventing developing corneal degradation.
Stromelysin has been implicated in the degradation of structural components of the glomerular basement membrane (GBM) of the kidney, the major function of which is to restrict passage of plasma proteins into the urine; W.H. Baricos, G. Murphy, Y. Zhou, H.H. Nguyen, S.V. Shah, "Degradation of glomerular basement membrane by purified mammalian meta!loproteinasesn, Biochem. J., 254, 609-612 ~1988). Proteinuria, a result of glomerular disease, is excess protein in the urine caused by increased permeability of the GBM to plasma proteins. The underlying causes of this increased GBM permeability are unknown, but proteinases including stromelysin may play an important role in glomerular diseases. Inhibition of this enzyme may alleviate the proteinura associated with kidney malfunction.
It is suggested that inhibition of stromelysir. activity may prevent the rupturing of atherosclerotic plaques leading to coronary thrombosis. The tearing or rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
Destabilization and degradation of the connective tissue matrix surrounding these plaques by proteolytic enzymes or cytokines released by infiltrating inflammatory cells has been proposed as a cause of plaque fissuring. Such tearing ot these plaques can cause an acute thrombolytic event as blood rapidly flows out of the blood vessel. High levels of stromelysin RNA message have been fqund to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery: A. M. Henney, P. R. Wakeley, M. J. Davies, K. Foster, R.
Hembry, G. Murphy, S. Humphries, "Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad. Sci. USA, 88, 8154 8158 SUBS~TUT~ Sl IEE~
: ~ `
WO 92/21360 PCl/US92/03809 . . ,, , . (,j I ., (1991). Inhibition of stromelysin by these compounds may aid in preventing or delaying the degradation of the connective tissue matrix that stabilizes the atherosclerotic plaques, thereby preventing events leading to acute coronary thrombosis.
It is also believed that specific inhibitors of 5 stromelysin and collagenase should be useful as birth control agents. There is evidence that expression of metalloendoproteinases, including stromelysin and collagenase, is observed in unfertilized eggs and zygotes and at further cleavage stages and increased at the blastocyst stage of fetal development and with endoderm differentiation: C.A. Brenner, R.R.
- Adler, D.A. Rappolee, R.A. Pedersen, Z. Werb, "Genes for extracellular matrix-degrading metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development", Genes 8~ Develop., 3, 848-59 (1989). By;analogy to tumor invasion, a blastocyst may express metalloproteinases in order to penetrate the extracellular matrix of the uterine wall dari;n g implantation. Inhibition of stromelysin and collagenase during these early developmental processes should presumably prevent normal embryonic development and/or implantation in the 20 uterus. Such intervention would constitute a novel method of ; birth control. In addition there is evidence that collagenase is important in ovulation processes. In this example, a covering of coilagen over the apical region of the follicle must be penetrated in order for the ovum to escape. Collagenase has been detected 25 during this process and an inhibitor has been shown to be effective in preventing ovulation: J.F. Woessner, N. Morioka, C.
Zhu, T. Mukaida, T. Butler, W.J. LeMaire "Connective tissue breakdown in ovulationn, Steroids, 54, 491-499 (1989). There may also be a role for stromelysin activity during ovuiation: C.K.L.
3-o ~OO, G.D. Bryant-Greenwood, F.C. Greenwood, "Relaxin increases the release of plasminogen activator, collagenase, and proteo-glycanase from rat granulosa cells in vitron, Endocrin., 11 5, 1043-1 D50 (1984).
;~ SUBSTITUTE SHEET
~ .
W O 92/21360 P ~ /US92/03X09 . ~; ~ ., - 9 , i~ . . i . j Collagenolytic and stromelysin activity have also been observed in dystrophobic epidermolysis bullosa: A. Kronberger, K.J. Valle, A.Z. Eisen, E.A. Bauer, J. Invest. Dermatol., 79 208-211 (1982); D. Sawamura, T. Sugawara, I. Hashimoto, L. Bruckmer-Tuderman, D. Fujimoto, Y. Okada, N. Utsumi, H. Shikata, Biochem.
Biophys. Res. Commun., 174, 1003-8 (1991). Inhibition of metalloendoproteinases should limit the rapid destruction of connective components of the skin.
In addition to extracellular matrix comprising structural components, stromelysin can degrade other in vivo - l0 substrates including the inhibitors a 1 -proteinase inhibitor and may therefore influence the activities of other proteinases such as elastase: P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W.
Carrell, G. Murphy, "Proteolytic inactivation of human a 1 -antitrypsin by human stromelysin", FEBS Letts., 279,; 1, 91-94 :: 15 :(1991). Inhibition of the matrix metalloendoproteinases may potentiate the antiproteinase activity of these endogenous inhibitors.
SUMMARY OF THE INVENTION
The invention encompasses novel N-carboxy-alkylpeptidyl compounds of formula I which are useful inhibitors of matrix metalloendoproteinase-mediated diseases including degenerative diseases (such as defined abo~re) and certain cancers.
R /~NH~Il[ ]X
) J ~ (~.) L
DETAILED DESCRIPTION OF THE INVENTION
, "
BSTITUrE SHEET
WO 92/21360 P~/US92/03809 -., i i . (~ .J ;J
The invention encompasses compounds of formula 1.
~ ~_ (~ (~,~) ' o or a pharmaceutically acceptable salt thereof wherein: :
R 1 is substituted C1 6alkyl, wherein the substituent is selected from the group consisting of:
(a) hydrogen, ~- 15 (b) carboxy, ,; ; ~ , ;
,: ~
~ ~ SU~STlT~)Tt SH~ET
:
_ __ _ _ _ _ _ _ __ _ __ _ . _ _ _ .. _ _. __ .. _ . _.. _ .. :.. : .. ' ~ .-- I--~'F ~.' '-- ' --WO 92/21360 PCI /US~2/03809 (c) -CNH2, (d) C 6 1 oaryl wherein the aryl group is selected from the group consisting of -(1 ) phenyl, (2) naphthyl, ~:
(3) pyridyl, -(4) furyl, (5) pyrryl, - (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, ~1 0) tetrazolyl, ( 1 1 ) pyrazinyl, (12) pyrirnidyl, (1 3) quinolyl, (14) isoquinolyl, : (15) benzofuryl, ( 16) isobenzofuryl, ( 17) benzothienyl, (1 8) pyrazolyl, (1 9) indolyl, (20) isoindolyl, (?1) purinyl, (22) carbazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, i . (26) benzthiazolyl, and (27) bsnzoxazolyl, and mono and di-substituted C6 10aryl as de~ined above in items (1 ) to (27) wherein the substitutents are independently selected from C1 6alkyl, C1 6alkyloxy, halo, ~ SUBSTITUTE SHEET
,~
, : ~
; ` ~. 3 hydroxy, amino, C1 6alkylamino, aminoC1 6alkyl, carboxyl, carboxylC1 6alkyl, and C1 6alkylcarbonyl;
o (e) -N-C-Ra Rb wherein Ra and Rb are each independently hydrogen; C6 10aryl and mono and di-substituted C6 10aryl as defined above (d); or substituted C1 6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the o nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring whereirl the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atorn;
O
: 15 (f ) -N-C-Ra -~ C-Rb, O wherein Ra and Rb are each independently hydrogen; C6- 1 oaryl and mono and di-substituted C6 1oaryl as defined above (d); or substituted : 20 C 1 6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they - are attached, there is formed a lactim or benzolactim ring wherein the laetim portion thereof is a ring of up to 8 atoms, said laetim or benzolactim have a single hetero atom; . `~
(g) amino and substituted amino wherein the substituent is selcted from C1 6alkyl and C6 1 oa ry l wher~in aryl is defined in (d);
R2 is CHRCRd wherein Rc is (a) H, (b) C 1 ~alkyl, or (c) hydroxyl;
, - ~IJBSTlTUTESHEET
, Rd is C6-10arYIC1-2alkYI or C6 10aryl substituted C 1 2alkyl wherein the substituent is C1 3alkyl or hydroxy, :
and wherein the aryl group is selected from the group consisting of:
(1 ) phenyl, ~:
(2) naphthyl, --(3) pyridyl, (4) pyrryl, `: (5) furyl, (6) thienyl, (7) isothiazolyl, (8) Imidazolyl, (9) benzimidazolyl, :.
,~
, : ~
; ` ~. 3 hydroxy, amino, C1 6alkylamino, aminoC1 6alkyl, carboxyl, carboxylC1 6alkyl, and C1 6alkylcarbonyl;
o (e) -N-C-Ra Rb wherein Ra and Rb are each independently hydrogen; C6 10aryl and mono and di-substituted C6 10aryl as defined above (d); or substituted C1 6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the o nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring whereirl the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atorn;
O
: 15 (f ) -N-C-Ra -~ C-Rb, O wherein Ra and Rb are each independently hydrogen; C6- 1 oaryl and mono and di-substituted C6 1oaryl as defined above (d); or substituted : 20 C 1 6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they - are attached, there is formed a lactim or benzolactim ring wherein the laetim portion thereof is a ring of up to 8 atoms, said laetim or benzolactim have a single hetero atom; . `~
(g) amino and substituted amino wherein the substituent is selcted from C1 6alkyl and C6 1 oa ry l wher~in aryl is defined in (d);
R2 is CHRCRd wherein Rc is (a) H, (b) C 1 ~alkyl, or (c) hydroxyl;
, - ~IJBSTlTUTESHEET
, Rd is C6-10arYIC1-2alkYI or C6 10aryl substituted C 1 2alkyl wherein the substituent is C1 3alkyl or hydroxy, :
and wherein the aryl group is selected from the group consisting of:
(1 ) phenyl, ~:
(2) naphthyl, --(3) pyridyl, (4) pyrryl, `: (5) furyl, (6) thienyl, (7) isothiazolyl, (8) Imidazolyl, (9) benzimidazolyl, :.
(10) ~tetrazolyl, :;~
( 1 1 ) pyrazinyl, lS ( 12) pyrimidyl, (1 3) quinolyl, : ( 14) isoquinolyl, (15) benzofuryl, I
( 16) isobenzofuryl, . :~
( 17) benzothienyl, (1 8) pyrazolyl, ;: ( 19) indolyl, (20) isoindolyl, (21 ) purinyi, (22) carbazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, ! ' i (26) benzthiazolyl, and - (27) benzoxazolyl, and mono and di-substituted C6 10aryl as defined above in items (1 ) to (27~ wherein the substitutents are indepen~ently selected from C1 6alkyl, C1 6alkyloxy, halo, -SUBSTITUTE SHE~T
WO 92/21360 PCI/US92~03809 i . . - 1 4 hydroxy, amino, C1 6alkylamino, aminoC1 6alkyl, carboxyl, ca~boxylC1 6alkyl, and C1 6alkylcarbonyl;
R3 is (a) H, (b) C 1-1 oaikyl, (C) G6 1 oaryl or C6 1 oaryl C1 3alkyl, wherein the aryl group is selected ~rom the group consisting of (1) phenyl, and (2) substituted phenyl, wherein the -substitutent is carboxy, carboxyC1 3alkyl, aminocarbonyl, C1 6alkylaminocarbonyl;
.
AA is an amino acid of formula ll Re - lS -N-C -C-H Rf l l , wherein Re and Rf are individually selected from:
(a) hydrogen, ~ (b) C1-6alkYI1 (c) mercapto C1 6alkyl, (d) hydroxy C1 6alkyl, (e) carboxy C; 6alkyl, (f) ami no substituted C 1 - 6 a I ky I
(9) aminocarbonyl C~ 6alkyl, (h) mono- or di~ 6alkyl amino Cl 6alkyl, (i) guanidino C1 6alkyl, (j) substituted phenyl C1 -6 alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (k) substituted indolyl C1 6alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C 1 - 4 alkyl, or G~4alkyloxy, ~UBSrlTUTE: SHEET
WO 92~21360 PCI`/US92/038~)9 1 5 - f ~ ~,r (I) substituted imidazolyl C2 6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (m) substituted pyridyl C 1 - 6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (n) substituted pyridylamino C1 6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C 1 - 4 alkyl, or C1 4alkyloxy, The above amino aeids of formula ll are intended to include but are not limited to glycine, alanine, valine, leucine, isole~ucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, Iysine, hydroxylysine, arginine, homohistidine, phenylalanine, tyrosine, 1S tryptophan, cyc;.eine, methionine, ornithine, homoserine, and citruiline .
X is Rs - N - R6 wherein Rs and P~6 are each individually selected from the group consisting of:
(a) H, - (b) C 1-1 ~alkyl, (c) C6 1oaryi or C6 l0arylC1 6alkyl, wherein the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) pyridyl, I4) pyrryl, !: (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidàzolyl, ~: (1 0) tetrazolyl, SU~S ~ IT~E SHEET
::
',? ~ 16 -(1 1 ) pyrazinyl, ( 12) pyrimidyl, ( 13) quinolyl, (14) isoquinolyl, ( 15) benzofuryl, ( 16) isobenzofuryl, ( 17) benzothienyl, (1 8) pyrazolyl, ( 19) indolyl, (20) isoindolyl, (21~ purinyl, (~2) carbazolyl, (23) isoxazolyl, .
(~4) benzthiazolyl, (25) benzoxazolyl (26) thiazolyl, and :~
(27) oxazolyl.
: One genus of this embodiment is tha compounds wherein~
~ ~ ~o R 1 is substituted C1 6alkyl, wherein the substituent is selected ~rom the group consisting of: :
(a) hydrogen, (b) carboxy, O ~ -~C) - C-NH2~
(d) C6-10arYI or c6-1oaryl C1 6alkyl wherein the aryl group is selected from the group consisting of (1 ) phenyl, - (2) naphthyl, - (3) thienyl, (4) imidazolyl, : . :
(5) benzimidazolyl, (6) pyrimidyl, . , , .
~ ~ ~;UBStlTllTE St!EET
, W O 92/21360 PCT/U~92/03809 ., . ; ... .
(7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6- 1 ~aryl as defined above in items ~1 ) to (9) wherein the substitutents are independently selected from C1 6alkyl, C1 6alkyloxy, halo, hydroxy, amino, C1 6alkylamino, and C1 6alkylcarbonyl;
o - (e) N-C-Ra - lO Rb wherein Ra and Rb are each independently ; hydrogen, C6- 1 o aryl wherein the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C~ 10 aryl as defin`ed above; or substituted C1 6alkyl wherein the substitutent is selected from hydroxy, halo, and benzyl, or wherein Ra and Rb are joined together to form a lactarn or benzolactam ring as defined above.
-~ ~ SUES~lTl~'~ S~tEET
:;~
WO 92/21360 PCl /US92/03809 One class of this genus is the compounds wherein:
R2 is CHRCRd wherein .
~c is (a) H, (b) C 1 3alkyl, or (c) hydroxyl;
Rd is C 6-1 oaryl C1 -2alkYI or C6 1 oaryl substituted C1 -2 alkyl, wherein the substituent is C1 3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of : :
(1 ) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, ~--~ (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6 10aryl as defined above in : items (1 ) to (93 wherein the substituents are independently selected~ from C1 6alkyl, C1 6alkyioxy, halo, hydroxy, and C 1 6alkylcarbonyl.
A sub-class of this class is the compounds wherein:
R3 is (a) H, ~- (b) C 1-1 oalkyi~
(c) phenyl, substitutsd phenyl, wherein the substitutent is carboxy, carbexy C1 3alkyl, amino carbonyl.
~: ' SUBSTIl-UTE SHEET
WO 92/21360 PCl`/US9Z/03809 ''" '~ '"I ''i '' ' ~ ' !
Within this sub-class are the compounds wherein:
AA is an amino acid including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, Iysine, hydroxy-lysine, homohistidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, homoserine, or -~
citrulline .
Alternatively, within this sub-class the amino acids AA
- lO can be defined :as follows:
AA is ~ Re -N-C - G-H Rf ; 15 wherein :Re and Rf are individually selected from:
(a) ~hyd!ogen~
~: ~ (b) C1 4alkyl, (c) mercapto C1 3alkyl (d) hydroxy C1 4alkyl, (e) carboxy C1 4alkyl, : (f) amino Ct 4alkyl, 5g) aminocarbor~yl Cl 4alkyl, ~: (h) mono - or di-C1 6alkyl amino C1 4alkyl, (i) guanidino C1 4alkyl, (j) substituted phanyl C1 4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1 3 alkyl, k) substituted indolyl C1 4 alkyl, wherein the - 30 substituent is hydrogen, hydroxy, carboxy, or C1 3 .. - . .
alkyl, (I) substituted imidazolyl C2 6alkyl wherein the substituent ~is hydrogen, hydroxy, carboxy, or C1 4 a!kyl. ~ ~:
SU~STITUTE ~ET
,~- .
WO 92/21360 PCT~US92/03809 One group o~ compounds may be further identified as that wherein X is wherein Rs and R6 are each individually selected from the group consisting of (a) H, - (b) C 1 -1 oalkyl, or (c) C6-10arYI, or c6-1oarylc1-6alkyl wherein - - the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) thiènyl, ~: ~ (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, ~; 20 (8) benzothienyl, ( 9 ) indolyl, and ( 10) pyridyl.
A smaller group within this sroup are the compounds 25 wherejn Rd is C1.4alkylC6-10arYIC1-2alkY
R3 is (a) H, or 30 ~ (b) C 1-1 oalkyl; and R1 is C6 10arYI C1 6alkyl; and Rb is H.
~ SUBSTITUTE SHEET
-WO 92/21360 PCI /US92/03~09 Exemplifying the invention are the following compounds:
(a) N-[1 (R)-Carboxy-ethyl]-oc-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(b) N-~1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl~glycine-(L)-isoleucine, N-phenylamide;
(c) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, N-phenylamide;
(d) N-~1 (R)-Carboxy-ethyll-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;
(e) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-benzyl ether, N-- phenylamide;
(f) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide;
~: 15 (9) N-~ Carboxy-ethyll-a-(S)-(2-ph~ny~-ethyl)]glycine-a-(S)-(2-phenyl-ethyl)glycine, N-: phenylamide;
(h) N-11 (R)-Carboxy-ethyl]-a-(S) -(2-phenyl-ethyl)glycine-(L)-norleucine, N-phenylamide;
(i) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-valine, N-phenylamide;
(j) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine, N-phenylamide hydrochloride;
(k) N-[1 (R)-Carboxy-ethyl~-a-(S~-~2-pheny`l-ethyl~glycine-(L)-asparagine, N-phenylamide;
(I) N-l1 (R)-Carboxy-ethyl~-a-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide . . hydrochloride;
. (m) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, N-phenylamide;
(n) N-[1 (R)-Carboxy-ethyl)]-a-;S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid, N-phenylamide;
SUBST~TUTE SHEET
WO 92/21360 PCI /US92/03$0g (o) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride;
(p) N-l1 (R)-Carboxy-5-(1 ,3-dioxo-isoindolin-2-yl)pentyl~-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(q) N-[1 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(r) N-11 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine-(S)-:arginine, N-phenylamide;
(s) N-[1 (R):-Carboxy-ethyl]-a-(S)-(2-(3-hydroxyphenyl)-ethyi)glycine-(S)-leucine, N-phenylamide hydrochloride;
-~ 15 : - (t) N-[1:(R)-Carboxy-ethyl]-a-(S)-(2-(4-methylp~hen~ylj-e~thyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(u) N-l1 (R)-Carboxy:-ethyl]-a-(S)-(2-(2'-~: thienyl)et~hyl)glycine-(L)-Leucine, N-phenylamide;
(v) N-(1(R)-Carboxy ethyl)-a-(S)-(2-(4-;~ ethylph~nyl)ethyi)glycine-(L)-leucine, N-phenylamide;
(w) N-[1 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentylJ-a-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(x) N-~1 (R)-Carboxy-ethyl)-a-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(y) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)]glycine-a-(S)-(2-cyclahexyl-ethyl)glyci~ne, N-phenylamide;
SUBSTITUTE SHEET
, . , ; , " ~ , WO 92/21360 PCl/US9~/03~09 - 23 - ,, ., ; J
(z) N-E1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)]glycine-a-(S)-(cyclohexyl)glycine, N-phenylamide;
(aa) N-[1 (R)-Carboxy-ethyl)]-oc-(S)-(2-phenyl-ethyl)~glycine-a-(S)-(cyclohexylmethyl)glycine, N-phenylamide;
(ab) N-~1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-13-naphthylalanine, N-phenylarnide;
(ac) N-~1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-a-naphthylalanine, N-- - phenylamide;
(ad3 N-[1 (R)-Garboxy-ethyl)]-a-~S)-(2-phenyl-- ethyl~glycine-[(L)-glutamio acid, a,~-bis- N-phenylamide];
lS (ae) N-11 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethy!)glycine-(L)-leucine, N-cyclohexylamide;
(ae) N-l(1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(4-hydroxyphenyl-ethyl)glyeine, N-pnenylamide;
(af) N-[1 (R)-Carboxy-ethyl)l-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide;
~1 (ag) N-l1 (R~-Carboxy-ethyl)~-a-(S~-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, N~-benzylamide, Na-phenylamide];
(ah) N-[1 (R)-Carboxy-ethyl)]-a-~S)-(2-pheriyl-ethyl)glycine-(L)-Ornithine, N-phenylamide;
(ai) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl~glycine-(L)-arginine, N-phenylamide;
!~ I (aj) N-11 (R)-Carboxy-ethyl)~-a-(S)-(2-phenyl-- 30 . ethyl)glycine-a-(S)-(3-phenylpropyl)glycine, N-phenylamide;
(ak) N-[1 ~R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-;: ethyl)~glycine-a-(S)-n-octylglycine, N-: ~ phenylamide;
SU~STITUTE SHET
-;
WO 92/21360 PCl`/US92/03809 ` ,3~ 24 -(al) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-carboxyphenyl)amide;
(am) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-s trifluoromethylphenyl)amide;
(an) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide;
(ao) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl) amide;
~; (ap) N-[1 (R~)-Carboxy-ethyl]-a-(S)-(2-(4-n-propylph~enyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(aq) N-[1 (R)-carboxy-ethyl]-a-($)-(2-(4-propylphenyl~ethyl)glycine-(L)-Arginine, N-~- phenylamide;
(ar) N-[1 (R)-Carboxy-ethyll-a-(S)-(2-(3,4-dimethyl~phenyl-ethyl))glycine-(L)-leucine, N-phenylamide.
This invention also concerns pharmaceutical composition and methods of treatment of stromelysin-mediated or implicated disorders or diseases (as described above) in a patient (whcih shall be defined to include man and/or mammalian 25 animals raised in the dairy, meat, or fur industries or às pets) in need of such treatment comprising administration of the stromelysin inhibitors of formula I as the active constituents.
Similarly, this invention also concerns j pharmaceutical compositions and methods of treatment of 30 collagenase mediated or implicated disorders or diseases (as . .
described above) in a pati~nt in need of such treatment comprising administration of the collagenase inhibitors of formula (I) as the active constituents.
SUBSTITUTE SHE~T
, ,, ; ~ `.,, :
- 2 5 - . i . . .i Similarly, this invention also concerns pharmaceutical compositions and methods of treatment of gelatinase-mediated or impiicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the gelatinase inhibitors of formula 5 (1) as the active constituents.
Moreover the invention also encompasses compositions, treatment, and method for co-administration of a compound of formula I with a PMN elastase inhibitor such as those described in EP 0 337 549 which published on October 18, 1989, which is hereby incorporated by reference.
Compounds of the instant invention are conveniently prepared using the procedures described generally below and more explicitly described in the Example section thereafter.
SCHEM~ I - METHOD A
R2 NaE~H3~ . I OR
-~ 20 A B C
C HCI C l-lAA]-X R3o2c R2 or TFA EDC/HOBVNMM R--NH~lMlx D o 3 o Ho2c R2 D 2. d/C ~ R--NH~IMl x E
S~JBSTITUTE SHE~T
:
WO 92t21360 PCI'/US92J03~09 .`` .' ! i: ~ I ' ' `' The reactions of Scheme I (Method A) involve the reductive amination of keto acid or ester derivative A with amino acid derivative B to form N-carboxylalkyl derivative C. The reaction is conveniently conducted in a mixture of pyridine and 5 acetic acid with slow addition of sodium cyanoborohydride. The diastereomers of C are conveniently separated by column chromatography or HPLC. Reaction of diester C with hydrochloric acid followed by condensation with a substituted amino acid - derivative [AA]-X results in Compound D. This reaction sequence advantageously employs the use of condensing agents such as dicyclohexylcarbodiimide (DDC) or water-soluble carbodiimide (N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide; EDC). This reaction is also assisted by the formation of active ester `intermediates such as those derived from 1-~-~ 15 hydroxybenzotriazole, 4-nitrophenol, or 4-picolyl alcohol. The ~ ~ amino a~id derivatives lAA]-X are prepared from appropriately :~ : protected N-protected amino acid derivatives condensed with X
under similar conditions cited for the formation of D. R3 may be removed by hydrogenolysis (when R3 = CH2aryl) or by basic -~ 20 hydrolysis to give amino acid E.
,~ .
SCHEME ll - METHOD B
25 ~32C R2 ot C H NaBH3CN R302C F'~2 R~NH3+C~ ~ pyr/HOAc Rf NH~ 4 9 A' B' An alternative method is shown in Scheme ll (Method B~. In a reductive amination process similar to the one described for Method A, amino acid derivative A' is reacted with keto ester derivative B' to :form~ N-carboxylalkyl derivative ~C. This diester C
is then modified as in Method A.
.,:
, ~ SUBSTITUTE SHEET
-wo 92/21360 t ~ PCr/Us92/o38o9 SCHEME lll - METHOD C
(F3Cso2) ~0 Cl-H3N~ ~ O-t-C~Hg R1 OH C2H5N(i-C3H7)2 C' `
A second alternative is shown in Scheme lll (Method C). In this variation an activated (S)-a-hydroxy ester is reacted with amino acid derivative B to form N-carboxyalkyl derivative C'. Compound C' is then reacted with lAA]-X as in Method A to 15 : form D.
,. ~ .
:
, -, j ~ `
,. ~ .
,.~
.,,; ` .
: 30 .
:: :
~ ~ ~ SUeSTlTUTl~ SHEET
.
.
..
W O 92/21360 PC~r/US92/03809 2 J J~ 28 -SCHEME IV- MethQd D
~o ~ AlCb ~ H2, Pd/C
TFA-NH C~!2C12 OH EtOAc, HOAc TFA-NH
R F
~ lAA]-X ~ Nl3, MeC)H
,OH ~ TFA-NH
G ~ H
R R
~ ~ ~ 15 ~ R~ ~ H2, Pd/C
T f 2O R32C f ~ -~: H2N~I l 2 6-llJt f ~IM]-X or OH-R
TFA = -COCF3 2 5 1 [M] -X
R~ NH
:' :
An alternative method involving the preparation of substituted phenylethyl amino acid is shewn in Scheme IV
(Method G). The Friedel-Crafts acylation of N-trifluoroacetyl-L-: ~ aspartic: acid anhydride~ (prepared: by the described method: M.
Lapidus,- M.:~:Sweeney ~:J.~:~Med. :Chem. 16, 163 (t973)) with a substituted~benzene~ i;n~the presence of aluminum chloride gave 5~ aroyl amioo ~ acid ~denvatlve F. The aryl ketone was reduced by Sl~ `TU~E S~lEET
"
WO 92/21360 PCr/US92/03809 - 29 ~ . , catalytic hydrogenation to G. Condensation of G with amino acid [AA]^X by the procedure described in M~thod A gave N-trifluoroacetamide dipeptide H. Deprotection of H with ammonia in methanol gave the free amine 1. Reaction with activated benzyl (L)-lactate by the procedure described in Method C gave N-5 carboxyethyl dipeptide benzyl ester D'. Catalytic hydrogenationas described in Method A gave the N-carboxyethyl dipeptide E' .
~ ' :~' : ; S~JE~TI~TU rE SHE~ T
w O 92~21360 P ~ /US92/03809 21~r~ ia 3(~
SCHEME V- METHOD E
R R
~ n ul ~\) 2CuCNLi2 R
0, THF ~ (~
10 Cbz-NH~ ' ,~
O L
R
L5 ~ IAAI-X ~ H2, Pd/C
EDG, HOBt, f ~: Cbz-NH O CbZ~NHJ~l~]-x M N
R R
~1 R ~ H2, Pd/C
f T f2O R3O2c ~ _ H2N~[MI~x 2,6-lut R, NH~[M~ x orOH~
O I o D~
,.
J
~O2C f R,--NH~
E~
.~ .
S~S, ITI ITE ~ET
., . :
WO 92/21360 PCr/US92/03809 - ~1 - .. . ` , ,. ~ , . .. .
An alternative method ~or the preparation of substituted phenylethyl amino acids is shown in Scheme V
(Method E). A substituted aryl iodide is lithiated with n-butyl lithium and reacted with copper(l) cyanide by the method of B. L
Lipschutz, D. Parker, J. A. Kozlowski J. Org. Chem., 48, 3334 (1983) to forrn the higher order cuprate complex J. lodoethyl glycine derivative K was reacted with J to form phenethyl amino acid derivative L. Basic hydrolysis gave free acid M which is subsequently coupled with amino acid derivative [AA]-X by the procedure described in Method A to give N. Catalytic hydrogenation of N gave the free amine I which is subsequently modified to N-carboxyalkyl dipeptides D' and E' according to the procedure described in Method D.
A representative number of compounds of the instant invention of the formula (I) are shown below to exhibit in ~itro inhibitory activities ~with respect to stromelysin, collagenase, and gelatinase. In particular, the compounds of formula (I) have been sh~own to inhibit the hydrolysis of substance P, (that is, Arg-P~ro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-~Met-NH2) by stromelysin employing the methoc described in detail in the literature: R.
: 20 Harrison, J. Teahan, R. Stein, "A semicontinuous, high-performance liquid chromatography-based assay for stromelysin", Analytical BiochemI 180, 1 10-1 13 (1989). Compounds of formula ~- I were shown to inhibit the cleavage of a thioester containing peptide, Ac-Pro-Leu-Gly-"S-Leu"-Leu-Gly-OC2Hs, by collagenase employing the previously described method: H. Weingarten, R.
Martin, J. Feder, Biochem, 24, 6730-34 (1985). Inhibition of gelatinase-mediated cleavage of the fluorogenic substrate Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-ArgNH2 by compounds of Formula I
I were demonstrated employing the method of M. S. Stack and R. D.
30 Gray, J. Biol. Chem. 264, 4277 (1989).
`
SUBSTITUTE SHEET
, , WO 92~213~) PCr/US92/03X09 U~
-O ~
~o ~ U) ~ :
.-- C~ 1` 1 ~
Q ~, 11 cr~ o~
c N I y a~ ~ o , o N o ~ ~
~C> ~ C~l ~ ~ C'~ O ~ o~ ~ ' 11 ~ O N O O ~ O O ~ -- ~ ~,' c ~ )~/
.
C
E o ~) I~ U~ N
D o 11 I~.
C U~
N c 15 o~ : '- s c c s I I ' c I z z z z z z c~ ~ I o ~=O E
20 ~ 0 C~ 0 ~ a~
_ ~I I I I I Ic~l I I C
1~ O O V V V O ~ 1l 2 5 N ~L N Q ~ Q CL Q n 5g~
N C'J N C~ N N N _ o o c.) o o . -3 0 , , , ~ c ~ E
- - E c s IL ~a Q Q ~;l ~ ~ ~ ~ N Q
) V t~ 1~
~ ~, rr ~ ~ ~ c ~ 3 ;~ : SUBSTITUTE SH~:T
, :
WO 92/21360 PCI`/USg2/03809 -- 3 3 ~
, j ,, . ,: , a, .
C ''''''''~'''~''~--------c -t C Q Q lL Q Q ~L ~L Q ~ Q. IL ~ ~ Q Q ~L ~ Q Q Q
I I I I I I :C I I I I I I I I I I I I I I
~; ZZZZZZZZZZZZZZZZZZZZZ
, 10 Vl I I ~ .
: ~ 0 0 0 0 0 o~ o~ a~ o~ ~ a~ a> ~ a) ~ C~l C~ ~ Q
I I 3 T I I I T I I I :C I~ I ,,~ Q N C') --~ I I
~'q .-: : ~
o o ,: , 't O
' s Q ~ -C -- s ~ C C ~ D ~ ~ C -- C r C -~ c ~ Z~ N C~ 3 ~, C~ N C~ C~
~ Q Q Z ~ ~ N ~J 1~l ~ c~ N N S~ ~J N N N N C~l C`~l C~l c N c~ V ~ V t ) c~ J
c 2 5 a) c ._ c cL
!, . i l O
3~ . ` a) ~ s ~D --E a~ ~ c c ~ c c ~
m ~ ~ E 3 ~ D 'O
:.',~ ~-::
SUBSTITUTE SHEET
-, ~
WO 92/21360 PCI/US92/03~09 -- 3~ --, t ... .. .. ... ... . ..
~D
-- s s s s -- -- -- -- -- s -- s -- s s s ~ c s s s --~ ZZZZZZZZZZZZ
,~ :
o " ~
0 ~-- C _ O _ Q Q Z
I I _ . O ~ O ~ ~ T O ~ C~ O ~ O I
'C C C C C C C s C C C ~ C ~ C c ' c c s C N
C~ Q Q 11. Q Q tL CL Q Il. Q Q 1~ Q Q 1~ Q ~ CL tL t~ ~ I
,'~ VVVVVVOO~VVVVc~V~ V(~o ~D
.
m :~
~ E ~ o Q ~O ~ ~ ~ ~ ~ 3 :
SU~^~Ti l-UTE S~lEET
~:
-- 3 5 ~
a: zzzzzzzzzzzzzzzzzzzzzzzz C~C`l N C~J
I II I :1:
;; Z ZZ Z Z
_ _ ~ T
~ Zc~ a) ~ a> a~ a) a~ a> ~ o) a~ Z Z~ Z Z
. ~-~ I I C~ _LL C~ O ( ) C~) 2 0 ~ ) O O ~,) C . ~ ~ C c c c c _ -- -- -- s s c s s s -- ~ C s s c s -- -- s s c -- ~C
I N C~ ~ ~J N ~J N N ~ ~J N ~ ~\1 N C~l N N C~l C~l N A ' I I I I I I I I I I T I I I I I I I I I I I
Q D_ Q ~, ~ c O N N N A ^ ' c ~ T I I I I I
-- -- _ _ D D D D ~ D ~ D Q 8 D D D D D ~ 3 D D D D
~ SUBSTITUTE SHEET
WO 92/21360 PCI`/US92/03X09 'J ~
~ ~ ~ S ~ ~ ~ ~ ~ ~ ~ ~ ~ S
Q Q Q Q Q Q Q Q. Q IL t~ Q ~
~ I I I ~ I I I I I I I I I I
C: Z Z Z Z Z Z Z Z Z Z Z Z Z Z
-, 10 I I I Q ~ Q Q Q Q Q Q I I I
- ~ ~ ~ W ~ C~ W W C~
-~ 15 ~ 20 -- -- -- -- ~ c -- -- -- -- s --~ Q ~ Q Q n c~ A aL Q
- W C~l W N W W W N C~J C~ N C~l N C~
Wl C~l Wl W W N C`J W C~l N C~ .l C`.l N
I I I I I I I I ~I I I I I I
Q _ _ ~_ _ _ _ _ _ _ _ _ _ _ _ ~' T
I I
2 5 c~
~ ~ I
~ o o c~
I I N O \~
O O O O O O O O O O O O 0 0~z~
3 ~ - I I I I I I I I I I 11 a~ Z ~ Z Z Z Z Z ~ C~ ~ E
C W ~ ;i W ~ ;i N ~
~ I :C I I T I I I I T I I T I
:~ :- m D 8 ~ a~ ~, c" ~ ,, ~ 1, ~, E c :,, ~,...
SUBSTlTlJ~E S.~EET
WO 92/21360 PCr/VS92/03809 - 37 _ : ;
~ . . , i . ..
O
~ O O O O ( ) O I IL IL -- -- -- E -- --- s ) C.) O O O ~c c a) -- ~ ~ ~ ~ ~ ~ t ~ ~ Q ~ Q Q ~ C
-C ~ L ~ ~ ~ ~ ~ ~ t t ~ ~ ~ ~ ~ ~.
~ :1: I I I I I I I I I I I I I I I I I I I I
a: zzzzzzzzzzzzzzzzzzzzz I I :C I ~ I I I: I I I I I I I I I I I I I
.-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- , ..--~' cn ,n^ n cn v~ vn v~ cn v~ vn fn vn cn vn cn vn n n v~ cn vn 1 5 -- -- -- -- _ _ _ _ I I
. I C
" ,~ s c s s s s s s s '-- s s c -- ~ s -- s s s . v Q Q Q , ~_ Q Q Q Q Q Q Q ~L Q Q Q Q Q Q
t~ N CU C~ J C~ l N N t:~J N ~I C~.l N 5~1 C`.l N C~
C`l N t~ t~J ~I C~J ~I C~l C`~l N N N l:~J N C~ N C~l Q C~
V C~ V V V O ~ t ) V O V (~ V V t~
~l vn v~ tn n ~ n n n ,n n tn n ,n tn r) ,_ n n v cn n i .. `. I
C C'~~ t~ tr~ t.~ t~ t.~ t.~ t.
E s ~I I I I I s T I I T I I I I T ,~ I I
J
m c o ~ ~ "~ ~ ~ 3 X ~ N tlS ~ ~ cn ~
SUBSTITUTE SHEET
.
WO 92/21360 PCI`/US~2/03809 , ( ~ 3 ~ -,.. .. .
This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloendoproteinase inhibitors of forrnula (I) as the active constituents.
Accordingly, the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloendoproteinases such as found in certain metastatic tumor cell lines.
For ~the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and indications resulting from the over-expression of matrix metalloendoproteinases such~ as found in certain metastati~ tumor cell lines or other diseases mediated by the matrix metalloendoproteinases, the compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectaliy in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasterna! injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitabl~ for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the ~manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected trom the group consisting of sw-etening agents, flavoring agents, coloring SUBSTITI.~'TE SHEET
~, - 3 9 - , . .:, .
agents and preserving agents in order to provide pharmaceutically elegant and paiatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, 5 such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for - example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108;
4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with 20 an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsulss wherein the - active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in 25 admixture with excipients suitable for the manu~acture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or 30 wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or SUBSTITUTE SHEET
.
WO 92/21360 PCI~/US92~03809 condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The 5 aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
` - Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame Pil or coconut oil, or in a mineral oil such as liquid paraffin.~ The oiiy suspensions may contain a thickening agent, for example beeswax, hard~paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may ~be preserved by the addition ~of an anti-oxidant such as ` ~ ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring 25 agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a ' mineral oil, for example liquid paraffin or mixtures of ~hese.
3b Saitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from~ fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the ` S~JB~TITl,r,rE SltE.T
, WO 92/21360 PCr/US92/03809 - 4 1 - ~i , ; ; j ~
said partial esters with ethylene oxid~, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or 5 . sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be tormulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in ~ a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Arnong the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In ~ addition, sterile, fixed oi!s are conventionally employed as a - soivent or suspending medium. For this purpose any bland fixed oil may be employed 20 including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compou~nds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared 25 by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, crearns, ointments, jellies, solutions 30 Qr suspensions, etc., containing the compounds of Formula (I) are employed. (For purposes of this application, topical application - shall include mouth washes and gargles.) Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in ., ~
S U BSTITUTE S H ~ET
-: , WO 92/21360 PCI`/US92~03809 the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms. per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
lS It will be understood, however, that the specific dose - ~ level for any particular patient will depend upon a variety o~
~: factors including the activity of the specific compound employed, the~ age, body weight, general health, sex, diet, time of . ~ administration, route of administration, rate of excration, drug - ~: 20 combination and the severity of the particular disease undergoing therapy.
The following Examples are intended to illustrate the preparation of compounds of Formula 1, and as such are not intended to limit the invention as set forth in tlie claims appended, thereto.
Example 1 .
~ 30 ~ SUBSTIT~E S~tEET
.
WO 92/21360 PCl /US92t0380g .... ~,;,, ~
- 43 - ~; . , , J, ~, ' J
HO2C ~
CH3 NH~ NHPh \--CH3 5a CH3 Employing:the procedure outlined in Scheme 1, Method A, compound number Sa was prepared as follows:
, 'hCH202C T ~ `
15. : H3C~O ~ HOAc, pyr PhCH202C fJ
: ~ Cl-H3N~O-t-C4Hg CH--NH~O-t-C4Hg N-[l (R)-Benzvloxy~arbonvl-ethvl~-a-~S!-(2-ph~nyl-ethvl)plv~ine t-butvl est~r ~1 !
To a solution of 10.5 9 of (S)-a - ( 2 - p h e n y I -ethyl)glycine, t-butyl ester in 50 mL each of acetic acid and 25 pyridine at 0 C was added 27.2 mL of a 1.0 M solution~ of sodium cyanoborohydride (NaBH3CN) in tetrahydrofuran (THF) foliowed by 18.1 mL of benzyl pyruvate. Additional NaH3BCN (50 mL, 1.0 M) was then added over 5 hours via syringe pump. The mixture was allowed to warm slowly to ambient temperature during the first 30 30 minutes of this addition. The reactlon mixture was then poured into a slurry of ice and 100 mL of concentrated hydrochloric acid (HCI) and extracted with 500 mL of 30%
ethcr/hexane` ~ (discarded).
~ ~ The: ;aqueous slurry (containing the desired HCI salt) was~ then :extracted: three:: times with ethyl acetate and the , , -,,, SU~STI ~tUr~ S~EET
~, WO 92/21360 PCl/US92/03809 !.J ~ l ,-.) (; `;
combined organic layers were washed three tim~s with saturated aqueous sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 20 9 of a yellow oil. The mixture was purified by flash column chromatography on silica-gel (120 x 200 mm column, 10% ethyl acetate/hexane) to give 6.40 9 of a colorless oil: Rf = 0.25 (10%
ethyl acetate/hexane): 1H NMR (200 MHz, CD30D) ~ 7.13-7.37 (m, 10H), 5.12 (ABq, 2H, J=5.1 Hz), 3.36 (q, lH, J=7.0 Hz), 3.15 (t, 1H, J=6.4 Hz), 2.65 ~m, 2H), 1.90 (m, 2H), 1.45 (s, 9H), 1.26 (d, 3H, J=7.0 Hz).
:: 15 J HCI CH3 PhCH202C ~' O
CH--NH~O-t-C~Hz EDC, HOBt, NMM CH--NHJ~rNHJI~NH
o CH3 :::
N-[1 (R)-Benzyloxycarbonyl-ethyl)]-~-~S!-(2-phenethyl)gly~ jne-(L)-leucine. N-phenylamide (2) N-[1 (R)-Benzyloxycarbonyl-ethyl)]-oc-(S)-(2-25 phenethyl)glycine, t-butyl ester (1 ) (6.40 9) was dissolved in a small amount of ethyl acetate and 250 mL of a saturated solution o~ anhydrous HCI in ethyl acetate was added. The mixture was held for 7 hours at 50C then cooled and concentrated in vacuo to ; give a colorless solid which was used without further 30 purification: 1H NMR (200 MHz, CD30D) ~ 7.41-7.20 (m, 10H), 5.25 (AB, 2H, J=12.1 Hz), 4.27 (q, 1H, J=7.3 Hz), 4.06 (t, 1H, J=6.6 Hz), 2.9-2.7 (m, 2H), 2.24 (m, 2H), 1.55 (d, 3H, J=7.4 Hz).
The crude aminoacid hydrochloride, (L)-Leucine, N-phenylamide hydrochloride (3.71 9, 18.0 mmol)1 and hydroxybe~nzotriazole (3.31 g j 24.5 mmol) were dissolved in 250 SUBSTITUTE SHEET
- 45 - ; .. ~, -mL of dimethyiformamide (DMF). N-methyl morpholine (NMM) (3.6 mL, 32.7 mmol) was added and the mixture cooled to 0C. Ethyl dimethylaminopropyl carbodiimide (EDAC, 3.7~ 9, 19.6 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The solution was diluted with 1 L of ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with water. The mixture was then dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale yellow oil. The product was purified by MPLC (35 x - 350 mm column, 30% ethyl acetate/hexane) to afford 8.31 g of o the desired peptide as a colorless glass: -1H NMR (200 MHz, CD30D) ~ 7.57-7~08 (m, 15H), 5.13 (ABq, 2H, J =
5 Hz), 4.57 (m, 1H), 3.47 (q, lH, J_7.1 Hz), 3.25 (t, lH, ~=6.4 Hz), 2.67 (t, 2H, J=8.1 Hz), 2.1-1.6 (m, 5H), 1.31 (d, 3H, J = 7.0 Hz), 0.98 (d, 3H, J=6.5 Hz), 0.96 (d, 3H, J=6.0 Hz).
~;- 'hCH202C ~ O ~' HO2C ~
INHJ~NHPh Pearlman s CH3--NH~ NHPh o ~ Catalyst 2 \rCH3 CrCH3 CH3 5 a 3 N-11 (R)-ca!boxy-ethyl]-oc-(s?-(2-phenyl-ethyl)~lycine leucine. N-phenylamide (5a) ` To a solution of 8.31 9 of N-[1(R)-benzyloxycarbonyl-30 ethyl)]-a-(S)-(2-phenethyl)glycine-(L)-leucine, N-phenylamide (2) in 125 mL of methanol was added 500 mg of Pearlman's catalyst. After 3 hours of vigorous stirring und3r an atmosphere of ~ hydrogen, the mixture was filtered through Celite filter aid and concentrated in vacuo to give 6.50 9 ot amino acid 5a as a ,. ~ , " ~ :
SUBSTITU~ S~EET
WO 9~/21360 PCr/US~/n~X09 colorless solid: 1H NMR (200 MHz, CH30D) ~ 7.59-7.08 (m, 10H), 4.65 (m, 1H), 3.96 (t, 1H, J = 6.8 Hz), 3.58 (q, 1H, J = 7.4 Hz), 2.9-2.6 (m, 2H), 2.15 (m, 2H), 1.52 (d, 3H, J = 7.4 Hz), 1.02 (d, 3H, J =
6.0 Hz), 1.00 (d, 3H, J = 6.0 Hz).
The following additional compounds were prepared according to the method of Example 1.
N-11 (R)-Carboxy-ethyl]-a-(S!-(2-phenyl-ethyl)alvcrine-(L!- .
- isoleucine~. N-phenvlamide (5w , 10 MS: mle 440 (M+) ~ :
1 H NMR: (CD3~0D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 2.0 Hz), 7.34-- 7.09 (m, 8H), 4.42 (d, 1H, J = 8.0 Hz), 4.01 (t, 1H, J = 6.0 Hz), 3.58 (q, 1H, J = 7.0 Hz), 2.68 (m, 2H), 2.14 (m, 2H), 1.64 (m, 1H), 1.48 lS (d,~3H,~ 7.:0~Hz), 1:.30 (m, 2H), 1.03 (d, 3H, J = 6.5 Hz), 0.96 (t, 3H, J
= 7.0:HZ)-,~ " ~, ~ , N-~:1 (R)-Carboxv-ethvl)l-a-(S)-(2-phenvl-ethyl)alycine-(L!-~ine. N-ehenylamide~) -- MS: m/e 398 (M+) -~ ~ 1H~NMR (CD30D,200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 2.0 Hz), 7.33--~ 7.19 (m, 8H), 4.56 (q, lH, J = 7.0 Hz,), 3.95 (t, 1H, J = 6 Hz), 3.60 (q, lH, J = 7.0 Hz), 2.75 (m, 2H), 2.17 ~m, 2H) 1.48 (d, 6~H, J = 7.0 Hz).
N-11 (R)-Carboxy-ethyl)l-a-(S!-(2-ehenvl-~thvl,~lycine-~L~Lenylalanine. N-~he~lylamide (5y) MS: m/e 474 (M~) 1H NMR (CD30D,200 MHz): ~ 7.51 (dd, 2H, J = 8.0, 2 Hz), 7.32-7.09 (m, 13H3, 4.93 ~(dd, 1H, J - 9.0, 6.0 Hz), 3.90 (t, lH, J - 6.0 Hz), ~; 3.40 (q, 1H,`J~- 7.0:~Hz, 3.26 ~(dd. 1H, J = A.0, 13 Hz), 3.01 (dd,1H, J
, .
," ~ , U6S~ITUTE SH~
,~ ~
, . , ,, ,._ ~ . ___~ ... ., .. . __. . . _.. . ... . . .... ..
WO 92/21360 PCr/US92/03809 - 47 - ~ ; . ;.J '_ = 9.0, 13 Hz), 2.68 (t, 2H, J = 8.0 Hz), 2.12 (dd, 2H, J = 6.0, 9.0 Hz), 1.29 (d, 3H, ~ = 7.0 Hz).
N-11 (R!-Carboxy-ethyl)]-a-(S~-(2-phenyl-ethyl!glycine-(L!-serine-O-benzyl ether. N-phenylamide _(5z) MS: m/e 504 (M+) 1H NMR (CD30D,200 MHz): ~ 7.55 (dd, 2H, J = 8.0, 2.0 Hz), 7.34-7.10 (m, 13H, ArH), 4.60 ppm (s, lH), 4.58 (s, 1H), 4.04 (t, lH, J =
- 6 Hz), 3.84 (d, 2H, J = 6.0 Hz), 3.75 (q, lH, J = 7.0 Hz), 2.74 (dd, 2H, lO J = 6.1 2.0 Hz), 2.18 (t, 2H, J = 7.0 Hz), 1.49 (d, 3H, J = 9.0 Hz).
.
arboxy-ethyl)l-a-(S)-(2-~enyl-ethyl)~lycine-(L)-tryptoehan. N-phenylamide (5ac) 5 MS: m/e 513 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.65 ~dd, 1H, J = 7.0, 2.0 Hz), 7.47 (dd, 2H, J = 8.0, 1.0 Hz), 7.30-6.99 (m, 12H), 4.94 (dd, 1H, J = 9.0, 7.0 Hz), 3.82 (t, 1H, J = 6.0 Hz), 3.34 (dd, 2H, J 4.0, 9.0 Hz), 3.27 (q, 1H, J - 6.0 Hz), 2.64 (m, 2H), 2.10 (td, 2H, J = 8.0, 2.0 Hz), 1.23 (d, 20 3H, J = 7.0 Hz).
N-[1 (R)-Carboxy-ethvl)]-~-(S)-(~-phenyl-~hyl)]~lycin~--(S)-(2~phenvl-ethvl)~lycine. N-phenylamid~ (5ad) ~5 MS: m/e 488 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.08 (m, 13H,), 4.58 (dd, 1H, J = 9.0, 7.0 Hz), 4.02 (t, lH, J = 6.0 Hz), 3.64 (q, 1H, J = 7.0 Hz), 2.74 (m, 4H), 2.16 (m, 4H~, 1.51 (d, 3H, J =17.0 Hz).
N-ll (R)-Carboxy-ethyl)~-a-($)-(2-phenyl-ethyl)gly~ine-(L)-norleucine. N-~henvlamide (5am ~ MS: m/e 440 (M I ) ; ~; SUBS~l~U,I.E_SHEET
WO 92/21360 PCr/US92/03X09 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.08 (m, 8H), 4.52 (dd, lH, J = 8.0, 6.0 Hz), 3.98 (t, 1H, J = 6.0 Hz), 3.~9 (q, lH, J = 7.0 Hz~, 2.71 (m, 2H), 2.16 (t, 2H, J = 8.0 Hz), 1.85 (m, 2H), 1.48 ppm (d, 3H, J = 7.0 Hz), 1.43 (m, 4H), 0.94 (t, 3H, J =
7.0 Hz).
N-[1 (R!-Carboxv-ethvl!]-a-(S)-(2-phenvl-ethyl!~lvcine-(L)-valine. N-phenylamid~ (5an) - MS: m/e 426 (M+) lO 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.09 (m, 8H), 4.37 (d, 1H, J = 8.0 Hz), 4.04 (t, 1H, J = 7.0 Hz,), 3.60 (q, 1H, J = 7.0 Hz), 2.68 (m, 2H), 2.16 (m, 3H), 1.49 (d, 3H, J = 7.0 Hz), 1.06 (d, 6H, J = 7 Hz).
~-: 15~ N-[1[R)-~ Qxy-ethyl)]-a-(S)-(2-phenvl ethyl)glycine-.
serine. N-phenylamide Hydrochloride (Sao) ; :
M~S- m/e 414 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 8.0, 1.0 Hz), 7.34-20 7.09 (m, 8H), 4.68 (t, 1H, J - 8.0 Hz), 3.88 (d, 2H, J = 6.0 Hz), 3.51 (t, 1H, J = 8.0 Hz), 3.10 (q, 1H, J = 7.0 Hz), 2.78 (m, 2H,), 2.24 (m, - 2H), 1.60 (d, 3H, J = 7.0 Hz~.
N-[1 (R)-Carboxy-ethvl)]-a-lSl-(2-phenyl-ethyl~glyine-25 (L~ c~gine. N-~henylamide ~5aa) MS: m/e 441 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 2.0, 8.0 Hz), 7.14-7.34 (m, 8H), 4.86 (d, 1H, J = 7.0 Hz), 3.92 (t, 1H, J = 6.0 Hz), 3.6430 (q, 1H, J = 7 Hz), 2.6-2.8 (m, 2H), 2.1-2.25 (m, 4H), 1.47 (d, 3H, J -7.0 Hz).
N-11 (R)-carboxy-ethvl!:~--(S)-(?-phenvl-ethyl)glycine-(L)-thr~nine. N-~henvlamide hvdrochloride (5ab) ., ~ .
~ ~ SllEST(~ S~EET
;:
WO 92/21360 PCl /US92/03~09 MS: m/e 428 ~M+) 1H NMR (CD30D,200 MHz): â 7.66 (d, 2H, J = 8.0 Hz), 7.12-7.34 (m, 8H), 4.~6 (d, 1H, J = 5.0 Hz), 4.1-4.3 (m, 2H), 4.09 (q, 1H, J = 7.0 Hz), 2.7-2.8 (m, 2H), 2.2-2.3 (m, 2H), 1.63 (d, 3H, J = 7.0 Hz), 1.32 5 (d, 3H, J = 6.0 Hz), .
N-11 (R)-Carboxy-ethyl)~-a-(S)-(2-phenyl-ethyl!alycine-(L)-lvsine. N-phenvlamide (5ae) lO MS: mle 455 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 2.0, 8.0 Hz), 7.04-7.29 (m, 8H), 4.55 (dd, 1H, J = 5.0, iO.0 Hz), 3.26 (t, 1H, J = 7.0 Hz), 3.19 (t, 1H, J = 7.0 Hz), 2.95 (t, 1H, J = 7.0 Hz), 2.69 (t, 2H, J =
8.0 Hz), 1.85-2.0 (br. m, 4H), 1.60, 1.70 (2m, 4H), 1.30 (d, 3H, J = 7 Hz).
,~ ~
N~ (R)-Carboxy-ethyl)1-a-(S)-(2-Dhenyl-ethvl)~lycine--glutamic acid. N-~henylamide (5ak) ~- 20 MS: m/e 456 (M+) lH NMR (CD30D, 200 MHz): â 7.57 (dd, 2H, J _ 2.0, 8.0 Hz), 7.12-7.33 (m, 8H), 4.67 (dd, 1H,.J = 6.0, 9.0 Hz), 4.02~(t, 1H, J = 6.0 Hz), 3.66 (q, 1H, J = 7.0 Hz), 2.67-2.74 ~t, 2H, J = 7.0 Hz), 2.46-2.54 (m, 2H), 2.1-2.23 (br. m, 4H), 1.51 (d, 3H, J = 7.0 Hz).
2s Combustion Analysis C24H29N3o6 (0-20 H2O) Calc: C, 62.79, H. 6.45, N, 9.15 Found: C, 62.79, H, 6.50, N. 9.15 N-[i (R)i-~arboxy-ethyl~-a-(S!-(~-ehenyl-ethyl!~lvcine-(L!-t~7rosine. N-phenylamide hydro~hlorid~ (5al) ,~ - . . .
MS: m/e 490 (M+ - HCI) H NMR (CD3~0D,: 200 MHz): ~ 7.53 (dd, 2H, J = 2.0, 8.0 Hz), 7.10-7.33 (m,~8H), 6.74 (dd, :2H, J 2.0, 8.0 Hz), 4.89 (dd, lH, = 6.0, 9.0 , .
.~ - . .
:: :
W O 92/21360 PC~r/US92/03809 ~ r~ 50 Hz), 3.99 (t, 1H, J = 6.0 Hz), 3.59 (q, 1H, J = 7.0 Hz), 3.24 (dd, ~H, J
= 8.0, 15.0 Hz)1, 2.93 (dd, lH, J = 10.0, 15.0 Hz), 2.67-2.76 (t, 2H, J = 7.0 Hz), 2.10-2.23 (br. m, 2H), 1.46 (d, 3H, J = 7.0 Hz).
Exa m ple 2 HO2C ~ O
1 0 ~NH~NHJI`NHPh : J: o ~ ~3 5d , ~
: ~ Employing the procedure outlined in Method B, N-[1(R)-~: Be:nzyloxycarbonyl-5-(1,3-dioxo-isoindolinyl-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine, t-butyl ester 4 was prepared and ~:- converted to compound 5d using methodology described in Method - A for ami:nodipeptide 2 and aminoacid 5a.
PhCH202C
_~NH3~CI- NaBH3a~1 PhCH202C
HOAc, pyr ~' O
~ O~o t C~Hg ~
R~ nzvloxycarbonvl-5~ diQxo-isoindolin-2-yl)p~ntyl]
H a-(S~-(2-Dhe:nvl-ethvl-~alucine~ t-butvl ester ~4) sv~sn l-uTE S~EET
WO 92~21360 PCI`/US92/03809 - 51 - ; ` ';` :
To a solution of -phthalimido tD)-Lysine benzyl ester hydrochloride (1.23 9, 3.05 mmol) in 2.5 mL each ef acetic acid and pyridine at 0C was added 0.5 mL of a 1.0 M solution of N a H 3 BCN in THF followed by t-butyl 2-oxo-4-phenylbutanoate (1.43 9, 6.11 mmol). Additional NaH3BCN (3.58 mL, 1.0 M) in THF
was then added over 3.5 hours via syringe pump. The mixture was allowed to warm slowly to ambient temperature during the first 30 minutes of this addition. The reaction mixture was poured into a slurry of ice and 15 mL of conc. HCI and extracted three times with ethyl acetate. The combined organic layers were washed three times with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo.
The mixture was purified by MPLC (35 x 300 mm column, 10-20%
ethyl acetate/hexane by linear gradient) to give 801 mg of the desired amino ester as a colorless oil:
1H NMR (CD30D, 200 MHz) ~ 7.82-7.71 (m, 4H~, 7.35-7.08 ~m, 10H), 5.09 (ABq, 2H, J = 11.9 Hz), 3.61 (t, 2H, J = 6.5 Hz), 3.21 (t, 1H, J =
6.0 Hz), 3.06 ~t, 1H, J = 7.2 Hz), 2.60 (t, 2H, J = 6.7 Hz), 2.0-1.3 (m, - 20 8H), 1.42 (s, 9H).
Substituted a-keto-esters~ were also conveniently prepared by one of the following proc:edures:
25 utyl 2-Oxo-5-phenylpentanQate To a suspension of magnesium turnings (1.22 g, 50.23 mmol) in 20 mL of ether was added 1-bromo-3-phenylpropane (7.64 mL, 50.23 mmoi) at a rate so as to maintain a gentle reflux.
After the addition was complete, the mixture was stirred an 30 additional 30 min. Di-tert-butyl oxylate (10.16 g, 50.23 mmol) was dissolved in 250 mL of ether and cooled to -78~C. The Grignard reagent was added dropwise so as to maintain an internal temperature S -75C. The mixture was stirred for an additional hour at-78~C, and poured into a mixture of ice, 300 mL
SU13STITIJTE StE~ET
WO 92~21360 PCI/US92/03809 j_ ., of 1 N hydrochloric acid and 200 mL of eth~r. The mixture was shaken vigorously and the iayers were separated. The ether layer was washed with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to give 15.2 9 of the title compound as a colorless oil: 1H NMR (200 MHz, CDCI3) ~ 7.36-7.04 (M, 5H), 2.79 (t, 2H), 2.67 (t, 2H), 1.97 (m, 2H), 1.57 (s, 9H).
t-Butyl 2-oxo-4-t4-methylpher!yl)-butan~e To a solution o~ 4-methylbenzaldehyde (2.5 mL, 21.2 mmol) in 25 mL of benzene was added 1 mL each of acetic acid and piperidine~. The mixture was heated to reflux with azeotropic removal of water via a Dean-Stark trap. A solution of t-butyl pyruvate~ (3.36~9, ~23.32~ mmol) in 5 mL of behzene was added over 7 h by syringe pump. The mixture was cooled, diluted with ethyl acetate and washed~three times with saturated aqueous sodium bicarbonate ~and ;thrée times with 1 ~J hydrochioric acid. The o rganics~ were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by MPLC on silica-gel ~eiuting with 2.5% ethyl acetate in hexane to give the desired ~product as a yeilow oil: 1H NMR (200 MHz, GDCI3) ~ 7.75 (d, 1H, J =
16.19 Hz), 7.49 (d, 2H, J = 8.25 Hz~, 7.24 (m, 3H), 2.37 (s, 3H), 1.58 (s, 9H). The above product was dissolved in ethyl acetate and held under hydrogen~ in the prësence of 100 mg of 10% palladium on carbon for 2 hours. The mixture was filtered and concentrated in vacuo to give 1.196 9 of the title compound as a pale-yellow oil:
1H NMR (200 MHz, CDCI3) ~ 7.1-6.9 ~mJ 4H), 3.12 (t, 2H, J = 6.8 Hz), 2.90 (t, 2H, J = 7.3 Hz), 1.56 (s, 9H).
, , , l ~ 30 :
, -:
SUBSnTU-ESHEET
, ~,, -.
,,, - - ,~
, ,"~
, :
- 53 - ..
O
J Cl H N~ ~ J
hCH202C I 3 NHPh PhCH202C ~ o O-~-C4H3 ~CH3 O o CH3 NA~ 4 EDC, HOBt, NMM N--4~ CH3 o~ o~ 5d' N-~ R)-Benzyloxycarbonyl-5-(1.3-dioxo-isoindolin-2-yl!pentyl]-5d') N-ll (R)~-Bènzyloxycarbonyl-5-(1 ,3-dioxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine, t-butyl ester 4 (210 l5;~ ~mg)~was dissolvèd~in~a sma~ll amount of ethyl acetate and 15 mL
of ~a ~saturated~ solution~ of anhydrous HCI in ethyl acetate was added.~ ; The~ mixture~ was` held for 4 hours at 50C then coole~ and conce:ntrated in vacuo to ~give a colorless solid which was used without purification. The crude amino acid hydrochloride, (L)-~-- 20 Leucine j N-phenylamide~ ~ hydrochloride (96 mg, 0.39 mmol), and hydroxybenzotriazole (97 mg, 0.72 mmol) were dissolved in 5 mL
of DMF. N-methyl morpho~line (165 ml, 32.7 mmol) was added and the mixture cooled to 0C. Ethyl dimethylaminopropyl carbodiimide (EDAC, 104 mg, 0.54 mmol) was added and the mixture stirred for 16 hours at ambient temperatùre. The solution was diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with water. The mixture was dried over anhydrous sodium sulfate, ,~ ~ I concentrated in vacuo, and purifîed by MPLC (22 x 300 mm ~olumn, 30% ethyl acetate/hexane) to afford 254 mg of the desired pcptide as a colorless glass which crystalliz~d upon standing:
H NMR (CD30D, 200 MHz)~ 7.82-7.06 (m, 19H), 5.08 (ABq, 2H, J .
( 1 1 ) pyrazinyl, lS ( 12) pyrimidyl, (1 3) quinolyl, : ( 14) isoquinolyl, (15) benzofuryl, I
( 16) isobenzofuryl, . :~
( 17) benzothienyl, (1 8) pyrazolyl, ;: ( 19) indolyl, (20) isoindolyl, (21 ) purinyi, (22) carbazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, ! ' i (26) benzthiazolyl, and - (27) benzoxazolyl, and mono and di-substituted C6 10aryl as defined above in items (1 ) to (27~ wherein the substitutents are indepen~ently selected from C1 6alkyl, C1 6alkyloxy, halo, -SUBSTITUTE SHE~T
WO 92/21360 PCI/US92~03809 i . . - 1 4 hydroxy, amino, C1 6alkylamino, aminoC1 6alkyl, carboxyl, ca~boxylC1 6alkyl, and C1 6alkylcarbonyl;
R3 is (a) H, (b) C 1-1 oaikyl, (C) G6 1 oaryl or C6 1 oaryl C1 3alkyl, wherein the aryl group is selected ~rom the group consisting of (1) phenyl, and (2) substituted phenyl, wherein the -substitutent is carboxy, carboxyC1 3alkyl, aminocarbonyl, C1 6alkylaminocarbonyl;
.
AA is an amino acid of formula ll Re - lS -N-C -C-H Rf l l , wherein Re and Rf are individually selected from:
(a) hydrogen, ~ (b) C1-6alkYI1 (c) mercapto C1 6alkyl, (d) hydroxy C1 6alkyl, (e) carboxy C; 6alkyl, (f) ami no substituted C 1 - 6 a I ky I
(9) aminocarbonyl C~ 6alkyl, (h) mono- or di~ 6alkyl amino Cl 6alkyl, (i) guanidino C1 6alkyl, (j) substituted phenyl C1 -6 alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (k) substituted indolyl C1 6alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C 1 - 4 alkyl, or G~4alkyloxy, ~UBSrlTUTE: SHEET
WO 92~21360 PCI`/US92/038~)9 1 5 - f ~ ~,r (I) substituted imidazolyl C2 6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (m) substituted pyridyl C 1 - 6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1 4 alkyl, or C1 4alkyloxy, (n) substituted pyridylamino C1 6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C 1 - 4 alkyl, or C1 4alkyloxy, The above amino aeids of formula ll are intended to include but are not limited to glycine, alanine, valine, leucine, isole~ucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, Iysine, hydroxylysine, arginine, homohistidine, phenylalanine, tyrosine, 1S tryptophan, cyc;.eine, methionine, ornithine, homoserine, and citruiline .
X is Rs - N - R6 wherein Rs and P~6 are each individually selected from the group consisting of:
(a) H, - (b) C 1-1 ~alkyl, (c) C6 1oaryi or C6 l0arylC1 6alkyl, wherein the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) pyridyl, I4) pyrryl, !: (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidàzolyl, ~: (1 0) tetrazolyl, SU~S ~ IT~E SHEET
::
',? ~ 16 -(1 1 ) pyrazinyl, ( 12) pyrimidyl, ( 13) quinolyl, (14) isoquinolyl, ( 15) benzofuryl, ( 16) isobenzofuryl, ( 17) benzothienyl, (1 8) pyrazolyl, ( 19) indolyl, (20) isoindolyl, (21~ purinyl, (~2) carbazolyl, (23) isoxazolyl, .
(~4) benzthiazolyl, (25) benzoxazolyl (26) thiazolyl, and :~
(27) oxazolyl.
: One genus of this embodiment is tha compounds wherein~
~ ~ ~o R 1 is substituted C1 6alkyl, wherein the substituent is selected ~rom the group consisting of: :
(a) hydrogen, (b) carboxy, O ~ -~C) - C-NH2~
(d) C6-10arYI or c6-1oaryl C1 6alkyl wherein the aryl group is selected from the group consisting of (1 ) phenyl, - (2) naphthyl, - (3) thienyl, (4) imidazolyl, : . :
(5) benzimidazolyl, (6) pyrimidyl, . , , .
~ ~ ~;UBStlTllTE St!EET
, W O 92/21360 PCT/U~92/03809 ., . ; ... .
(7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6- 1 ~aryl as defined above in items ~1 ) to (9) wherein the substitutents are independently selected from C1 6alkyl, C1 6alkyloxy, halo, hydroxy, amino, C1 6alkylamino, and C1 6alkylcarbonyl;
o - (e) N-C-Ra - lO Rb wherein Ra and Rb are each independently ; hydrogen, C6- 1 o aryl wherein the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C~ 10 aryl as defin`ed above; or substituted C1 6alkyl wherein the substitutent is selected from hydroxy, halo, and benzyl, or wherein Ra and Rb are joined together to form a lactarn or benzolactam ring as defined above.
-~ ~ SUES~lTl~'~ S~tEET
:;~
WO 92/21360 PCl /US92/03809 One class of this genus is the compounds wherein:
R2 is CHRCRd wherein .
~c is (a) H, (b) C 1 3alkyl, or (c) hydroxyl;
Rd is C 6-1 oaryl C1 -2alkYI or C6 1 oaryl substituted C1 -2 alkyl, wherein the substituent is C1 3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of : :
(1 ) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, ~--~ (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6 10aryl as defined above in : items (1 ) to (93 wherein the substituents are independently selected~ from C1 6alkyl, C1 6alkyioxy, halo, hydroxy, and C 1 6alkylcarbonyl.
A sub-class of this class is the compounds wherein:
R3 is (a) H, ~- (b) C 1-1 oalkyi~
(c) phenyl, substitutsd phenyl, wherein the substitutent is carboxy, carbexy C1 3alkyl, amino carbonyl.
~: ' SUBSTIl-UTE SHEET
WO 92/21360 PCl`/US9Z/03809 ''" '~ '"I ''i '' ' ~ ' !
Within this sub-class are the compounds wherein:
AA is an amino acid including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, Iysine, hydroxy-lysine, homohistidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, homoserine, or -~
citrulline .
Alternatively, within this sub-class the amino acids AA
- lO can be defined :as follows:
AA is ~ Re -N-C - G-H Rf ; 15 wherein :Re and Rf are individually selected from:
(a) ~hyd!ogen~
~: ~ (b) C1 4alkyl, (c) mercapto C1 3alkyl (d) hydroxy C1 4alkyl, (e) carboxy C1 4alkyl, : (f) amino Ct 4alkyl, 5g) aminocarbor~yl Cl 4alkyl, ~: (h) mono - or di-C1 6alkyl amino C1 4alkyl, (i) guanidino C1 4alkyl, (j) substituted phanyl C1 4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1 3 alkyl, k) substituted indolyl C1 4 alkyl, wherein the - 30 substituent is hydrogen, hydroxy, carboxy, or C1 3 .. - . .
alkyl, (I) substituted imidazolyl C2 6alkyl wherein the substituent ~is hydrogen, hydroxy, carboxy, or C1 4 a!kyl. ~ ~:
SU~STITUTE ~ET
,~- .
WO 92/21360 PCT~US92/03809 One group o~ compounds may be further identified as that wherein X is wherein Rs and R6 are each individually selected from the group consisting of (a) H, - (b) C 1 -1 oalkyl, or (c) C6-10arYI, or c6-1oarylc1-6alkyl wherein - - the aryl group is selected from the group consisting of ( 1 ) phenyl, (2) naphthyl, (3) thiènyl, ~: ~ (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, ~; 20 (8) benzothienyl, ( 9 ) indolyl, and ( 10) pyridyl.
A smaller group within this sroup are the compounds 25 wherejn Rd is C1.4alkylC6-10arYIC1-2alkY
R3 is (a) H, or 30 ~ (b) C 1-1 oalkyl; and R1 is C6 10arYI C1 6alkyl; and Rb is H.
~ SUBSTITUTE SHEET
-WO 92/21360 PCI /US92/03~09 Exemplifying the invention are the following compounds:
(a) N-[1 (R)-Carboxy-ethyl]-oc-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(b) N-~1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl~glycine-(L)-isoleucine, N-phenylamide;
(c) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, N-phenylamide;
(d) N-~1 (R)-Carboxy-ethyll-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;
(e) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-benzyl ether, N-- phenylamide;
(f) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide;
~: 15 (9) N-~ Carboxy-ethyll-a-(S)-(2-ph~ny~-ethyl)]glycine-a-(S)-(2-phenyl-ethyl)glycine, N-: phenylamide;
(h) N-11 (R)-Carboxy-ethyl]-a-(S) -(2-phenyl-ethyl)glycine-(L)-norleucine, N-phenylamide;
(i) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-valine, N-phenylamide;
(j) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-serine, N-phenylamide hydrochloride;
(k) N-[1 (R)-Carboxy-ethyl~-a-(S~-~2-pheny`l-ethyl~glycine-(L)-asparagine, N-phenylamide;
(I) N-l1 (R)-Carboxy-ethyl~-a-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide . . hydrochloride;
. (m) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, N-phenylamide;
(n) N-[1 (R)-Carboxy-ethyl)]-a-;S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid, N-phenylamide;
SUBST~TUTE SHEET
WO 92/21360 PCI /US92/03$0g (o) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride;
(p) N-l1 (R)-Carboxy-5-(1 ,3-dioxo-isoindolin-2-yl)pentyl~-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(q) N-[1 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(r) N-11 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine-(S)-:arginine, N-phenylamide;
(s) N-[1 (R):-Carboxy-ethyl]-a-(S)-(2-(3-hydroxyphenyl)-ethyi)glycine-(S)-leucine, N-phenylamide hydrochloride;
-~ 15 : - (t) N-[1:(R)-Carboxy-ethyl]-a-(S)-(2-(4-methylp~hen~ylj-e~thyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(u) N-l1 (R)-Carboxy:-ethyl]-a-(S)-(2-(2'-~: thienyl)et~hyl)glycine-(L)-Leucine, N-phenylamide;
(v) N-(1(R)-Carboxy ethyl)-a-(S)-(2-(4-;~ ethylph~nyl)ethyi)glycine-(L)-leucine, N-phenylamide;
(w) N-[1 (R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentylJ-a-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(x) N-~1 (R)-Carboxy-ethyl)-a-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(y) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)]glycine-a-(S)-(2-cyclahexyl-ethyl)glyci~ne, N-phenylamide;
SUBSTITUTE SHEET
, . , ; , " ~ , WO 92/21360 PCl/US9~/03~09 - 23 - ,, ., ; J
(z) N-E1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)]glycine-a-(S)-(cyclohexyl)glycine, N-phenylamide;
(aa) N-[1 (R)-Carboxy-ethyl)]-oc-(S)-(2-phenyl-ethyl)~glycine-a-(S)-(cyclohexylmethyl)glycine, N-phenylamide;
(ab) N-~1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-13-naphthylalanine, N-phenylarnide;
(ac) N-~1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-(L)-a-naphthylalanine, N-- - phenylamide;
(ad3 N-[1 (R)-Garboxy-ethyl)]-a-~S)-(2-phenyl-- ethyl~glycine-[(L)-glutamio acid, a,~-bis- N-phenylamide];
lS (ae) N-11 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethy!)glycine-(L)-leucine, N-cyclohexylamide;
(ae) N-l(1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl)glycine-a-(S)-(4-hydroxyphenyl-ethyl)glyeine, N-pnenylamide;
(af) N-[1 (R)-Carboxy-ethyl)l-a-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide;
~1 (ag) N-l1 (R~-Carboxy-ethyl)~-a-(S~-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, N~-benzylamide, Na-phenylamide];
(ah) N-[1 (R)-Carboxy-ethyl)]-a-~S)-(2-pheriyl-ethyl)glycine-(L)-Ornithine, N-phenylamide;
(ai) N-[1 (R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-ethyl~glycine-(L)-arginine, N-phenylamide;
!~ I (aj) N-11 (R)-Carboxy-ethyl)~-a-(S)-(2-phenyl-- 30 . ethyl)glycine-a-(S)-(3-phenylpropyl)glycine, N-phenylamide;
(ak) N-[1 ~R)-Carboxy-ethyl)]-a-(S)-(2-phenyl-;: ethyl)~glycine-a-(S)-n-octylglycine, N-: ~ phenylamide;
SU~STITUTE SHET
-;
WO 92/21360 PCl`/US92/03809 ` ,3~ 24 -(al) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-carboxyphenyl)amide;
(am) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4-s trifluoromethylphenyl)amide;
(an) N-l1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide;
(ao) N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl) amide;
~; (ap) N-[1 (R~)-Carboxy-ethyl]-a-(S)-(2-(4-n-propylph~enyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(aq) N-[1 (R)-carboxy-ethyl]-a-($)-(2-(4-propylphenyl~ethyl)glycine-(L)-Arginine, N-~- phenylamide;
(ar) N-[1 (R)-Carboxy-ethyll-a-(S)-(2-(3,4-dimethyl~phenyl-ethyl))glycine-(L)-leucine, N-phenylamide.
This invention also concerns pharmaceutical composition and methods of treatment of stromelysin-mediated or implicated disorders or diseases (as described above) in a patient (whcih shall be defined to include man and/or mammalian 25 animals raised in the dairy, meat, or fur industries or às pets) in need of such treatment comprising administration of the stromelysin inhibitors of formula I as the active constituents.
Similarly, this invention also concerns j pharmaceutical compositions and methods of treatment of 30 collagenase mediated or implicated disorders or diseases (as . .
described above) in a pati~nt in need of such treatment comprising administration of the collagenase inhibitors of formula (I) as the active constituents.
SUBSTITUTE SHE~T
, ,, ; ~ `.,, :
- 2 5 - . i . . .i Similarly, this invention also concerns pharmaceutical compositions and methods of treatment of gelatinase-mediated or impiicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the gelatinase inhibitors of formula 5 (1) as the active constituents.
Moreover the invention also encompasses compositions, treatment, and method for co-administration of a compound of formula I with a PMN elastase inhibitor such as those described in EP 0 337 549 which published on October 18, 1989, which is hereby incorporated by reference.
Compounds of the instant invention are conveniently prepared using the procedures described generally below and more explicitly described in the Example section thereafter.
SCHEM~ I - METHOD A
R2 NaE~H3~ . I OR
-~ 20 A B C
C HCI C l-lAA]-X R3o2c R2 or TFA EDC/HOBVNMM R--NH~lMlx D o 3 o Ho2c R2 D 2. d/C ~ R--NH~IMl x E
S~JBSTITUTE SHE~T
:
WO 92t21360 PCI'/US92J03~09 .`` .' ! i: ~ I ' ' `' The reactions of Scheme I (Method A) involve the reductive amination of keto acid or ester derivative A with amino acid derivative B to form N-carboxylalkyl derivative C. The reaction is conveniently conducted in a mixture of pyridine and 5 acetic acid with slow addition of sodium cyanoborohydride. The diastereomers of C are conveniently separated by column chromatography or HPLC. Reaction of diester C with hydrochloric acid followed by condensation with a substituted amino acid - derivative [AA]-X results in Compound D. This reaction sequence advantageously employs the use of condensing agents such as dicyclohexylcarbodiimide (DDC) or water-soluble carbodiimide (N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide; EDC). This reaction is also assisted by the formation of active ester `intermediates such as those derived from 1-~-~ 15 hydroxybenzotriazole, 4-nitrophenol, or 4-picolyl alcohol. The ~ ~ amino a~id derivatives lAA]-X are prepared from appropriately :~ : protected N-protected amino acid derivatives condensed with X
under similar conditions cited for the formation of D. R3 may be removed by hydrogenolysis (when R3 = CH2aryl) or by basic -~ 20 hydrolysis to give amino acid E.
,~ .
SCHEME ll - METHOD B
25 ~32C R2 ot C H NaBH3CN R302C F'~2 R~NH3+C~ ~ pyr/HOAc Rf NH~ 4 9 A' B' An alternative method is shown in Scheme ll (Method B~. In a reductive amination process similar to the one described for Method A, amino acid derivative A' is reacted with keto ester derivative B' to :form~ N-carboxylalkyl derivative ~C. This diester C
is then modified as in Method A.
.,:
, ~ SUBSTITUTE SHEET
-wo 92/21360 t ~ PCr/Us92/o38o9 SCHEME lll - METHOD C
(F3Cso2) ~0 Cl-H3N~ ~ O-t-C~Hg R1 OH C2H5N(i-C3H7)2 C' `
A second alternative is shown in Scheme lll (Method C). In this variation an activated (S)-a-hydroxy ester is reacted with amino acid derivative B to form N-carboxyalkyl derivative C'. Compound C' is then reacted with lAA]-X as in Method A to 15 : form D.
,. ~ .
:
, -, j ~ `
,. ~ .
,.~
.,,; ` .
: 30 .
:: :
~ ~ ~ SUeSTlTUTl~ SHEET
.
.
..
W O 92/21360 PC~r/US92/03809 2 J J~ 28 -SCHEME IV- MethQd D
~o ~ AlCb ~ H2, Pd/C
TFA-NH C~!2C12 OH EtOAc, HOAc TFA-NH
R F
~ lAA]-X ~ Nl3, MeC)H
,OH ~ TFA-NH
G ~ H
R R
~ ~ ~ 15 ~ R~ ~ H2, Pd/C
T f 2O R32C f ~ -~: H2N~I l 2 6-llJt f ~IM]-X or OH-R
TFA = -COCF3 2 5 1 [M] -X
R~ NH
:' :
An alternative method involving the preparation of substituted phenylethyl amino acid is shewn in Scheme IV
(Method G). The Friedel-Crafts acylation of N-trifluoroacetyl-L-: ~ aspartic: acid anhydride~ (prepared: by the described method: M.
Lapidus,- M.:~:Sweeney ~:J.~:~Med. :Chem. 16, 163 (t973)) with a substituted~benzene~ i;n~the presence of aluminum chloride gave 5~ aroyl amioo ~ acid ~denvatlve F. The aryl ketone was reduced by Sl~ `TU~E S~lEET
"
WO 92/21360 PCr/US92/03809 - 29 ~ . , catalytic hydrogenation to G. Condensation of G with amino acid [AA]^X by the procedure described in M~thod A gave N-trifluoroacetamide dipeptide H. Deprotection of H with ammonia in methanol gave the free amine 1. Reaction with activated benzyl (L)-lactate by the procedure described in Method C gave N-5 carboxyethyl dipeptide benzyl ester D'. Catalytic hydrogenationas described in Method A gave the N-carboxyethyl dipeptide E' .
~ ' :~' : ; S~JE~TI~TU rE SHE~ T
w O 92~21360 P ~ /US92/03809 21~r~ ia 3(~
SCHEME V- METHOD E
R R
~ n ul ~\) 2CuCNLi2 R
0, THF ~ (~
10 Cbz-NH~ ' ,~
O L
R
L5 ~ IAAI-X ~ H2, Pd/C
EDG, HOBt, f ~: Cbz-NH O CbZ~NHJ~l~]-x M N
R R
~1 R ~ H2, Pd/C
f T f2O R3O2c ~ _ H2N~[MI~x 2,6-lut R, NH~[M~ x orOH~
O I o D~
,.
J
~O2C f R,--NH~
E~
.~ .
S~S, ITI ITE ~ET
., . :
WO 92/21360 PCr/US92/03809 - ~1 - .. . ` , ,. ~ , . .. .
An alternative method ~or the preparation of substituted phenylethyl amino acids is shown in Scheme V
(Method E). A substituted aryl iodide is lithiated with n-butyl lithium and reacted with copper(l) cyanide by the method of B. L
Lipschutz, D. Parker, J. A. Kozlowski J. Org. Chem., 48, 3334 (1983) to forrn the higher order cuprate complex J. lodoethyl glycine derivative K was reacted with J to form phenethyl amino acid derivative L. Basic hydrolysis gave free acid M which is subsequently coupled with amino acid derivative [AA]-X by the procedure described in Method A to give N. Catalytic hydrogenation of N gave the free amine I which is subsequently modified to N-carboxyalkyl dipeptides D' and E' according to the procedure described in Method D.
A representative number of compounds of the instant invention of the formula (I) are shown below to exhibit in ~itro inhibitory activities ~with respect to stromelysin, collagenase, and gelatinase. In particular, the compounds of formula (I) have been sh~own to inhibit the hydrolysis of substance P, (that is, Arg-P~ro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-~Met-NH2) by stromelysin employing the methoc described in detail in the literature: R.
: 20 Harrison, J. Teahan, R. Stein, "A semicontinuous, high-performance liquid chromatography-based assay for stromelysin", Analytical BiochemI 180, 1 10-1 13 (1989). Compounds of formula ~- I were shown to inhibit the cleavage of a thioester containing peptide, Ac-Pro-Leu-Gly-"S-Leu"-Leu-Gly-OC2Hs, by collagenase employing the previously described method: H. Weingarten, R.
Martin, J. Feder, Biochem, 24, 6730-34 (1985). Inhibition of gelatinase-mediated cleavage of the fluorogenic substrate Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-ArgNH2 by compounds of Formula I
I were demonstrated employing the method of M. S. Stack and R. D.
30 Gray, J. Biol. Chem. 264, 4277 (1989).
`
SUBSTITUTE SHEET
, , WO 92~213~) PCr/US92/03X09 U~
-O ~
~o ~ U) ~ :
.-- C~ 1` 1 ~
Q ~, 11 cr~ o~
c N I y a~ ~ o , o N o ~ ~
~C> ~ C~l ~ ~ C'~ O ~ o~ ~ ' 11 ~ O N O O ~ O O ~ -- ~ ~,' c ~ )~/
.
C
E o ~) I~ U~ N
D o 11 I~.
C U~
N c 15 o~ : '- s c c s I I ' c I z z z z z z c~ ~ I o ~=O E
20 ~ 0 C~ 0 ~ a~
_ ~I I I I I Ic~l I I C
1~ O O V V V O ~ 1l 2 5 N ~L N Q ~ Q CL Q n 5g~
N C'J N C~ N N N _ o o c.) o o . -3 0 , , , ~ c ~ E
- - E c s IL ~a Q Q ~;l ~ ~ ~ ~ N Q
) V t~ 1~
~ ~, rr ~ ~ ~ c ~ 3 ;~ : SUBSTITUTE SH~:T
, :
WO 92/21360 PCI`/USg2/03809 -- 3 3 ~
, j ,, . ,: , a, .
C ''''''''~'''~''~--------c -t C Q Q lL Q Q ~L ~L Q ~ Q. IL ~ ~ Q Q ~L ~ Q Q Q
I I I I I I :C I I I I I I I I I I I I I I
~; ZZZZZZZZZZZZZZZZZZZZZ
, 10 Vl I I ~ .
: ~ 0 0 0 0 0 o~ o~ a~ o~ ~ a~ a> ~ a) ~ C~l C~ ~ Q
I I 3 T I I I T I I I :C I~ I ,,~ Q N C') --~ I I
~'q .-: : ~
o o ,: , 't O
' s Q ~ -C -- s ~ C C ~ D ~ ~ C -- C r C -~ c ~ Z~ N C~ 3 ~, C~ N C~ C~
~ Q Q Z ~ ~ N ~J 1~l ~ c~ N N S~ ~J N N N N C~l C`~l C~l c N c~ V ~ V t ) c~ J
c 2 5 a) c ._ c cL
!, . i l O
3~ . ` a) ~ s ~D --E a~ ~ c c ~ c c ~
m ~ ~ E 3 ~ D 'O
:.',~ ~-::
SUBSTITUTE SHEET
-, ~
WO 92/21360 PCI/US92/03~09 -- 3~ --, t ... .. .. ... ... . ..
~D
-- s s s s -- -- -- -- -- s -- s -- s s s ~ c s s s --~ ZZZZZZZZZZZZ
,~ :
o " ~
0 ~-- C _ O _ Q Q Z
I I _ . O ~ O ~ ~ T O ~ C~ O ~ O I
'C C C C C C C s C C C ~ C ~ C c ' c c s C N
C~ Q Q 11. Q Q tL CL Q Il. Q Q 1~ Q Q 1~ Q ~ CL tL t~ ~ I
,'~ VVVVVVOO~VVVVc~V~ V(~o ~D
.
m :~
~ E ~ o Q ~O ~ ~ ~ ~ ~ 3 :
SU~^~Ti l-UTE S~lEET
~:
-- 3 5 ~
a: zzzzzzzzzzzzzzzzzzzzzzzz C~C`l N C~J
I II I :1:
;; Z ZZ Z Z
_ _ ~ T
~ Zc~ a) ~ a> a~ a) a~ a> ~ o) a~ Z Z~ Z Z
. ~-~ I I C~ _LL C~ O ( ) C~) 2 0 ~ ) O O ~,) C . ~ ~ C c c c c _ -- -- -- s s c s s s -- ~ C s s c s -- -- s s c -- ~C
I N C~ ~ ~J N ~J N N ~ ~J N ~ ~\1 N C~l N N C~l C~l N A ' I I I I I I I I I I T I I I I I I I I I I I
Q D_ Q ~, ~ c O N N N A ^ ' c ~ T I I I I I
-- -- _ _ D D D D ~ D ~ D Q 8 D D D D D ~ 3 D D D D
~ SUBSTITUTE SHEET
WO 92/21360 PCI`/US92/03X09 'J ~
~ ~ ~ S ~ ~ ~ ~ ~ ~ ~ ~ ~ S
Q Q Q Q Q Q Q Q. Q IL t~ Q ~
~ I I I ~ I I I I I I I I I I
C: Z Z Z Z Z Z Z Z Z Z Z Z Z Z
-, 10 I I I Q ~ Q Q Q Q Q Q I I I
- ~ ~ ~ W ~ C~ W W C~
-~ 15 ~ 20 -- -- -- -- ~ c -- -- -- -- s --~ Q ~ Q Q n c~ A aL Q
- W C~l W N W W W N C~J C~ N C~l N C~
Wl C~l Wl W W N C`J W C~l N C~ .l C`.l N
I I I I I I I I ~I I I I I I
Q _ _ ~_ _ _ _ _ _ _ _ _ _ _ _ ~' T
I I
2 5 c~
~ ~ I
~ o o c~
I I N O \~
O O O O O O O O O O O O 0 0~z~
3 ~ - I I I I I I I I I I 11 a~ Z ~ Z Z Z Z Z ~ C~ ~ E
C W ~ ;i W ~ ;i N ~
~ I :C I I T I I I I T I I T I
:~ :- m D 8 ~ a~ ~, c" ~ ,, ~ 1, ~, E c :,, ~,...
SUBSTlTlJ~E S.~EET
WO 92/21360 PCr/VS92/03809 - 37 _ : ;
~ . . , i . ..
O
~ O O O O ( ) O I IL IL -- -- -- E -- --- s ) C.) O O O ~c c a) -- ~ ~ ~ ~ ~ ~ t ~ ~ Q ~ Q Q ~ C
-C ~ L ~ ~ ~ ~ ~ ~ t t ~ ~ ~ ~ ~ ~.
~ :1: I I I I I I I I I I I I I I I I I I I I
a: zzzzzzzzzzzzzzzzzzzzz I I :C I ~ I I I: I I I I I I I I I I I I I
.-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- .-- , ..--~' cn ,n^ n cn v~ vn v~ cn v~ vn fn vn cn vn cn vn n n v~ cn vn 1 5 -- -- -- -- _ _ _ _ I I
. I C
" ,~ s c s s s s s s s '-- s s c -- ~ s -- s s s . v Q Q Q , ~_ Q Q Q Q Q Q Q ~L Q Q Q Q Q Q
t~ N CU C~ J C~ l N N t:~J N ~I C~.l N 5~1 C`.l N C~
C`l N t~ t~J ~I C~J ~I C~l C`~l N N N l:~J N C~ N C~l Q C~
V C~ V V V O ~ t ) V O V (~ V V t~
~l vn v~ tn n ~ n n n ,n n tn n ,n tn r) ,_ n n v cn n i .. `. I
C C'~~ t~ tr~ t.~ t~ t.~ t.~ t.
E s ~I I I I I s T I I T I I I I T ,~ I I
J
m c o ~ ~ "~ ~ ~ 3 X ~ N tlS ~ ~ cn ~
SUBSTITUTE SHEET
.
WO 92/21360 PCI`/US~2/03809 , ( ~ 3 ~ -,.. .. .
This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloendoproteinase inhibitors of forrnula (I) as the active constituents.
Accordingly, the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloendoproteinases such as found in certain metastatic tumor cell lines.
For ~the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and indications resulting from the over-expression of matrix metalloendoproteinases such~ as found in certain metastati~ tumor cell lines or other diseases mediated by the matrix metalloendoproteinases, the compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectaliy in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasterna! injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitabl~ for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the ~manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected trom the group consisting of sw-etening agents, flavoring agents, coloring SUBSTITI.~'TE SHEET
~, - 3 9 - , . .:, .
agents and preserving agents in order to provide pharmaceutically elegant and paiatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, 5 such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for - example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108;
4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with 20 an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsulss wherein the - active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in 25 admixture with excipients suitable for the manu~acture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or 30 wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or SUBSTITUTE SHEET
.
WO 92/21360 PCI~/US92~03809 condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The 5 aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
` - Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame Pil or coconut oil, or in a mineral oil such as liquid paraffin.~ The oiiy suspensions may contain a thickening agent, for example beeswax, hard~paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may ~be preserved by the addition ~of an anti-oxidant such as ` ~ ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring 25 agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a ' mineral oil, for example liquid paraffin or mixtures of ~hese.
3b Saitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from~ fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the ` S~JB~TITl,r,rE SltE.T
, WO 92/21360 PCr/US92/03809 - 4 1 - ~i , ; ; j ~
said partial esters with ethylene oxid~, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or 5 . sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be tormulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in ~ a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Arnong the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In ~ addition, sterile, fixed oi!s are conventionally employed as a - soivent or suspending medium. For this purpose any bland fixed oil may be employed 20 including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compou~nds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared 25 by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, crearns, ointments, jellies, solutions 30 Qr suspensions, etc., containing the compounds of Formula (I) are employed. (For purposes of this application, topical application - shall include mouth washes and gargles.) Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in ., ~
S U BSTITUTE S H ~ET
-: , WO 92/21360 PCI`/US92~03809 the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms. per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
lS It will be understood, however, that the specific dose - ~ level for any particular patient will depend upon a variety o~
~: factors including the activity of the specific compound employed, the~ age, body weight, general health, sex, diet, time of . ~ administration, route of administration, rate of excration, drug - ~: 20 combination and the severity of the particular disease undergoing therapy.
The following Examples are intended to illustrate the preparation of compounds of Formula 1, and as such are not intended to limit the invention as set forth in tlie claims appended, thereto.
Example 1 .
~ 30 ~ SUBSTIT~E S~tEET
.
WO 92/21360 PCl /US92t0380g .... ~,;,, ~
- 43 - ~; . , , J, ~, ' J
HO2C ~
CH3 NH~ NHPh \--CH3 5a CH3 Employing:the procedure outlined in Scheme 1, Method A, compound number Sa was prepared as follows:
, 'hCH202C T ~ `
15. : H3C~O ~ HOAc, pyr PhCH202C fJ
: ~ Cl-H3N~O-t-C4Hg CH--NH~O-t-C4Hg N-[l (R)-Benzvloxy~arbonvl-ethvl~-a-~S!-(2-ph~nyl-ethvl)plv~ine t-butvl est~r ~1 !
To a solution of 10.5 9 of (S)-a - ( 2 - p h e n y I -ethyl)glycine, t-butyl ester in 50 mL each of acetic acid and 25 pyridine at 0 C was added 27.2 mL of a 1.0 M solution~ of sodium cyanoborohydride (NaBH3CN) in tetrahydrofuran (THF) foliowed by 18.1 mL of benzyl pyruvate. Additional NaH3BCN (50 mL, 1.0 M) was then added over 5 hours via syringe pump. The mixture was allowed to warm slowly to ambient temperature during the first 30 30 minutes of this addition. The reactlon mixture was then poured into a slurry of ice and 100 mL of concentrated hydrochloric acid (HCI) and extracted with 500 mL of 30%
ethcr/hexane` ~ (discarded).
~ ~ The: ;aqueous slurry (containing the desired HCI salt) was~ then :extracted: three:: times with ethyl acetate and the , , -,,, SU~STI ~tUr~ S~EET
~, WO 92/21360 PCl/US92/03809 !.J ~ l ,-.) (; `;
combined organic layers were washed three tim~s with saturated aqueous sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 20 9 of a yellow oil. The mixture was purified by flash column chromatography on silica-gel (120 x 200 mm column, 10% ethyl acetate/hexane) to give 6.40 9 of a colorless oil: Rf = 0.25 (10%
ethyl acetate/hexane): 1H NMR (200 MHz, CD30D) ~ 7.13-7.37 (m, 10H), 5.12 (ABq, 2H, J=5.1 Hz), 3.36 (q, lH, J=7.0 Hz), 3.15 (t, 1H, J=6.4 Hz), 2.65 ~m, 2H), 1.90 (m, 2H), 1.45 (s, 9H), 1.26 (d, 3H, J=7.0 Hz).
:: 15 J HCI CH3 PhCH202C ~' O
CH--NH~O-t-C~Hz EDC, HOBt, NMM CH--NHJ~rNHJI~NH
o CH3 :::
N-[1 (R)-Benzyloxycarbonyl-ethyl)]-~-~S!-(2-phenethyl)gly~ jne-(L)-leucine. N-phenylamide (2) N-[1 (R)-Benzyloxycarbonyl-ethyl)]-oc-(S)-(2-25 phenethyl)glycine, t-butyl ester (1 ) (6.40 9) was dissolved in a small amount of ethyl acetate and 250 mL of a saturated solution o~ anhydrous HCI in ethyl acetate was added. The mixture was held for 7 hours at 50C then cooled and concentrated in vacuo to ; give a colorless solid which was used without further 30 purification: 1H NMR (200 MHz, CD30D) ~ 7.41-7.20 (m, 10H), 5.25 (AB, 2H, J=12.1 Hz), 4.27 (q, 1H, J=7.3 Hz), 4.06 (t, 1H, J=6.6 Hz), 2.9-2.7 (m, 2H), 2.24 (m, 2H), 1.55 (d, 3H, J=7.4 Hz).
The crude aminoacid hydrochloride, (L)-Leucine, N-phenylamide hydrochloride (3.71 9, 18.0 mmol)1 and hydroxybe~nzotriazole (3.31 g j 24.5 mmol) were dissolved in 250 SUBSTITUTE SHEET
- 45 - ; .. ~, -mL of dimethyiformamide (DMF). N-methyl morpholine (NMM) (3.6 mL, 32.7 mmol) was added and the mixture cooled to 0C. Ethyl dimethylaminopropyl carbodiimide (EDAC, 3.7~ 9, 19.6 mmol) was added and the mixture stirred for 16 hours at ambient temperature. The solution was diluted with 1 L of ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with water. The mixture was then dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale yellow oil. The product was purified by MPLC (35 x - 350 mm column, 30% ethyl acetate/hexane) to afford 8.31 g of o the desired peptide as a colorless glass: -1H NMR (200 MHz, CD30D) ~ 7.57-7~08 (m, 15H), 5.13 (ABq, 2H, J =
5 Hz), 4.57 (m, 1H), 3.47 (q, lH, J_7.1 Hz), 3.25 (t, lH, ~=6.4 Hz), 2.67 (t, 2H, J=8.1 Hz), 2.1-1.6 (m, 5H), 1.31 (d, 3H, J = 7.0 Hz), 0.98 (d, 3H, J=6.5 Hz), 0.96 (d, 3H, J=6.0 Hz).
~;- 'hCH202C ~ O ~' HO2C ~
INHJ~NHPh Pearlman s CH3--NH~ NHPh o ~ Catalyst 2 \rCH3 CrCH3 CH3 5 a 3 N-11 (R)-ca!boxy-ethyl]-oc-(s?-(2-phenyl-ethyl)~lycine leucine. N-phenylamide (5a) ` To a solution of 8.31 9 of N-[1(R)-benzyloxycarbonyl-30 ethyl)]-a-(S)-(2-phenethyl)glycine-(L)-leucine, N-phenylamide (2) in 125 mL of methanol was added 500 mg of Pearlman's catalyst. After 3 hours of vigorous stirring und3r an atmosphere of ~ hydrogen, the mixture was filtered through Celite filter aid and concentrated in vacuo to give 6.50 9 ot amino acid 5a as a ,. ~ , " ~ :
SUBSTITU~ S~EET
WO 9~/21360 PCr/US~/n~X09 colorless solid: 1H NMR (200 MHz, CH30D) ~ 7.59-7.08 (m, 10H), 4.65 (m, 1H), 3.96 (t, 1H, J = 6.8 Hz), 3.58 (q, 1H, J = 7.4 Hz), 2.9-2.6 (m, 2H), 2.15 (m, 2H), 1.52 (d, 3H, J = 7.4 Hz), 1.02 (d, 3H, J =
6.0 Hz), 1.00 (d, 3H, J = 6.0 Hz).
The following additional compounds were prepared according to the method of Example 1.
N-11 (R)-Carboxy-ethyl]-a-(S!-(2-phenyl-ethyl)alvcrine-(L!- .
- isoleucine~. N-phenvlamide (5w , 10 MS: mle 440 (M+) ~ :
1 H NMR: (CD3~0D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 2.0 Hz), 7.34-- 7.09 (m, 8H), 4.42 (d, 1H, J = 8.0 Hz), 4.01 (t, 1H, J = 6.0 Hz), 3.58 (q, 1H, J = 7.0 Hz), 2.68 (m, 2H), 2.14 (m, 2H), 1.64 (m, 1H), 1.48 lS (d,~3H,~ 7.:0~Hz), 1:.30 (m, 2H), 1.03 (d, 3H, J = 6.5 Hz), 0.96 (t, 3H, J
= 7.0:HZ)-,~ " ~, ~ , N-~:1 (R)-Carboxv-ethvl)l-a-(S)-(2-phenvl-ethyl)alycine-(L!-~ine. N-ehenylamide~) -- MS: m/e 398 (M+) -~ ~ 1H~NMR (CD30D,200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 2.0 Hz), 7.33--~ 7.19 (m, 8H), 4.56 (q, lH, J = 7.0 Hz,), 3.95 (t, 1H, J = 6 Hz), 3.60 (q, lH, J = 7.0 Hz), 2.75 (m, 2H), 2.17 ~m, 2H) 1.48 (d, 6~H, J = 7.0 Hz).
N-11 (R)-Carboxy-ethyl)l-a-(S!-(2-ehenvl-~thvl,~lycine-~L~Lenylalanine. N-~he~lylamide (5y) MS: m/e 474 (M~) 1H NMR (CD30D,200 MHz): ~ 7.51 (dd, 2H, J = 8.0, 2 Hz), 7.32-7.09 (m, 13H3, 4.93 ~(dd, 1H, J - 9.0, 6.0 Hz), 3.90 (t, lH, J - 6.0 Hz), ~; 3.40 (q, 1H,`J~- 7.0:~Hz, 3.26 ~(dd. 1H, J = A.0, 13 Hz), 3.01 (dd,1H, J
, .
," ~ , U6S~ITUTE SH~
,~ ~
, . , ,, ,._ ~ . ___~ ... ., .. . __. . . _.. . ... . . .... ..
WO 92/21360 PCr/US92/03809 - 47 - ~ ; . ;.J '_ = 9.0, 13 Hz), 2.68 (t, 2H, J = 8.0 Hz), 2.12 (dd, 2H, J = 6.0, 9.0 Hz), 1.29 (d, 3H, ~ = 7.0 Hz).
N-11 (R!-Carboxy-ethyl)]-a-(S~-(2-phenyl-ethyl!glycine-(L!-serine-O-benzyl ether. N-phenylamide _(5z) MS: m/e 504 (M+) 1H NMR (CD30D,200 MHz): ~ 7.55 (dd, 2H, J = 8.0, 2.0 Hz), 7.34-7.10 (m, 13H, ArH), 4.60 ppm (s, lH), 4.58 (s, 1H), 4.04 (t, lH, J =
- 6 Hz), 3.84 (d, 2H, J = 6.0 Hz), 3.75 (q, lH, J = 7.0 Hz), 2.74 (dd, 2H, lO J = 6.1 2.0 Hz), 2.18 (t, 2H, J = 7.0 Hz), 1.49 (d, 3H, J = 9.0 Hz).
.
arboxy-ethyl)l-a-(S)-(2-~enyl-ethyl)~lycine-(L)-tryptoehan. N-phenylamide (5ac) 5 MS: m/e 513 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.65 ~dd, 1H, J = 7.0, 2.0 Hz), 7.47 (dd, 2H, J = 8.0, 1.0 Hz), 7.30-6.99 (m, 12H), 4.94 (dd, 1H, J = 9.0, 7.0 Hz), 3.82 (t, 1H, J = 6.0 Hz), 3.34 (dd, 2H, J 4.0, 9.0 Hz), 3.27 (q, 1H, J - 6.0 Hz), 2.64 (m, 2H), 2.10 (td, 2H, J = 8.0, 2.0 Hz), 1.23 (d, 20 3H, J = 7.0 Hz).
N-[1 (R)-Carboxy-ethvl)]-~-(S)-(~-phenyl-~hyl)]~lycin~--(S)-(2~phenvl-ethvl)~lycine. N-phenylamid~ (5ad) ~5 MS: m/e 488 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.08 (m, 13H,), 4.58 (dd, 1H, J = 9.0, 7.0 Hz), 4.02 (t, lH, J = 6.0 Hz), 3.64 (q, 1H, J = 7.0 Hz), 2.74 (m, 4H), 2.16 (m, 4H~, 1.51 (d, 3H, J =17.0 Hz).
N-ll (R)-Carboxy-ethyl)~-a-($)-(2-phenyl-ethyl)gly~ine-(L)-norleucine. N-~henvlamide (5am ~ MS: m/e 440 (M I ) ; ~; SUBS~l~U,I.E_SHEET
WO 92/21360 PCr/US92/03X09 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.08 (m, 8H), 4.52 (dd, lH, J = 8.0, 6.0 Hz), 3.98 (t, 1H, J = 6.0 Hz), 3.~9 (q, lH, J = 7.0 Hz~, 2.71 (m, 2H), 2.16 (t, 2H, J = 8.0 Hz), 1.85 (m, 2H), 1.48 ppm (d, 3H, J = 7.0 Hz), 1.43 (m, 4H), 0.94 (t, 3H, J =
7.0 Hz).
N-[1 (R!-Carboxv-ethvl!]-a-(S)-(2-phenvl-ethyl!~lvcine-(L)-valine. N-phenylamid~ (5an) - MS: m/e 426 (M+) lO 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 8.0, 1.0 Hz), 7.33-7.09 (m, 8H), 4.37 (d, 1H, J = 8.0 Hz), 4.04 (t, 1H, J = 7.0 Hz,), 3.60 (q, 1H, J = 7.0 Hz), 2.68 (m, 2H), 2.16 (m, 3H), 1.49 (d, 3H, J = 7.0 Hz), 1.06 (d, 6H, J = 7 Hz).
~-: 15~ N-[1[R)-~ Qxy-ethyl)]-a-(S)-(2-phenvl ethyl)glycine-.
serine. N-phenylamide Hydrochloride (Sao) ; :
M~S- m/e 414 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 8.0, 1.0 Hz), 7.34-20 7.09 (m, 8H), 4.68 (t, 1H, J - 8.0 Hz), 3.88 (d, 2H, J = 6.0 Hz), 3.51 (t, 1H, J = 8.0 Hz), 3.10 (q, 1H, J = 7.0 Hz), 2.78 (m, 2H,), 2.24 (m, - 2H), 1.60 (d, 3H, J = 7.0 Hz~.
N-[1 (R)-Carboxy-ethvl)]-a-lSl-(2-phenyl-ethyl~glyine-25 (L~ c~gine. N-~henylamide ~5aa) MS: m/e 441 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 2.0, 8.0 Hz), 7.14-7.34 (m, 8H), 4.86 (d, 1H, J = 7.0 Hz), 3.92 (t, 1H, J = 6.0 Hz), 3.6430 (q, 1H, J = 7 Hz), 2.6-2.8 (m, 2H), 2.1-2.25 (m, 4H), 1.47 (d, 3H, J -7.0 Hz).
N-11 (R)-carboxy-ethvl!:~--(S)-(?-phenvl-ethyl)glycine-(L)-thr~nine. N-~henvlamide hvdrochloride (5ab) ., ~ .
~ ~ SllEST(~ S~EET
;:
WO 92/21360 PCl /US92/03~09 MS: m/e 428 ~M+) 1H NMR (CD30D,200 MHz): â 7.66 (d, 2H, J = 8.0 Hz), 7.12-7.34 (m, 8H), 4.~6 (d, 1H, J = 5.0 Hz), 4.1-4.3 (m, 2H), 4.09 (q, 1H, J = 7.0 Hz), 2.7-2.8 (m, 2H), 2.2-2.3 (m, 2H), 1.63 (d, 3H, J = 7.0 Hz), 1.32 5 (d, 3H, J = 6.0 Hz), .
N-11 (R)-Carboxy-ethyl)~-a-(S)-(2-phenyl-ethyl!alycine-(L)-lvsine. N-phenvlamide (5ae) lO MS: mle 455 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.57 (dd, 2H, J = 2.0, 8.0 Hz), 7.04-7.29 (m, 8H), 4.55 (dd, 1H, J = 5.0, iO.0 Hz), 3.26 (t, 1H, J = 7.0 Hz), 3.19 (t, 1H, J = 7.0 Hz), 2.95 (t, 1H, J = 7.0 Hz), 2.69 (t, 2H, J =
8.0 Hz), 1.85-2.0 (br. m, 4H), 1.60, 1.70 (2m, 4H), 1.30 (d, 3H, J = 7 Hz).
,~ ~
N~ (R)-Carboxy-ethyl)1-a-(S)-(2-Dhenyl-ethvl)~lycine--glutamic acid. N-~henylamide (5ak) ~- 20 MS: m/e 456 (M+) lH NMR (CD30D, 200 MHz): â 7.57 (dd, 2H, J _ 2.0, 8.0 Hz), 7.12-7.33 (m, 8H), 4.67 (dd, 1H,.J = 6.0, 9.0 Hz), 4.02~(t, 1H, J = 6.0 Hz), 3.66 (q, 1H, J = 7.0 Hz), 2.67-2.74 ~t, 2H, J = 7.0 Hz), 2.46-2.54 (m, 2H), 2.1-2.23 (br. m, 4H), 1.51 (d, 3H, J = 7.0 Hz).
2s Combustion Analysis C24H29N3o6 (0-20 H2O) Calc: C, 62.79, H. 6.45, N, 9.15 Found: C, 62.79, H, 6.50, N. 9.15 N-[i (R)i-~arboxy-ethyl~-a-(S!-(~-ehenyl-ethyl!~lvcine-(L!-t~7rosine. N-phenylamide hydro~hlorid~ (5al) ,~ - . . .
MS: m/e 490 (M+ - HCI) H NMR (CD3~0D,: 200 MHz): ~ 7.53 (dd, 2H, J = 2.0, 8.0 Hz), 7.10-7.33 (m,~8H), 6.74 (dd, :2H, J 2.0, 8.0 Hz), 4.89 (dd, lH, = 6.0, 9.0 , .
.~ - . .
:: :
W O 92/21360 PC~r/US92/03809 ~ r~ 50 Hz), 3.99 (t, 1H, J = 6.0 Hz), 3.59 (q, 1H, J = 7.0 Hz), 3.24 (dd, ~H, J
= 8.0, 15.0 Hz)1, 2.93 (dd, lH, J = 10.0, 15.0 Hz), 2.67-2.76 (t, 2H, J = 7.0 Hz), 2.10-2.23 (br. m, 2H), 1.46 (d, 3H, J = 7.0 Hz).
Exa m ple 2 HO2C ~ O
1 0 ~NH~NHJI`NHPh : J: o ~ ~3 5d , ~
: ~ Employing the procedure outlined in Method B, N-[1(R)-~: Be:nzyloxycarbonyl-5-(1,3-dioxo-isoindolinyl-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine, t-butyl ester 4 was prepared and ~:- converted to compound 5d using methodology described in Method - A for ami:nodipeptide 2 and aminoacid 5a.
PhCH202C
_~NH3~CI- NaBH3a~1 PhCH202C
HOAc, pyr ~' O
~ O~o t C~Hg ~
R~ nzvloxycarbonvl-5~ diQxo-isoindolin-2-yl)p~ntyl]
H a-(S~-(2-Dhe:nvl-ethvl-~alucine~ t-butvl ester ~4) sv~sn l-uTE S~EET
WO 92~21360 PCI`/US92/03809 - 51 - ; ` ';` :
To a solution of -phthalimido tD)-Lysine benzyl ester hydrochloride (1.23 9, 3.05 mmol) in 2.5 mL each ef acetic acid and pyridine at 0C was added 0.5 mL of a 1.0 M solution of N a H 3 BCN in THF followed by t-butyl 2-oxo-4-phenylbutanoate (1.43 9, 6.11 mmol). Additional NaH3BCN (3.58 mL, 1.0 M) in THF
was then added over 3.5 hours via syringe pump. The mixture was allowed to warm slowly to ambient temperature during the first 30 minutes of this addition. The reaction mixture was poured into a slurry of ice and 15 mL of conc. HCI and extracted three times with ethyl acetate. The combined organic layers were washed three times with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo.
The mixture was purified by MPLC (35 x 300 mm column, 10-20%
ethyl acetate/hexane by linear gradient) to give 801 mg of the desired amino ester as a colorless oil:
1H NMR (CD30D, 200 MHz) ~ 7.82-7.71 (m, 4H~, 7.35-7.08 ~m, 10H), 5.09 (ABq, 2H, J = 11.9 Hz), 3.61 (t, 2H, J = 6.5 Hz), 3.21 (t, 1H, J =
6.0 Hz), 3.06 ~t, 1H, J = 7.2 Hz), 2.60 (t, 2H, J = 6.7 Hz), 2.0-1.3 (m, - 20 8H), 1.42 (s, 9H).
Substituted a-keto-esters~ were also conveniently prepared by one of the following proc:edures:
25 utyl 2-Oxo-5-phenylpentanQate To a suspension of magnesium turnings (1.22 g, 50.23 mmol) in 20 mL of ether was added 1-bromo-3-phenylpropane (7.64 mL, 50.23 mmoi) at a rate so as to maintain a gentle reflux.
After the addition was complete, the mixture was stirred an 30 additional 30 min. Di-tert-butyl oxylate (10.16 g, 50.23 mmol) was dissolved in 250 mL of ether and cooled to -78~C. The Grignard reagent was added dropwise so as to maintain an internal temperature S -75C. The mixture was stirred for an additional hour at-78~C, and poured into a mixture of ice, 300 mL
SU13STITIJTE StE~ET
WO 92~21360 PCI/US92/03809 j_ ., of 1 N hydrochloric acid and 200 mL of eth~r. The mixture was shaken vigorously and the iayers were separated. The ether layer was washed with water and saturated sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to give 15.2 9 of the title compound as a colorless oil: 1H NMR (200 MHz, CDCI3) ~ 7.36-7.04 (M, 5H), 2.79 (t, 2H), 2.67 (t, 2H), 1.97 (m, 2H), 1.57 (s, 9H).
t-Butyl 2-oxo-4-t4-methylpher!yl)-butan~e To a solution o~ 4-methylbenzaldehyde (2.5 mL, 21.2 mmol) in 25 mL of benzene was added 1 mL each of acetic acid and piperidine~. The mixture was heated to reflux with azeotropic removal of water via a Dean-Stark trap. A solution of t-butyl pyruvate~ (3.36~9, ~23.32~ mmol) in 5 mL of behzene was added over 7 h by syringe pump. The mixture was cooled, diluted with ethyl acetate and washed~three times with saturated aqueous sodium bicarbonate ~and ;thrée times with 1 ~J hydrochioric acid. The o rganics~ were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by MPLC on silica-gel ~eiuting with 2.5% ethyl acetate in hexane to give the desired ~product as a yeilow oil: 1H NMR (200 MHz, GDCI3) ~ 7.75 (d, 1H, J =
16.19 Hz), 7.49 (d, 2H, J = 8.25 Hz~, 7.24 (m, 3H), 2.37 (s, 3H), 1.58 (s, 9H). The above product was dissolved in ethyl acetate and held under hydrogen~ in the prësence of 100 mg of 10% palladium on carbon for 2 hours. The mixture was filtered and concentrated in vacuo to give 1.196 9 of the title compound as a pale-yellow oil:
1H NMR (200 MHz, CDCI3) ~ 7.1-6.9 ~mJ 4H), 3.12 (t, 2H, J = 6.8 Hz), 2.90 (t, 2H, J = 7.3 Hz), 1.56 (s, 9H).
, , , l ~ 30 :
, -:
SUBSnTU-ESHEET
, ~,, -.
,,, - - ,~
, ,"~
, :
- 53 - ..
O
J Cl H N~ ~ J
hCH202C I 3 NHPh PhCH202C ~ o O-~-C4H3 ~CH3 O o CH3 NA~ 4 EDC, HOBt, NMM N--4~ CH3 o~ o~ 5d' N-~ R)-Benzyloxycarbonyl-5-(1.3-dioxo-isoindolin-2-yl!pentyl]-5d') N-ll (R)~-Bènzyloxycarbonyl-5-(1 ,3-dioxo-isoindolin-2-yl)pentyl]-a-(S)-(2-phenyl-ethyl)glycine, t-butyl ester 4 (210 l5;~ ~mg)~was dissolvèd~in~a sma~ll amount of ethyl acetate and 15 mL
of ~a ~saturated~ solution~ of anhydrous HCI in ethyl acetate was added.~ ; The~ mixture~ was` held for 4 hours at 50C then coole~ and conce:ntrated in vacuo to ~give a colorless solid which was used without purification. The crude amino acid hydrochloride, (L)-~-- 20 Leucine j N-phenylamide~ ~ hydrochloride (96 mg, 0.39 mmol), and hydroxybenzotriazole (97 mg, 0.72 mmol) were dissolved in 5 mL
of DMF. N-methyl morpho~line (165 ml, 32.7 mmol) was added and the mixture cooled to 0C. Ethyl dimethylaminopropyl carbodiimide (EDAC, 104 mg, 0.54 mmol) was added and the mixture stirred for 16 hours at ambient temperatùre. The solution was diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with water. The mixture was dried over anhydrous sodium sulfate, ,~ ~ I concentrated in vacuo, and purifîed by MPLC (22 x 300 mm ~olumn, 30% ethyl acetate/hexane) to afford 254 mg of the desired pcptide as a colorless glass which crystalliz~d upon standing:
H NMR (CD30D, 200 MHz)~ 7.82-7.06 (m, 19H), 5.08 (ABq, 2H, J .
12.5;~Hz), 4.54~(t,~1~H~;J . 6.3 Hz), 3.61 (t, 2H, J = 6.6 Hz), 3.35 (t, SUBS~ITUTE S~IEET
~,,, ~ , ~
.,","
,,~. . , ~ , , ,?: : ~ ., 54 -(., . . ~, .
1H, J = 6.0 Hz), 3.19 (dd, 1H, J = 5.7, 6.9 Hz), 2.64 (m, 2H), 2.1-1.3 (m, 11H), 0.9~ (d, 3H, J = 6.4 Hz), 0.94 (d, 3H, J = 6.42).
s l~
J HO2C ~ O
'hCH202C ~ O
NHJI~ ~`NH~NH~N
f NH ~ . NHPh H2~ J
~ \rCH3 Pearlman'S~ O \rCH3 _D CH3 Catalyst N--4;
~ 5d' o~ 5d lS
N-~11 (R!-Carboxv-5-(1 .3-dioxQ-isoindolin-2-vl)pentyll-a-(S)-(2- `' ~h~nvl-ethvl])~lycine-(L)-leucine. N-ehenylamide ~5d!
To a solution of 25~ mg of [N-[1 (R)-20 benzyloxycarbonyl-5-(1,3-dioxo-isoindolin-2-yl~pentyl-a-(S)-(2-phenylethyl)]glycine-(L)-Leucine, N-phenylamide (5d') in 10 mL
of methanol was added 10 mg of Pearlman's catalyst. After 1 - hour of vigorous stirring under an atmosphere of hydrogen, the mixture was filtered through Ceiite filter aid and concentrated in 25 vacuo to give 220 mg of [N-[1 (R)-carboxy-4-(1 ,3-dioxo-2-isoindolin-2-yl)pentyl-a-(S)-12-phenylethyl]]glycine-(L)-Leucine, N-phenylamide 5d as a colorless so,id:
1H NMP~ (CD30D, 200 MH7) ~ 7.85-7.08 (m, 14H), 4.62 (m, 1H), 3.81 !' I (t, 1H, J = 7.1 Hz), 3.69 (t, 2H, J = 6.6 Hz), 3.48 (t, lH, J - 6.2 Hz), 3~ 2.8-2.6 (m, 2H), 2.3-1.4 (m, 11H), 0.98 (d, 6H, J = 4.8 Hz).
The following additional compounds were prepared according to the method of Example 2.
SU3STI~UTE SHEET
WO 92~21360 PCr/US92/03B09 ~5 ;;. ,' N- ~ 1 ( R)-C arboxy-5- ( 1 -oxo- iso i ndo l i n-2-vl ! penty l]-a- ( S)- (2-phenyl-ethyl)glvcine-(L!-leucine. N-phenylamid~ hydrochloride (5bs) MS: m/e 613 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.81-7.09 (m, 14H), 4.66 (m, 1H), 4.53 (S, 2H), 4.09 (dd, 1H, J = 5.24, 8.86 Hz), 3.94 (t, 1H, J = 6.10 Hz), 3.8-3.5 (m, 2H), 2.9-2.6 (m, 2H), 2.3-1.3 (m, 9H), 0.99 (d, 3H, J =
5.93 Hz), 0.98 (d, 3H, J = 6.03 Hz).
N-[1 (R)-Carboxy-5-(1 -oxo-isoindolin-2-vl)pentyll-a-(S!-~2-phçnyl-ethy!~g!y~ine-(L)-~rginine. N-phenvlamide (5bt) , 10 MS: m/e 656 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.76-7.0 (m, 14H), 4.66 (m, 1H), 4.48 (s, 2H), 3.63 (t, 2H, J = 7.69 Hz), 3.15-3.08 (m, 4H), 2.63 (t, 2H, ~ =
6.25 Hz), 2.1-1.4 (m, 13H).
N-[l-lR)~ ~y--çthyl]-a-(s)-(2-(3-hydroxyehenyl!-ethyl)~!ycine-(L)-leucine. N-phenvlamide hvdrochlQride (5bi) ~:~ MS: m/e 456 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.56 (dd, 2H, J = 1.17, 8.33 Hz), 7.30 20 (t, 2H, J = 7.69 Hz), 7.2-7.0 (m, 3H), 6.7-6.6 (m, 2H), 4.7-4.6 (m, 1H), 4.15-4.0 (m, 2H), 2.8-2.55 (m, 2H), 2.3-2.1 (m, 2H), 1.9-1.6 (m, 3H), 1.58 (d, 3H, J = 7.30 Hz), 1.03 (d, 3H, J = 6.06 Hz), 1.01 (d, - 3H, 5.96 Hz).
-"
' ' ~
SUBSTITUT~: SHEET
,- ~
:
WO 92/21360 PCI /US92/~3809 ' ~ ' ! `~ .` ' ` \ '`, !
N-~1 (R)-Carboxy-ethvl~-a-(S!-(2-(4-methylphenyl)-ethyi)Q~ne-(L!-leucine. N-phenylamide bydrochloride (5be) MS: m/e 4~4 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.57 ~dd, 2H, J = 1.90,8.99 Hz),7.30 (t, 2H, J = 7.26 Hz), 7.15-7.10 (m, 1H), 7.05 ts, 4H), 4.75-4.65 (m, 1 H), 4.15-4.0 (m, 2H), 2.8-2.55 (m, 2H), 2.3-2.1 (m, 2H), 2.26 (s, 3H), 1.9-1.65 (m, 3H), 1.58 (d, 3H, J = 7.68 Hz), 1.03 (d, 3H, J =
6.04 Hz),1.01 (d, 3H,5.96 Hz).
N-[1~ ~arboxy-~thyll-~-(S!,-(2-(2'-thienyl)ethyl!~lycine-(L)-leu~ r~a_~Ehenylamide (5v!
MS: m/e 446 (M+); 468 (M + Na); 484 (M + K).
1H NMR (CD3OD,200 MHz): ~ 7.62-6.88 (m,8H); 4.69 (dd, lH); 4.10 (t, 1H); 3.98 (q,1H); 3.04 (m, 2H); 2.30 (m, 2H); 1.78 (m, 3H); 1.62 (d,3H); 1.08 (2dj 6H).
N:-11 (R)-Carboxv-ethyll-a-(S!-(2-S4-ethvlphenyl)ethvl~alycine-(L)-leu~ine. N-phenylamide (5bj~
MS: m/e 468 (M+1) 1H NMR (CD3OD, 400 MHz): ~ 7.57 (d,2H, J = 8 Hz),7.30 (t, 2H, J =
20 8 Hz), 7.12-7.04 (m, 5H), 4.66(dd, lH, J = 9, 5 Hz), 4.10-4.02 (m, 2H),2.73 (td, lH, J = 12,6 Hz),2.64 (td, lH, J = 12,6 Hz),2.57 (q, 2H, J = 7 Hz), 2.24-2.08 (m, 2H), 1.82-1.63 (m, 3H), 1.59(d, 3H, J -7Hz),1.18(t,3H,J=7Hz),1.03(d,3H,J=6Hz),1.00(d,3H,J=
- 6 Hz).
25 1!1-~1~)-Car~oxY-5-(1-oxo-isoindo~ yl)pentx!]-a-($j~ (4 prQpylphçnyl~el~h~QIvcine-(l,~-Leucine! N-ehenvlamide (5bu) MS: m/e 655 (M+1~
1H NMR (CD30D, 400 MHz): ~ 7.76 (d, 1H, J = 7 Hz), 7.61-7.53 (m, 30 4H), 7.47 (t, 1H, J = 7 Hz), 7.29 (t, 2H, J = 8 Hz), 7.08 (t, 1~H, J =
7.5 Hz), 7.04 (d, 2H, J = 7 Hz), 7.01 (d, 2H, J = 7 Hz), 4.62(dd, 1H, J
, 9, 5 Hz), 4.51(s, 2H), 3.86 (dd, 1H, J = 7, 5 Hz), 3.74-3.56 (m, 2H), 3.50 (t, lH, J = 6 Hz), 2.74-2.56 (m, 2H), 2.50 (t, 2H, J = 7.5 Hz), 2.16-1.40 (m, 11H), 1.58 (hextet, 2H, J, 7 Hz), 0.98 (d, 6H, J
~ 6 Hz), 0.90 (t, 3H, J = 7 Hz).
: ~iUBSTITUTE SHEE:T
WO 92/21360 PCl`/US92/03809 N~ R!-Carboxy-ethyl)-çc-(S!-(2-(4-chloropherlyl~ lycine-(L)-leucine. N-phenylamide (~bn MS: m/e 474 (M+1) 1 H NMR ~GD30D, 200 MHz): ~ 7.55 (d, 2H, J = 8Hz), 7.29 (t, 2H, J = 8 Hz),7.22(d,2H,J=8Hz),7.16(d,2H,J=8Hz),7.09(t, 1H,J=8 Hz), 4.65 (dd, 1H, J = 8, 5 Hz), 4.06-3.96 (m, 2H), 2.88-2.56 (m, - 2H), 2.30-2.04 (m, 2H), 1.84-1.46 (m, 3H), 1.58 (d, 3H, J = 7 Hz), 1.02 (bd, 6H, J = 7 Hz).
Example 3 . 10 HO2C ~
CH3--NH~NHJI`NHPh 1 5 0 ~
j ~ ~CH3 5a CH3 Employing the procedure ou,lined in Method C, amino 20 acid ester 1 was prepared as a single diastereomer and converted to compound 5a using methodology described in Example 1.
~,,, ~ , ~
.,","
,,~. . , ~ , , ,?: : ~ ., 54 -(., . . ~, .
1H, J = 6.0 Hz), 3.19 (dd, 1H, J = 5.7, 6.9 Hz), 2.64 (m, 2H), 2.1-1.3 (m, 11H), 0.9~ (d, 3H, J = 6.4 Hz), 0.94 (d, 3H, J = 6.42).
s l~
J HO2C ~ O
'hCH202C ~ O
NHJI~ ~`NH~NH~N
f NH ~ . NHPh H2~ J
~ \rCH3 Pearlman'S~ O \rCH3 _D CH3 Catalyst N--4;
~ 5d' o~ 5d lS
N-~11 (R!-Carboxv-5-(1 .3-dioxQ-isoindolin-2-vl)pentyll-a-(S)-(2- `' ~h~nvl-ethvl])~lycine-(L)-leucine. N-ehenylamide ~5d!
To a solution of 25~ mg of [N-[1 (R)-20 benzyloxycarbonyl-5-(1,3-dioxo-isoindolin-2-yl~pentyl-a-(S)-(2-phenylethyl)]glycine-(L)-Leucine, N-phenylamide (5d') in 10 mL
of methanol was added 10 mg of Pearlman's catalyst. After 1 - hour of vigorous stirring under an atmosphere of hydrogen, the mixture was filtered through Ceiite filter aid and concentrated in 25 vacuo to give 220 mg of [N-[1 (R)-carboxy-4-(1 ,3-dioxo-2-isoindolin-2-yl)pentyl-a-(S)-12-phenylethyl]]glycine-(L)-Leucine, N-phenylamide 5d as a colorless so,id:
1H NMP~ (CD30D, 200 MH7) ~ 7.85-7.08 (m, 14H), 4.62 (m, 1H), 3.81 !' I (t, 1H, J = 7.1 Hz), 3.69 (t, 2H, J = 6.6 Hz), 3.48 (t, lH, J - 6.2 Hz), 3~ 2.8-2.6 (m, 2H), 2.3-1.4 (m, 11H), 0.98 (d, 6H, J = 4.8 Hz).
The following additional compounds were prepared according to the method of Example 2.
SU3STI~UTE SHEET
WO 92~21360 PCr/US92/03B09 ~5 ;;. ,' N- ~ 1 ( R)-C arboxy-5- ( 1 -oxo- iso i ndo l i n-2-vl ! penty l]-a- ( S)- (2-phenyl-ethyl)glvcine-(L!-leucine. N-phenylamid~ hydrochloride (5bs) MS: m/e 613 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.81-7.09 (m, 14H), 4.66 (m, 1H), 4.53 (S, 2H), 4.09 (dd, 1H, J = 5.24, 8.86 Hz), 3.94 (t, 1H, J = 6.10 Hz), 3.8-3.5 (m, 2H), 2.9-2.6 (m, 2H), 2.3-1.3 (m, 9H), 0.99 (d, 3H, J =
5.93 Hz), 0.98 (d, 3H, J = 6.03 Hz).
N-[1 (R)-Carboxy-5-(1 -oxo-isoindolin-2-vl)pentyll-a-(S!-~2-phçnyl-ethy!~g!y~ine-(L)-~rginine. N-phenvlamide (5bt) , 10 MS: m/e 656 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.76-7.0 (m, 14H), 4.66 (m, 1H), 4.48 (s, 2H), 3.63 (t, 2H, J = 7.69 Hz), 3.15-3.08 (m, 4H), 2.63 (t, 2H, ~ =
6.25 Hz), 2.1-1.4 (m, 13H).
N-[l-lR)~ ~y--çthyl]-a-(s)-(2-(3-hydroxyehenyl!-ethyl)~!ycine-(L)-leucine. N-phenvlamide hvdrochlQride (5bi) ~:~ MS: m/e 456 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.56 (dd, 2H, J = 1.17, 8.33 Hz), 7.30 20 (t, 2H, J = 7.69 Hz), 7.2-7.0 (m, 3H), 6.7-6.6 (m, 2H), 4.7-4.6 (m, 1H), 4.15-4.0 (m, 2H), 2.8-2.55 (m, 2H), 2.3-2.1 (m, 2H), 1.9-1.6 (m, 3H), 1.58 (d, 3H, J = 7.30 Hz), 1.03 (d, 3H, J = 6.06 Hz), 1.01 (d, - 3H, 5.96 Hz).
-"
' ' ~
SUBSTITUT~: SHEET
,- ~
:
WO 92/21360 PCI /US92/~3809 ' ~ ' ! `~ .` ' ` \ '`, !
N-~1 (R)-Carboxy-ethvl~-a-(S!-(2-(4-methylphenyl)-ethyi)Q~ne-(L!-leucine. N-phenylamide bydrochloride (5be) MS: m/e 4~4 (M+1) 1H NMR (200 MHz, CD30D) ~ 7.57 ~dd, 2H, J = 1.90,8.99 Hz),7.30 (t, 2H, J = 7.26 Hz), 7.15-7.10 (m, 1H), 7.05 ts, 4H), 4.75-4.65 (m, 1 H), 4.15-4.0 (m, 2H), 2.8-2.55 (m, 2H), 2.3-2.1 (m, 2H), 2.26 (s, 3H), 1.9-1.65 (m, 3H), 1.58 (d, 3H, J = 7.68 Hz), 1.03 (d, 3H, J =
6.04 Hz),1.01 (d, 3H,5.96 Hz).
N-[1~ ~arboxy-~thyll-~-(S!,-(2-(2'-thienyl)ethyl!~lycine-(L)-leu~ r~a_~Ehenylamide (5v!
MS: m/e 446 (M+); 468 (M + Na); 484 (M + K).
1H NMR (CD3OD,200 MHz): ~ 7.62-6.88 (m,8H); 4.69 (dd, lH); 4.10 (t, 1H); 3.98 (q,1H); 3.04 (m, 2H); 2.30 (m, 2H); 1.78 (m, 3H); 1.62 (d,3H); 1.08 (2dj 6H).
N:-11 (R)-Carboxv-ethyll-a-(S!-(2-S4-ethvlphenyl)ethvl~alycine-(L)-leu~ine. N-phenylamide (5bj~
MS: m/e 468 (M+1) 1H NMR (CD3OD, 400 MHz): ~ 7.57 (d,2H, J = 8 Hz),7.30 (t, 2H, J =
20 8 Hz), 7.12-7.04 (m, 5H), 4.66(dd, lH, J = 9, 5 Hz), 4.10-4.02 (m, 2H),2.73 (td, lH, J = 12,6 Hz),2.64 (td, lH, J = 12,6 Hz),2.57 (q, 2H, J = 7 Hz), 2.24-2.08 (m, 2H), 1.82-1.63 (m, 3H), 1.59(d, 3H, J -7Hz),1.18(t,3H,J=7Hz),1.03(d,3H,J=6Hz),1.00(d,3H,J=
- 6 Hz).
25 1!1-~1~)-Car~oxY-5-(1-oxo-isoindo~ yl)pentx!]-a-($j~ (4 prQpylphçnyl~el~h~QIvcine-(l,~-Leucine! N-ehenvlamide (5bu) MS: m/e 655 (M+1~
1H NMR (CD30D, 400 MHz): ~ 7.76 (d, 1H, J = 7 Hz), 7.61-7.53 (m, 30 4H), 7.47 (t, 1H, J = 7 Hz), 7.29 (t, 2H, J = 8 Hz), 7.08 (t, 1~H, J =
7.5 Hz), 7.04 (d, 2H, J = 7 Hz), 7.01 (d, 2H, J = 7 Hz), 4.62(dd, 1H, J
, 9, 5 Hz), 4.51(s, 2H), 3.86 (dd, 1H, J = 7, 5 Hz), 3.74-3.56 (m, 2H), 3.50 (t, lH, J = 6 Hz), 2.74-2.56 (m, 2H), 2.50 (t, 2H, J = 7.5 Hz), 2.16-1.40 (m, 11H), 1.58 (hextet, 2H, J, 7 Hz), 0.98 (d, 6H, J
~ 6 Hz), 0.90 (t, 3H, J = 7 Hz).
: ~iUBSTITUTE SHEE:T
WO 92/21360 PCl`/US92/03809 N~ R!-Carboxy-ethyl)-çc-(S!-(2-(4-chloropherlyl~ lycine-(L)-leucine. N-phenylamide (~bn MS: m/e 474 (M+1) 1 H NMR ~GD30D, 200 MHz): ~ 7.55 (d, 2H, J = 8Hz), 7.29 (t, 2H, J = 8 Hz),7.22(d,2H,J=8Hz),7.16(d,2H,J=8Hz),7.09(t, 1H,J=8 Hz), 4.65 (dd, 1H, J = 8, 5 Hz), 4.06-3.96 (m, 2H), 2.88-2.56 (m, - 2H), 2.30-2.04 (m, 2H), 1.84-1.46 (m, 3H), 1.58 (d, 3H, J = 7 Hz), 1.02 (bd, 6H, J = 7 Hz).
Example 3 . 10 HO2C ~
CH3--NH~NHJI`NHPh 1 5 0 ~
j ~ ~CH3 5a CH3 Employing the procedure ou,lined in Method C, amino 20 acid ester 1 was prepared as a single diastereomer and converted to compound 5a using methodology described in Example 1.
~ 13 'hCH202C Cl H3N~O-t-C4Hg J
~ (F3C~)2)20 o PhCH202C
CH3~ OH G2HsN(i-c3H7)2 CH3--NH~O-t-C4Hg O
N-11 (R)-Benzvloxvcarbonyl-ethyl]-oc-(S)-(2-phenvl-cthyl!glycine.
t-butvl ester~
SI"IBSTJT~
, ~ .
:
::
WO 92~21360 PCI/USg2/n3809 j j "
,. ~ ,, To a solu~ion of benzyl (S)-lactate (3.75 9, 20.8 mmol) in dry methylene chloride (75 mL) cooled to 0C was added trifluoromethanesulfonic anhydride (3.75 mL, 22.3 mmol) dropwise over 5 minutes with stirring under an inert atmosphere.
After 5 minutes at 0C, 2,6-lutidine (2.77 mL, 23.8 mmol) was 5 added in one portion. After stirring 10 minutes, at O~C, N,~l-diisopropylethylamine (4.0 mL, 23.0 mmol) was added followed immediately by a solution of (L)-homophenylalanine t-butyl ester (4.97 9, 21.1 mmol) in methylene chloride (40 mL) dropwise over 15 minutes with stirring. The cooling bath was then removed, and the mixture was stirred for 24 hours at room temperature. The ~ mixture was diluted with methylene chloride (150 mL) which was successively washed with water, saturated aqueous sodium bicarbonate solution, saturated salt solution, dried over anhydrous magnesium sulfate and rotoevaporated. Purification 15 was achieved by means of ~lash column chromatography on silica - gel~ using initially 5~/O ethyl acetate in hexane and subsequently - ~ 10% ethyl acetate in hexane as the mobile phase. The product was obtained as an oil; yield 6.90 9 (83%) and converted to 5a by the methodology described in Example 1.
The following examples were prepared from intermediates described in Example 3.
N-lJ (~ arb~xY-ethyl)]-a-(s~-(2-phç~yl-ethyl)~]~lyGine 25 (2-çy~!~2~xyl-ethyl)5~llycin~ N-pheny!amide (~
MS: mJe 494 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.34-- ! 7.10 (m, 8H), 4.51 (dd, 1H, J = 8.0, 6.0 Hz), 4.19 (m, 1H), 2.71 (m, 30 211), 2.19 (m, 2H), t.96-1.60 (m, aliphatic H's), 1.56 (dd, 3H, J =
7.0, 3.0 Hz), 1.39-1.18 (m, aliphatic H's), 1.00-0.88 (m, aliphatic H's).
SUB~;TITUTE S~ ET
~, , ~ , W O 92/21360 P ~ /US92/03809 S ' ' \ `,; ` , !
- ~9 !:i ,. ":, ;, , , N-[1 (R?-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)~lycine-a-(S)-cyclohexyl-alvcine. N-phenylamide (5aq!
MS: m/e 466 (M+) 1H NMR (CD30D, 200 MHz): â 7.57 (dd, 2H, J = 7.0, 1.0 Hz), 7.30-s 7.16 (m, 8H), 4.23-4.05 (m, 2H), 3.99 (d, lH, J = 1.0 Hz, 2.67 (m, 2H), 2.40-2.05 (m, 2H), 1.90-1.62 (m, aliphatic H's), 1.57 (d, 3H, J
= 7.0 Hz), 1.4-1.19 (m, aliphatic H's).
N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)~lycine-oc-(S)-çyclohexylmethyl-plvcine. N-phenylamide (5ar MS: m/e 480 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.33-7.08 (m, 8H), 4.67 (t, 1H, J = 8.0 Hz), 3.99 (t, lH, J = 7.0 Hz), 3.63 15 - (q, 1H, J = 7.0 Hz), 2.69 (m, 2H), 2.16 (m, 2H), 1.81 (m, 2H), 1.74 - (m, 8H), 1.49 (d, 3H, J = 7.0 Hz), 1.23 (td, J = 7.0, 2.0 Hz), 1.02 (m, 2H).
N-11 (R)-Carboxy-eth~ -a-(S)-(2-phenyl-ethyl)alvcine-(L)-B-naphthylalanine. N-phenylamide (5as) MS: m/e 524 (M~) ., 1H NMR (CD30D, 200 MHz): ~ 7.82-7.07 (m, 17H), 5.00 (dd, 1H, J =
8.0, 6.0 Hz), 3.85 (t, 1H, J = 7.0 Hz), 3.42 (dd, lH, J = 14.0, 6.0 Hz), 3.33 (q, lH, J = 7.0 Hz), 3.20 (dd, 1H~ J 3 14.0, 9.0 Hz), 2.65 (t, 2H, J = 9.0 Hz), 2.09 (t, 2H, J = 8.0 Hz), 1.10 (d, 3H, J = 7.0 Hz).
N-11 (R)-Carboxv-ethyl)]-a-(S!-(2-pheny!-ethyl~lycine-(L~
na~hthylalanine. N-phenylamide (5at .
MS: m/e 524 (M+) 1H NMR (CD30D, 200 MHz): ~ 8.27-7.09 (m, 17H), 5.02 (t, 1H, J, 8.0 Hz), 3.83 (t, 1H, J . 7.0 Hz), 3.63 (dd, 2H, J = 8.0, 4.0 Hz), 3.35 -; SUBSTITUTE S~EET
, :: :
WO 92/21360 PCI`/US92/03809 - 6() -(q, 1H, J = 7.0 Hz), 2.62 (t, 2H, J = 9.0 Hz), 2.Q9 (t, 2H, J = 8.0 Hz), 1.30 (d, 3H, J = 7.0 Hz).
N-~1 (R)-Carboxy-ethyl)~-a-(S)-(2-~henyl-ethyl)~lycine-[(L)-~lutamjc acid. oc~-bis- N-phenylamide] (5au) MS: m/e 531 (M+) 1H NMR (CD30D, 200 MHzj: ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.55 (dd, 2H, J = 7.0, 1.0 Hz), 7.34-7.07 (m, 11 H), 4.62 (dd, 1H, J = 8.0, 6.0 Hz), 3.90 (t, lH, J = 7.0 Hz), 3.62 (t, 1H, J = 7.0 Hz), 2.71 (m, 2H, J
lO = 6.0 Hz), 2.58 (t, 2H, J = 7.0 Hz), 2.30 (m, 2H), 2.15 ~m, 2H, J = 8.0 Hz), 1.48 (d, 3H, J = 7.0 Hz).
-[,1 (R)-Carboxy-ethyl~a-(S)-(2-eheny!-ethyl)~lycine-(L)-leucine~l~h~ylamide (5av!
MS: m/e 446 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.27-7.17 (m, 5H), 4.46 (dd, 1H, J =
8.0, 6.0 Hz), 3.90 (t, 1H, J = 7.0 Hz), 3.54 (q, lH, J = 7.0 Hz), 2.65 (m, 2H), 2.12 (t, 2H, J = 7.0 Hz), 1.86-1.57 (m, aliphatic H`~), 1.45 20 (d, 3H, J = 7.0 Hz), 1.32-1.17 (m, aliphatic H's), 0.96 (dd, 6H, J =
8.0, 6.0 Hz).
N-~,(l,~R)-C:arl20xy-ethyl)]-a-(S)-(2-phen~vl-ethyl~g!ycirlQ-a-(S~-~2-(4-hydrpxyphenvl!ethyl)glycine, N~h~nylamide ($aw~
MS: m/e 504 (M+) 1 H NMR (C~30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.29 (dd, 2H, J = 8.0, 7.0 Hz), 7.04 (d, 1H, J = 9.0 Hz), 7.29-7.05 (m, 7H), 6.70 (d, 2H, J = 8.0 Hz), 4.53 (dd, 1H, J = 8.0, 6.0 Hz), 3.95 (t, 1H, J
30 =-7.0 Hz), 3.60 (q, 1H, J = 7.0 Hz), 2.70 (m, 4H), 2.17 (m, 4H), 1.50 - (d, 3H, J = 7.0 Hz).
N-l1 (R)-Carboxy-ethyl)l-a-(S)-(2-phenyl-ethyl)~lycine-(L)-ehenyl~lvcine. N-~henylamide (5ax!
SUB~;TITUT~ SHEET
~' MS: m/e 460 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.54 (dd, 2H, J = 7.0, 1.0 Hz), 7.41-7.07 (m, 13H), 5.63 (s, lH), 4.01 (t, 1H, J = 7.0 Hz), 3.56 (q, 1H, ~ =
7.0 Hz), 2.80 (m, 2H), 2.17 (m, 2H), 1.42 (d, 3H, J = 7.0 Hz).
N-[1 (R)-Carboxy-ethyll-oc-(S)-(2-phenyl-ethyl!~lycine-~(L)-~luta~j~ a~d,~-benzylamide. Na-p~nylamide] (5ay) MS: m/e 545 (M+) 1 H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.33-7.09 (m, 13H), 4.58 (dd, lHj J = 8.0, 6.0 Hz), 4.37 (s, 2H), 3.91 (t, 1H, J = 7.0 Hz), 3.61 (q, 1H, J = 7.0 Hz), 2.72 (m, 2H), 2.44 (t, 2H, J
= 7.0 Hz), 2.17 (m, 2H), 1.N (d, 3H, J = 7.0 Hz).
:
lS -11 (R)-Carboxy-ethyl)]--(S)-(2-phenyl-ethy~ 1ycine-(L)-Ornithine. N-phenylamide (5az!
~: : MS: m/e 441 (M+) 1H NMR (C~30D, 200 MHz): ~ 7.47 (dd, 2H, J = 7.0, 1.0 Hz)j 7.23-- 20 7.00 (m, 8H), 4.62 (dd, 1H, J = 8.0, 5.0 Hz), 3.27 (t, 1H, J = 7.0 Hz), 3.14 (q, 1H, J = 7.0 Hz), 2.96 (m, 2H), 2.69 (t, 2H, J = 8.0 Hz), 2.01-1.78 (m, 6H), 1.30 (d, 3H, J,= 7.0 Hz).
~::
N-l1 (R)-c:~pxy-ethyl]-a-($)-(2-~Qhenyl-ethvl)alycine-(L~
ar~inine. N phenvlamide (5bc) MS: m/e 483 (M~) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.29-7.05 (m, 8H), 4.55 (dd, 1H, J - 8.0, 6.0 Hz), 3.39 (t, 1H, J = 7.0 Hz), 3.22 (m, 3 H), 2.68 (t, 2H, J, 8.0 Hz), 2.05-1.70 (m, 6H), 1.32 (d, 3H, J = 7.0 Hz).
carboxv-ethvl j1-a-(5)-(2-phenyl-e~hvi!~lvcine-a-(S)-(3-yl~lycine. N-phenylamide (5bb) SUBSTiTUTE S tET
.
WO 92/21360 PCI`/US92/03809 MS: m/e 502 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd,2H,J = 7.0,1.0 Hz), 7.33-7.08 (m, 13H), 4.56 (dd, lH, J = 9.0, 7.0 Hz), 3.98 (t, 1H, J = 7.0 Hz), 3.59 (q,1H,J = 7.0 Hz),2.68 (m,4H),2.15 (m, 2H,J = 8.0 Hz), 1.80 (m,4H),1.46 (d,3H,J = 7.0 Hz).
N-[l(~)-carboxy-ethyll-~-(S)-(2-pheny!-ethyl)~lycine-~-(S!-n-Qctyl~lycine. N-ehenylamide (5de) o MS: mie 496(M+) - 1H WMR~(CD30D, 200 MHz): ~ 7.56 (dd,2H,J = 7.0,1.0 Hz), 7.33-7.08 (m, 8H),4.52 (dd,1H,J = 8.0,6.0 Hz),3.99 (t,1H,J = 7.0 Hz), 3.60 (q, 1H, J z 7.0 Hz), 2.71 (m, 2H), 2.15 (m, 2H), 1.84 (m, 2H), 1.48 (d, 3H, J = 7.0 Hz), 1.44-1.36 (m, 12H), 1.28 (t, 2H, J = 7.0 ~Hz).
Iq~ Lsacboxybhenyl)amide (5cp) MS: m/e 484 (M+1);506(M+Na);544 (M+K).
1H NMR (CD30D),200MHz): ~ 8.02-7.76 (2d,4H);7.26 (m,5H);4.72 (dd,1H); 4.12 (dd,1H); 3.94 (q,tH); 2.78 (m,2H); 2.22 (m,2H); 1.80 (m,3H); 1.60 (d,3H);1.08 (2p,6H).
N-~l(R)-Carboxv-ethvl]-a-(S!-(2-phenyl-ethyl!alvcine-(L!-25 leucine. N-(4-trif!uoromethylphenyl)amide (5çv) MS: mte 508(M+1);529(M+Na) 1H NMR (CD30D),200MHz): ~ 7.86-7.62 (2d,4H);7.26 (m,5H);4.72 (ddj1H); 4.04 (dd,1H); 3.66 (q,1H); 2.74 (m,2H); 2.22 (m,2H); 1.80 , (m,3H); 1.56 (m,3H); 1.08 (2d,6H).
N'-11 (R)-Carboxy-~thyl]-a-(S)-(2-phenyl-ethyl)~lycine-(L)-l0ucine. N-(3-~yridyl)amide (Scy) MS;n~e 441(M+1);463 (M~Na) SUBSTlTlJTE S~EET
WO 92/21360 PCI'/US92/03X09 ,. -. '; , , 1H NMR (CD30D),200MHz): ~ 8.86 (d~lH); 8.30 (ddl1H); 8.18 ~m,1H);
7.46 (m,1H); 7.26 (m,5H); 4.72 (dd,1H); 4.04 (dd,1H); 3.66 (q,1H);
2.78 (m,2H); 2.22 (m,2H); 1.84 (m,3H); 1.56 (d,3H); 1.08 (2d,6H).
N-[1 (R)-Carboxy-ethvl]-a-(S!-(2-phenvl-ethvl!alvcine-(L!-leucine. N-(benzthiazol-2-yl)amide (5db~
MS: m/e 498 (M+1) 1H NA~R (CD30D),200MHz): ~ 7.90-7.18 (m,9H); 4.84 (dd,1H); 4.10 (dd,1H); 3.70 (q,1H); 2.78 (m,2H); 2.24 (m,2H); 1.84 (m,3H); 1.56 (d,3H); 1.08 (2d,6H).
, 10 Example 4 n-c3H7 , ~ ~ J
- HO2C ~
- I NHJ~ NHPh 2 0 o \rCH3 5bk CH3 - Employing the procedure outlined in Method D, N-25 benzyloxycarbo-ethyl dipeptide lQ was prepared and converted to compound ~bk using methodology described in Example 1 for the preparation of 5a.
, - .
S'J~STfTE JT~ SH~T
WO 92/21360 PCI`/US92/1~3X09 '/ '` '`. ' ~; ' ` , n-c3H7 TFA-NH~ ¢~ CH2C12 ,~
TFA-NH OH
- N-Trifl~ (s)-(2-(4--~propy~ h-en oxoethyl)glycine (6) Aluminum chloride (1.7 gm, 7.5 mmol) was added to an ice c~oled solution of N-trifluoroacetyl-(L)-asp~rtic acid anhydride (1.0 gm, 4.7 mmol) and n-propylbenzene (1.4 mL, 10 mmol) in dry methylene chloride (15 mL) under a dry nitrogen 5 atmosphare. The solution was stirred at room temperature for 5 days and then quenched in a mixture of ice/ 2N HCI / ethyl acetate. The mixture was extracted with ethyl acetate (3 x 50 mL.), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was partitioned between acetonitrile (100 20 :mL) and hexanes (500 mL) The acetonitrile layer was separated, - washed with hexanes (2 x 500 mL), and dried over anhydrous : - sodium sulfate. The solvent. was evaporated in vacuo and the : residue dissolved in ethyl acetate (150 mL). Activated charcoal(10 gm3 was added, the solution filtered through celite filter aid, 25 and evaporated in vacuo. The product was crystallized from ethyl acetate / hexanes (0.67 gm, 43% yield).
1 H NMR (CDCI3, 200 MHz): ~ 7.84 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J =
8.0 Hz), 5.0 (m, 1H, J = 4.0 Hz), 3.92 (ABq/d, 2H, J = 18 Hz, J = 5 Hz), 2.65 (t, 2H, J = 6.0 Hz), 1.65 (m, 2H, J = 8.0 Hz), 0.94 (t, 3H, J
30 6 0 H ) 5~JBSTITUTE SHEET
- . .
:`:
WO 92/21360 PCJ`/US92/03X09 - 65 ~ J
n-C ~H7 n-c3H7 H2, Pd/C
~o -- . J
TFA-NH~ EtOAc, HOAc TFA-NH~
lo N-Trifluoroacetyl-a:-(S)-(2-(4-n-propylphenvl~ethy~ ycine (7?
:
A so lution of N-trif l uoro acety l-a - ( S ) - ( 2 - ( 4 - n -propylphenyl)-2-oxoethyl)glycine 6 (140 mg, 0.43 mmo!) in ethyl acetate (10 mL) containing acetic acid (0.25 m~) and 10%
~`~ 15- palladium on ~carbon (10: mg) was stirred under one atmosphere of hydrogen gas. After two days, the catalyst was filtered off and : fresh ;catalyst was added~and the reaction stirred under hydrogen overnight. The rnixture was filtered and the solvent evaporated in ~-: vacuo to yield the product 7 (127 mg, 93% yield).
20 MS: m/e 318 (M+1), 340 (M+Na) 1 H NMR (CD3OD, 200 MHz): ~ 7.08 ~s, 4H), 4.37 (dd, 1H, J = 4.0 Hz), -: . 2.65 (m, 2H), 2.54 (t, 2H, .1= 7.0 Hz), 2.3-2.0 (br. m, 2H), 1.62 (m, 2H, J = 8.0 Hz), 1.92 ~t, 3H, J = 8.0 Hz) n-c3H7 n-C3H~
~ 30. ~ 2 J~NHPh EDC, HOBt, TFA-NH~ CHa TFA-NH NHJI~NHPh 7 ~ 8 ~--CH3 , ~ ,. . . .
,;, , Sl~sT~TuTE s iEET
WO 92t21360 PCl /US92/03809 ~. ~ . S ', `, N-(Trifiuoroacetyl!-a-(S)-(2-(4-n-propylphenyl!ethyl!glvcine-(L)-leucine._t~-phenyLamide (8!
A solution of N-tri~luoroacetyl-a - ( S ) - ( 2 - (4 - n -propylphenyl)ethyl)glycine 7 ( 127 mg, 0.40 mmol) in methylene chloride (10 mL) was cooled to 0 C under a dry nitrogen atmosphere. N-methyl morpholine (48 ~lL, 0.44 mmol) was added followed by N-hydroxybenztriazole (81 mg, 0.6 mmol). After stirring for 15 minutes, (L)-Leucine, N-phenylamide (108 mg, 0.5 mmol~ was added followed by N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide (EDAC, 115 mg, 0.6 mmol). The solution was stirred overnight at room temperature, diluted with ethyl aGetate (100 mL) and washed with 2N HCI (3 x 20 mL), saturated sodium bicarbonate solution ~2 x 20 mL), and water (20 mL). The solution was dried over anhydrous sodium sulfate and evaporated in vacuo.
The product was purifed by preparative thin layer chromatography on ~ silica gel plates eluted twice with 1.5% methanol in - ~ ~ chloroform, then rechromatographed with 1% methanol in chioroform (122 mg, 61% yield).
1 H NMR (CD30D, 400 MHz): ~ 7.53 (d, 2H, J = 7.7 Hz~, 7.28 (m, 2H), 7.06 (m, 5H), 4.54 (m, 1H), 4.42 ~m, 1H), 2.7-2.6 (m, 2H), 2.52 (t, 2H, J = 6.0 Hz), 2.2-2.0 (br. m, 2H), 1.8-1.6 (br. m, 2H), 1.59 (m, 2H, J = 8.0 Hz), 0.97 (dd, 6H, J = 6.0 Hz), 0.91 (t, 3H, J = 6.4 Hz) 2 5n-C3H7 n-C3H7 ¢~ ~
J NH3,MeOH
O ~ O
TFA-NH' ~NHV~NHPh H NNHJ~NHPh 8 \--CH3 9\--CH3 - : SUBSTITUTE SHEET
WO 92/21360 PCr/US92/03809 '? ' r; .
~-(S!-(2-(4-n-Propylehenyl)ethyl)~!ycin~-(L)-leucine~
N-phenylamide (9~
Ammonia gas was bubbled into methanol (20 mL) at 5 -20 C for 30 minutes then placed in a pressure tube with N-trifluoroacetyl-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide 8 (120 mg, 0.23 mmol), sealed, and stirred at room temperature for 5 days. The tube was cooled to -20~ C before opening~ and then the solvent was evaporated in ~vacuo. The product was purified by; preparative thin layer chromatography on silica gel eluted with 2% methanoi in chloroform ~(95~ mg, 100% yield).
1 H NMR (CD30D,~ 400 MHz)~ ~ 7.55 (d, 2H, J . 8.6 Hz), 7.29 (t, 2H, J
= 8.5 Hz), 7.1-7.0 (m, 5H), 4.56 (m, 1H), 3.4 (t, 1H ~ = 6.0 Hz), 2.61 (t, 2H,~J = 8.0 Hz),~2.51 (t, 2H, J = 7.0 Hz), 2.0-1.6 (br. m, 4H), 1.59 (m, 2H, J = 7.5 Hz), 0.99 (t, 6H, J = 6.0 Hz), 0.90 (t, 3H, J = 7.4 Hz) n-C3H7 n-C3H~
~ PhCH2O~
O Ch3~ OH J
NHJ~ PhCH202C f O
H2N lr NHPh2,6-lUt CH3--NH~ J~NHPh N-[1 (R)-Benzyloxycarbonvl-ethyl]-a-(s)-(2-(4-n-O propylph~ny~)~hy~glyine-(L)-leucine. N-phenyl~mide (1 !
: To a solution of benzyl (L)-lactate (39 mg, 0.21 mmol) in ~methylene chloride ;(2; ml~ a~;0 C under a dry nitrogen ~- atmosph~re ~was:~ added- 2,6^!utidine :;(28 ~lL, 0.24 mmol) followed by ~tri11ic ~anh~ydride i~(39~ ~L, ~0.23 mmol). After stirring for 10 SUBSTITUTE SHE~T
, ~, : - :
: ~ :
. -, , minutes at 0 C, a solution of diisopropylethylamine (41 IlL, 0.24 mmol) and a-(S)-~2-(4-n-propylphenyl)ethyl)glycine-(L)-Leucine, N-Phenylamide 9 (95 mg, 0.24 mmol) in methylene chloride (1 mL) was added. The solution was stirred at room temperature overnight, diluted with methylene chloride (20 mL), and washed 5 successively with water (2 x 5 mL), saturated sodium bicarbonate (2 x 5 mL), and saturated salt solution (5 mL). The solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The product was purified by HPLC on silica gel eluted with 2% acetone in methylene chloride (103 mg, 85% yield).
n-C3H7 n-c3H7 ¢1 ¢~
'hCH202C ~ O H2, Pd/C HO2C ~
CH--NH~NHJ~ NHPh CH--NH~NHJ~
O ~ O ~
r~CH3 rCH3 10 CH3 5bk CH3 N~ Rl-Carbcxyethvl~-a-(S~-(2-(4-n-propylphenvl!ethyl!glvcine-(L)-!eucine. N-~h~lamide (5bk!
A solution of N-[1 (R)-benzyloxycarbonylethyl]-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide 10 (103 mg, 0.18 mmol) in ethyl acetate (t 0 mL) containing Pearlman's catalyst (15 mg) was stirred under 1 atmosphere of I hydrogen gas overnight. The mixture was filtered and the solvent eYaporated in vacuo to give 5bk (70 mg, 82% yield):
MS: m/e 483 (M+1) 1H NMR (CD30D, 200 MHz):~ ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37-7.28 (m, 3H), 7.09-7.05 (m, 4H), 5.15 ~dd, 1H, J = 7.0, 2.0 Hz), 4.67 (t, 1H, J
6.~0 Hz), 4.00 (t, 1H, J = 6.0 Hz), 3.75 (m, lH), 2.68 (br. m, 2H), SUBS~ITuTE SHEET
- 69 - ;.;;~ -2.51 (t, ~H, J = 7.0 Hz), 2.12 (m, 2H), 1.80-1.58 (m, 6H), 1.51 (d, 3H, J = 7.0 Hz), 1.31 (br. m, 4H), 1.01 (dd, 6H, J = 6.0 Hz), 0.90 tt, 3H, J = 7.0 Hz).
The following additional compounds were prepared 5 according to the method of Example 4.
~N-(l (R)-Carboxy-ethyl)-a-(S!-[2-(4-eropylehenyl!ethyl]]glycine-~ ar~ jne. N-phenylamide (5bv) MS: m/e 525 (M+1) lO 1H NMR (CD30D, 400 MHz): ~ 7.57 (d, 2H, J = 8 Hz), 7.25 (t, 2H, J =
~8 Hz), 7.11-7~01 (m, 5H), 4.52 ~dd, 1H, J = 8.5, 4.5 Hz), 3.27-3.18 (m, ~3H), 3.15 (q, lH, J = 7 Hz), 2.63 (t, 2H, J = 7.5 Hz), 2.51 (t, 2H, J =:7 Hz3, 2~02-1~80 (m, 4H), 1~78-1~66 (m, 2H), 159 (hextet, 2H, J
= 7 Hz), 1.27 (d, 3 H, J = 7 Hz), 0.90 (t, 3H, J = 7 Hz).
Example 5 J
HO2C~ 1~ O
CH3--NH~NHJ` NHPh O ~
~CH3 5~q CH3 Employing the procedure outlined in Method E, 30 dipeptide 14 was prepared and converted to compound 5bq using methodology described in Example 4 for the preparation of 5bk.
SUBSTITUTE SHEET
WO 92/21360 PCI /US92tO3809 ~,CH3 CH3~ Cbz-NH~OCH3 )2CuCNLi2 Cbz-NH OCH3 ., ~
N-Benzyloxycarbony~ c-(S)-(2-(3.4-dimethyiphenyl)ethyl)~iycine. methvl este~ (1'1 ) A~ solutbn of n-butyl lithium in hexanes (1.6N, 2.5 mL) was~added~to~i~3,4~-dimetll)rliodobenzene (870 mg, 4 mmol) in a 25 mL round ~bottom~ flask th~at had been cooled to -78 C under a dry nitrogen~atmosphere. ~'~The~solution was slowly~ warmed to 40 C
and~ stirred;~for~ hour.- The solution was; cooled to 0 C and slowly tran,sfe~rred `via~ cannula to a dry flas k under dry nitrogen atmosphere~ containing copper(l) cyanide~ (179 ~mg, 2 mmol) in 5 mL THF.~ The mixture was stirred until homogeneous and the solvent evaporated with a stream of nitrogen ~gas. The residue was redissolved in THF and stirred for 1 hour at 0 C to yield a greenish solution.
Approximately half of the THF cuprate solution (~1.4 mmol) was diluted in dry THF (20 mL) and cooled to 0 C. This solution was slowly added via a syringe pump over a period of 1 hour to a solution of N-carbobenzyloxy-a - ( S ) - ~ 2 -iodoet~,yl)lglyci~ne, methy! ester (277 mg, 0.70 mmol) in THF (5 mL). The~solution was ~stirred at room temperature for 5 hours.
The reaction~,was quenched with 10% ammonium chloride solution (5 mL) and extracted with rnethylene chloride (3 x 20 mL). The solution~was dried over anhydrous magnesium sulfate and the solvent and~excess;~iodoxylené evaporated under~ high vacuum. The product'was~purified~by~ flash column chromatography on silica gel~éluted~ h~20% ethyl acetate in hexanes (78 mg, 31% yield).
,," ~ "
~ SUBSTITUTE 5HEET
" .. . .
- 7 1 - ~ . J
1H NMR (CDCI3, 200 MHz): â 7.36 (bs, 5H), 7.05 (d, 1H, J _ 7.0 Hz), 6.08-6.94 (m, 2H,), 536 (d, 1H, J = 8Hz), 5.13 (s, 2H,), 4.05 (bm, 1H, ), 3.73 (s, 3H,), 2.6 (t, 2H, J = 9.0 Hz),.2.23 (s, 6H), 2.15 (m, 1H, J=8 Hz), 1.95 (m, 1H, J=8 Hz), OH- ~CH3 ;; 10 ~ ,~
Cbz-NH~OCH3 Cbz-NH
~ ~ 15~
N-Be~nzyloxvcarbonvl-a-(S!-(2-(3.4-dimethvlphenvl!~thyl!alvcine A solution of N-carbobenzyloxy~ ( S ) - ( 3, 4 -20 dimethylphenethyl)glycine, methyl ester 11 (209 mg, 0.59 mmol), wa~ disolved in 6 mL of methanol and 3 mL of water. The solution was degased and flushed~with nitrogen. One equivalent (24 mg) of LiO`H was added to the solution, the flask sealed and stirred overnight at room temperature. The solution was acidified with 25 1.1 equivalents of acetic acid (39 mg) and the solvent evaporated in vacuo. The residue was washed with water and filtered. The precipitate was dried in vacuo (204 mg, 100% yield). The product was used without further purification.
i , , 30 1H NMR (CD30D, 20`0 MHz): ~ 7.36 (br m, 5H), 7.0-6.8 (m, 3H, J, 7.0 Hz), 5.08 (s, 2H), 5.13 (s, 2H), 4.08 (br m, lH), 2.56 (t, 2H, ~, 9.0 Hz),.2.19 (s, 6H), 2.1;5-1.9 (bm, 2H) ~ "
SU~STITUTE S tEET
~, . , ; , ` .
,~ ~
WO 92/21360 PCr/US92/03809 ~,CH3 ¢~CH3 H2N~NHPh EDC, HOBt, ~ o S ~ \~CH3 ~ ~ - NHPh Cbz-NH ~OH CH3 ~
O 12 13 rCH3 lO N-Ben~zyloxycàrbonyl--(S)-~2-(3 4-dime _-(L)-leucine. N-ph~y~de (13) ` ` A ~ ~ solution of N-Carbobenzyloxy-a - ( S ) - ( 3, 4 -dimethylphenethyl)glycine 12 (207 mg, 0~.55 mmol), (L)-leucine, l5 N-phenylamide ~ 12~5~m~g, 0.61 mmol), N-hydmxybenztriazole (87 mg,~ 0~6 mmol),~and N-methyl morpholine (130 ,uL, 1.1 mmol) in THF~(3~~mL)~was ~stirred at room temperature for 10 minutes.
ED~C~ (158 ~mg;,~0.83 mmol) was added and the solution stirred for 4 ~hours. Methylene chloride (25 mL) was added and the solution 20 ~ washed successively with 2~1 HCI (3 x 5 -mL) ~and saturated sodium bicarbo~nate solution (3 x 5 mL). After ~ drying over anhydrous magne~ium sulfate, the soJvent was evaporated in vacuo and the product purified by flash column chromatography on silica gel eluted with 2% ethyl acetate in methylen~ chloride (148 mg, 53%
25 yield).
lH NMR~(CD3OD, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.42-7.28 (m, 7H), 7.16-6.83 ~m, 4H), 5.15 (S, 2H), 4.60 (t, lH, J = 6.0 Hz), 4.16 ' (t, 1H, Jl= 6.0 Hz), 2.6 (br. m, 2H), 2.2 (S, 6H), 2.2-1.8 (m, 2H), 1.8-30 1.6 (br~m, 2H),1.31 (br m, 1H), 1.01 (s, 6H, J, 6.0 Hz).
SUBSTITUTE SHEET
", .,, ;~
WO 92/21360 PCl/US92/03809 CH~ CH3 ;:
¢~' H2, Pd/C ¢~
~ O ~/bOH
Cb~-NH J~NHPh H N~NHJ`NHPh O ~ O ~ ,.
1 3 1H3CH3 14 ~CH3 - 1~ a-(S)-(2-(3.4-dimethylehenyl!ethyl)Qly~ine-(L)-leUCine._ N-phenylamide (1 4) To a solution of 3 ml of methanol and N-carbobenzyloxy-a-(S)-(3,4-dimethylphenethyl)glycine-(L)-leucine, N-phenylamide 15 (148 mg) was added 10 mg of 10% palladium on carbon in a 10 ml round bottom flask titted with a stirring bar and rubber septum. ;
Ths flask was flushed with hydrogen via syringe attached to a balloon reservoir. Stirring was continued for 1 hr, during which the starting material was converted to product and the reaction 2~ mixture became homogeneousr Filtration through a 2 micron filter removed the palladium catalyst and the methanol solvent - ~ was removed under reduc~ed pressure. The product was recovered (89 mg, 98% yield) and used in the subsequent step without purification.
1 H NMR (CD30D, 200 MHz): ~ 7.56 ~d, 2H, J = 7.7 Hz), 7.42-7.28 (m, 2H), 7.18-7.1 (m, H), 6.8 (S, 3H), 4.63 ~t, lH, J = 6.0 Hz), 3.42 (t, lH, J = 6.0 Hz), 2.6 (t, 2H, J = 6 Hz, ), 2.2 (S, 6H), 2.1-1.8 (m, 2H), 1.8-1.6 (br m, 2H),1.31 (br m, 1H), 1.01 (m, 6H, ).
SU8STITUTE SHE~T' ~, ~
'-? ' " ` ` `
PhcH2o~ ¢~CH3 J Ch3 OH J
O -- PhCH202C ~ O
,~ NHJ~ Tf20 1 NHJ~
2 ~ NHPh 2, 6 - I U t CH3 NH ~ NHPh O
~ (F3C~)2)20 o PhCH202C
CH3~ OH G2HsN(i-c3H7)2 CH3--NH~O-t-C4Hg O
N-11 (R)-Benzvloxvcarbonyl-ethyl]-oc-(S)-(2-phenvl-cthyl!glycine.
t-butvl ester~
SI"IBSTJT~
, ~ .
:
::
WO 92~21360 PCI/USg2/n3809 j j "
,. ~ ,, To a solu~ion of benzyl (S)-lactate (3.75 9, 20.8 mmol) in dry methylene chloride (75 mL) cooled to 0C was added trifluoromethanesulfonic anhydride (3.75 mL, 22.3 mmol) dropwise over 5 minutes with stirring under an inert atmosphere.
After 5 minutes at 0C, 2,6-lutidine (2.77 mL, 23.8 mmol) was 5 added in one portion. After stirring 10 minutes, at O~C, N,~l-diisopropylethylamine (4.0 mL, 23.0 mmol) was added followed immediately by a solution of (L)-homophenylalanine t-butyl ester (4.97 9, 21.1 mmol) in methylene chloride (40 mL) dropwise over 15 minutes with stirring. The cooling bath was then removed, and the mixture was stirred for 24 hours at room temperature. The ~ mixture was diluted with methylene chloride (150 mL) which was successively washed with water, saturated aqueous sodium bicarbonate solution, saturated salt solution, dried over anhydrous magnesium sulfate and rotoevaporated. Purification 15 was achieved by means of ~lash column chromatography on silica - gel~ using initially 5~/O ethyl acetate in hexane and subsequently - ~ 10% ethyl acetate in hexane as the mobile phase. The product was obtained as an oil; yield 6.90 9 (83%) and converted to 5a by the methodology described in Example 1.
The following examples were prepared from intermediates described in Example 3.
N-lJ (~ arb~xY-ethyl)]-a-(s~-(2-phç~yl-ethyl)~]~lyGine 25 (2-çy~!~2~xyl-ethyl)5~llycin~ N-pheny!amide (~
MS: mJe 494 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.34-- ! 7.10 (m, 8H), 4.51 (dd, 1H, J = 8.0, 6.0 Hz), 4.19 (m, 1H), 2.71 (m, 30 211), 2.19 (m, 2H), t.96-1.60 (m, aliphatic H's), 1.56 (dd, 3H, J =
7.0, 3.0 Hz), 1.39-1.18 (m, aliphatic H's), 1.00-0.88 (m, aliphatic H's).
SUB~;TITUTE S~ ET
~, , ~ , W O 92/21360 P ~ /US92/03809 S ' ' \ `,; ` , !
- ~9 !:i ,. ":, ;, , , N-[1 (R?-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)~lycine-a-(S)-cyclohexyl-alvcine. N-phenylamide (5aq!
MS: m/e 466 (M+) 1H NMR (CD30D, 200 MHz): â 7.57 (dd, 2H, J = 7.0, 1.0 Hz), 7.30-s 7.16 (m, 8H), 4.23-4.05 (m, 2H), 3.99 (d, lH, J = 1.0 Hz, 2.67 (m, 2H), 2.40-2.05 (m, 2H), 1.90-1.62 (m, aliphatic H's), 1.57 (d, 3H, J
= 7.0 Hz), 1.4-1.19 (m, aliphatic H's).
N-[1 (R)-Carboxy-ethyl]-a-(S)-(2-phenyl-ethyl)~lycine-oc-(S)-çyclohexylmethyl-plvcine. N-phenylamide (5ar MS: m/e 480 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.33-7.08 (m, 8H), 4.67 (t, 1H, J = 8.0 Hz), 3.99 (t, lH, J = 7.0 Hz), 3.63 15 - (q, 1H, J = 7.0 Hz), 2.69 (m, 2H), 2.16 (m, 2H), 1.81 (m, 2H), 1.74 - (m, 8H), 1.49 (d, 3H, J = 7.0 Hz), 1.23 (td, J = 7.0, 2.0 Hz), 1.02 (m, 2H).
N-11 (R)-Carboxy-eth~ -a-(S)-(2-phenyl-ethyl)alvcine-(L)-B-naphthylalanine. N-phenylamide (5as) MS: m/e 524 (M~) ., 1H NMR (CD30D, 200 MHz): ~ 7.82-7.07 (m, 17H), 5.00 (dd, 1H, J =
8.0, 6.0 Hz), 3.85 (t, 1H, J = 7.0 Hz), 3.42 (dd, lH, J = 14.0, 6.0 Hz), 3.33 (q, lH, J = 7.0 Hz), 3.20 (dd, 1H~ J 3 14.0, 9.0 Hz), 2.65 (t, 2H, J = 9.0 Hz), 2.09 (t, 2H, J = 8.0 Hz), 1.10 (d, 3H, J = 7.0 Hz).
N-11 (R)-Carboxv-ethyl)]-a-(S!-(2-pheny!-ethyl~lycine-(L~
na~hthylalanine. N-phenylamide (5at .
MS: m/e 524 (M+) 1H NMR (CD30D, 200 MHz): ~ 8.27-7.09 (m, 17H), 5.02 (t, 1H, J, 8.0 Hz), 3.83 (t, 1H, J . 7.0 Hz), 3.63 (dd, 2H, J = 8.0, 4.0 Hz), 3.35 -; SUBSTITUTE S~EET
, :: :
WO 92/21360 PCI`/US92/03809 - 6() -(q, 1H, J = 7.0 Hz), 2.62 (t, 2H, J = 9.0 Hz), 2.Q9 (t, 2H, J = 8.0 Hz), 1.30 (d, 3H, J = 7.0 Hz).
N-~1 (R)-Carboxy-ethyl)~-a-(S)-(2-~henyl-ethyl)~lycine-[(L)-~lutamjc acid. oc~-bis- N-phenylamide] (5au) MS: m/e 531 (M+) 1H NMR (CD30D, 200 MHzj: ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.55 (dd, 2H, J = 7.0, 1.0 Hz), 7.34-7.07 (m, 11 H), 4.62 (dd, 1H, J = 8.0, 6.0 Hz), 3.90 (t, lH, J = 7.0 Hz), 3.62 (t, 1H, J = 7.0 Hz), 2.71 (m, 2H, J
lO = 6.0 Hz), 2.58 (t, 2H, J = 7.0 Hz), 2.30 (m, 2H), 2.15 ~m, 2H, J = 8.0 Hz), 1.48 (d, 3H, J = 7.0 Hz).
-[,1 (R)-Carboxy-ethyl~a-(S)-(2-eheny!-ethyl)~lycine-(L)-leucine~l~h~ylamide (5av!
MS: m/e 446 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.27-7.17 (m, 5H), 4.46 (dd, 1H, J =
8.0, 6.0 Hz), 3.90 (t, 1H, J = 7.0 Hz), 3.54 (q, lH, J = 7.0 Hz), 2.65 (m, 2H), 2.12 (t, 2H, J = 7.0 Hz), 1.86-1.57 (m, aliphatic H`~), 1.45 20 (d, 3H, J = 7.0 Hz), 1.32-1.17 (m, aliphatic H's), 0.96 (dd, 6H, J =
8.0, 6.0 Hz).
N-~,(l,~R)-C:arl20xy-ethyl)]-a-(S)-(2-phen~vl-ethyl~g!ycirlQ-a-(S~-~2-(4-hydrpxyphenvl!ethyl)glycine, N~h~nylamide ($aw~
MS: m/e 504 (M+) 1 H NMR (C~30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.29 (dd, 2H, J = 8.0, 7.0 Hz), 7.04 (d, 1H, J = 9.0 Hz), 7.29-7.05 (m, 7H), 6.70 (d, 2H, J = 8.0 Hz), 4.53 (dd, 1H, J = 8.0, 6.0 Hz), 3.95 (t, 1H, J
30 =-7.0 Hz), 3.60 (q, 1H, J = 7.0 Hz), 2.70 (m, 4H), 2.17 (m, 4H), 1.50 - (d, 3H, J = 7.0 Hz).
N-l1 (R)-Carboxy-ethyl)l-a-(S)-(2-phenyl-ethyl)~lycine-(L)-ehenyl~lvcine. N-~henylamide (5ax!
SUB~;TITUT~ SHEET
~' MS: m/e 460 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.54 (dd, 2H, J = 7.0, 1.0 Hz), 7.41-7.07 (m, 13H), 5.63 (s, lH), 4.01 (t, 1H, J = 7.0 Hz), 3.56 (q, 1H, ~ =
7.0 Hz), 2.80 (m, 2H), 2.17 (m, 2H), 1.42 (d, 3H, J = 7.0 Hz).
N-[1 (R)-Carboxy-ethyll-oc-(S)-(2-phenyl-ethyl!~lycine-~(L)-~luta~j~ a~d,~-benzylamide. Na-p~nylamide] (5ay) MS: m/e 545 (M+) 1 H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.33-7.09 (m, 13H), 4.58 (dd, lHj J = 8.0, 6.0 Hz), 4.37 (s, 2H), 3.91 (t, 1H, J = 7.0 Hz), 3.61 (q, 1H, J = 7.0 Hz), 2.72 (m, 2H), 2.44 (t, 2H, J
= 7.0 Hz), 2.17 (m, 2H), 1.N (d, 3H, J = 7.0 Hz).
:
lS -11 (R)-Carboxy-ethyl)]--(S)-(2-phenyl-ethy~ 1ycine-(L)-Ornithine. N-phenylamide (5az!
~: : MS: m/e 441 (M+) 1H NMR (C~30D, 200 MHz): ~ 7.47 (dd, 2H, J = 7.0, 1.0 Hz)j 7.23-- 20 7.00 (m, 8H), 4.62 (dd, 1H, J = 8.0, 5.0 Hz), 3.27 (t, 1H, J = 7.0 Hz), 3.14 (q, 1H, J = 7.0 Hz), 2.96 (m, 2H), 2.69 (t, 2H, J = 8.0 Hz), 2.01-1.78 (m, 6H), 1.30 (d, 3H, J,= 7.0 Hz).
~::
N-l1 (R)-c:~pxy-ethyl]-a-($)-(2-~Qhenyl-ethvl)alycine-(L~
ar~inine. N phenvlamide (5bc) MS: m/e 483 (M~) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd, 2H, J = 7.0, 1.0 Hz), 7.29-7.05 (m, 8H), 4.55 (dd, 1H, J - 8.0, 6.0 Hz), 3.39 (t, 1H, J = 7.0 Hz), 3.22 (m, 3 H), 2.68 (t, 2H, J, 8.0 Hz), 2.05-1.70 (m, 6H), 1.32 (d, 3H, J = 7.0 Hz).
carboxv-ethvl j1-a-(5)-(2-phenyl-e~hvi!~lvcine-a-(S)-(3-yl~lycine. N-phenylamide (5bb) SUBSTiTUTE S tET
.
WO 92/21360 PCI`/US92/03809 MS: m/e 502 (M+) 1H NMR (CD30D, 200 MHz): ~ 7.56 (dd,2H,J = 7.0,1.0 Hz), 7.33-7.08 (m, 13H), 4.56 (dd, lH, J = 9.0, 7.0 Hz), 3.98 (t, 1H, J = 7.0 Hz), 3.59 (q,1H,J = 7.0 Hz),2.68 (m,4H),2.15 (m, 2H,J = 8.0 Hz), 1.80 (m,4H),1.46 (d,3H,J = 7.0 Hz).
N-[l(~)-carboxy-ethyll-~-(S)-(2-pheny!-ethyl)~lycine-~-(S!-n-Qctyl~lycine. N-ehenylamide (5de) o MS: mie 496(M+) - 1H WMR~(CD30D, 200 MHz): ~ 7.56 (dd,2H,J = 7.0,1.0 Hz), 7.33-7.08 (m, 8H),4.52 (dd,1H,J = 8.0,6.0 Hz),3.99 (t,1H,J = 7.0 Hz), 3.60 (q, 1H, J z 7.0 Hz), 2.71 (m, 2H), 2.15 (m, 2H), 1.84 (m, 2H), 1.48 (d, 3H, J = 7.0 Hz), 1.44-1.36 (m, 12H), 1.28 (t, 2H, J = 7.0 ~Hz).
Iq~ Lsacboxybhenyl)amide (5cp) MS: m/e 484 (M+1);506(M+Na);544 (M+K).
1H NMR (CD30D),200MHz): ~ 8.02-7.76 (2d,4H);7.26 (m,5H);4.72 (dd,1H); 4.12 (dd,1H); 3.94 (q,tH); 2.78 (m,2H); 2.22 (m,2H); 1.80 (m,3H); 1.60 (d,3H);1.08 (2p,6H).
N-~l(R)-Carboxv-ethvl]-a-(S!-(2-phenyl-ethyl!alvcine-(L!-25 leucine. N-(4-trif!uoromethylphenyl)amide (5çv) MS: mte 508(M+1);529(M+Na) 1H NMR (CD30D),200MHz): ~ 7.86-7.62 (2d,4H);7.26 (m,5H);4.72 (ddj1H); 4.04 (dd,1H); 3.66 (q,1H); 2.74 (m,2H); 2.22 (m,2H); 1.80 , (m,3H); 1.56 (m,3H); 1.08 (2d,6H).
N'-11 (R)-Carboxy-~thyl]-a-(S)-(2-phenyl-ethyl)~lycine-(L)-l0ucine. N-(3-~yridyl)amide (Scy) MS;n~e 441(M+1);463 (M~Na) SUBSTlTlJTE S~EET
WO 92/21360 PCI'/US92/03X09 ,. -. '; , , 1H NMR (CD30D),200MHz): ~ 8.86 (d~lH); 8.30 (ddl1H); 8.18 ~m,1H);
7.46 (m,1H); 7.26 (m,5H); 4.72 (dd,1H); 4.04 (dd,1H); 3.66 (q,1H);
2.78 (m,2H); 2.22 (m,2H); 1.84 (m,3H); 1.56 (d,3H); 1.08 (2d,6H).
N-[1 (R)-Carboxy-ethvl]-a-(S!-(2-phenvl-ethvl!alvcine-(L!-leucine. N-(benzthiazol-2-yl)amide (5db~
MS: m/e 498 (M+1) 1H NA~R (CD30D),200MHz): ~ 7.90-7.18 (m,9H); 4.84 (dd,1H); 4.10 (dd,1H); 3.70 (q,1H); 2.78 (m,2H); 2.24 (m,2H); 1.84 (m,3H); 1.56 (d,3H); 1.08 (2d,6H).
, 10 Example 4 n-c3H7 , ~ ~ J
- HO2C ~
- I NHJ~ NHPh 2 0 o \rCH3 5bk CH3 - Employing the procedure outlined in Method D, N-25 benzyloxycarbo-ethyl dipeptide lQ was prepared and converted to compound ~bk using methodology described in Example 1 for the preparation of 5a.
, - .
S'J~STfTE JT~ SH~T
WO 92/21360 PCI`/US92/1~3X09 '/ '` '`. ' ~; ' ` , n-c3H7 TFA-NH~ ¢~ CH2C12 ,~
TFA-NH OH
- N-Trifl~ (s)-(2-(4--~propy~ h-en oxoethyl)glycine (6) Aluminum chloride (1.7 gm, 7.5 mmol) was added to an ice c~oled solution of N-trifluoroacetyl-(L)-asp~rtic acid anhydride (1.0 gm, 4.7 mmol) and n-propylbenzene (1.4 mL, 10 mmol) in dry methylene chloride (15 mL) under a dry nitrogen 5 atmosphare. The solution was stirred at room temperature for 5 days and then quenched in a mixture of ice/ 2N HCI / ethyl acetate. The mixture was extracted with ethyl acetate (3 x 50 mL.), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was partitioned between acetonitrile (100 20 :mL) and hexanes (500 mL) The acetonitrile layer was separated, - washed with hexanes (2 x 500 mL), and dried over anhydrous : - sodium sulfate. The solvent. was evaporated in vacuo and the : residue dissolved in ethyl acetate (150 mL). Activated charcoal(10 gm3 was added, the solution filtered through celite filter aid, 25 and evaporated in vacuo. The product was crystallized from ethyl acetate / hexanes (0.67 gm, 43% yield).
1 H NMR (CDCI3, 200 MHz): ~ 7.84 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J =
8.0 Hz), 5.0 (m, 1H, J = 4.0 Hz), 3.92 (ABq/d, 2H, J = 18 Hz, J = 5 Hz), 2.65 (t, 2H, J = 6.0 Hz), 1.65 (m, 2H, J = 8.0 Hz), 0.94 (t, 3H, J
30 6 0 H ) 5~JBSTITUTE SHEET
- . .
:`:
WO 92/21360 PCJ`/US92/03X09 - 65 ~ J
n-C ~H7 n-c3H7 H2, Pd/C
~o -- . J
TFA-NH~ EtOAc, HOAc TFA-NH~
lo N-Trifluoroacetyl-a:-(S)-(2-(4-n-propylphenvl~ethy~ ycine (7?
:
A so lution of N-trif l uoro acety l-a - ( S ) - ( 2 - ( 4 - n -propylphenyl)-2-oxoethyl)glycine 6 (140 mg, 0.43 mmo!) in ethyl acetate (10 mL) containing acetic acid (0.25 m~) and 10%
~`~ 15- palladium on ~carbon (10: mg) was stirred under one atmosphere of hydrogen gas. After two days, the catalyst was filtered off and : fresh ;catalyst was added~and the reaction stirred under hydrogen overnight. The rnixture was filtered and the solvent evaporated in ~-: vacuo to yield the product 7 (127 mg, 93% yield).
20 MS: m/e 318 (M+1), 340 (M+Na) 1 H NMR (CD3OD, 200 MHz): ~ 7.08 ~s, 4H), 4.37 (dd, 1H, J = 4.0 Hz), -: . 2.65 (m, 2H), 2.54 (t, 2H, .1= 7.0 Hz), 2.3-2.0 (br. m, 2H), 1.62 (m, 2H, J = 8.0 Hz), 1.92 ~t, 3H, J = 8.0 Hz) n-c3H7 n-C3H~
~ 30. ~ 2 J~NHPh EDC, HOBt, TFA-NH~ CHa TFA-NH NHJI~NHPh 7 ~ 8 ~--CH3 , ~ ,. . . .
,;, , Sl~sT~TuTE s iEET
WO 92t21360 PCl /US92/03809 ~. ~ . S ', `, N-(Trifiuoroacetyl!-a-(S)-(2-(4-n-propylphenyl!ethyl!glvcine-(L)-leucine._t~-phenyLamide (8!
A solution of N-tri~luoroacetyl-a - ( S ) - ( 2 - (4 - n -propylphenyl)ethyl)glycine 7 ( 127 mg, 0.40 mmol) in methylene chloride (10 mL) was cooled to 0 C under a dry nitrogen atmosphere. N-methyl morpholine (48 ~lL, 0.44 mmol) was added followed by N-hydroxybenztriazole (81 mg, 0.6 mmol). After stirring for 15 minutes, (L)-Leucine, N-phenylamide (108 mg, 0.5 mmol~ was added followed by N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide (EDAC, 115 mg, 0.6 mmol). The solution was stirred overnight at room temperature, diluted with ethyl aGetate (100 mL) and washed with 2N HCI (3 x 20 mL), saturated sodium bicarbonate solution ~2 x 20 mL), and water (20 mL). The solution was dried over anhydrous sodium sulfate and evaporated in vacuo.
The product was purifed by preparative thin layer chromatography on ~ silica gel plates eluted twice with 1.5% methanol in - ~ ~ chloroform, then rechromatographed with 1% methanol in chioroform (122 mg, 61% yield).
1 H NMR (CD30D, 400 MHz): ~ 7.53 (d, 2H, J = 7.7 Hz~, 7.28 (m, 2H), 7.06 (m, 5H), 4.54 (m, 1H), 4.42 ~m, 1H), 2.7-2.6 (m, 2H), 2.52 (t, 2H, J = 6.0 Hz), 2.2-2.0 (br. m, 2H), 1.8-1.6 (br. m, 2H), 1.59 (m, 2H, J = 8.0 Hz), 0.97 (dd, 6H, J = 6.0 Hz), 0.91 (t, 3H, J = 6.4 Hz) 2 5n-C3H7 n-C3H7 ¢~ ~
J NH3,MeOH
O ~ O
TFA-NH' ~NHV~NHPh H NNHJ~NHPh 8 \--CH3 9\--CH3 - : SUBSTITUTE SHEET
WO 92/21360 PCr/US92/03809 '? ' r; .
~-(S!-(2-(4-n-Propylehenyl)ethyl)~!ycin~-(L)-leucine~
N-phenylamide (9~
Ammonia gas was bubbled into methanol (20 mL) at 5 -20 C for 30 minutes then placed in a pressure tube with N-trifluoroacetyl-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide 8 (120 mg, 0.23 mmol), sealed, and stirred at room temperature for 5 days. The tube was cooled to -20~ C before opening~ and then the solvent was evaporated in ~vacuo. The product was purified by; preparative thin layer chromatography on silica gel eluted with 2% methanoi in chloroform ~(95~ mg, 100% yield).
1 H NMR (CD30D,~ 400 MHz)~ ~ 7.55 (d, 2H, J . 8.6 Hz), 7.29 (t, 2H, J
= 8.5 Hz), 7.1-7.0 (m, 5H), 4.56 (m, 1H), 3.4 (t, 1H ~ = 6.0 Hz), 2.61 (t, 2H,~J = 8.0 Hz),~2.51 (t, 2H, J = 7.0 Hz), 2.0-1.6 (br. m, 4H), 1.59 (m, 2H, J = 7.5 Hz), 0.99 (t, 6H, J = 6.0 Hz), 0.90 (t, 3H, J = 7.4 Hz) n-C3H7 n-C3H~
~ PhCH2O~
O Ch3~ OH J
NHJ~ PhCH202C f O
H2N lr NHPh2,6-lUt CH3--NH~ J~NHPh N-[1 (R)-Benzyloxycarbonvl-ethyl]-a-(s)-(2-(4-n-O propylph~ny~)~hy~glyine-(L)-leucine. N-phenyl~mide (1 !
: To a solution of benzyl (L)-lactate (39 mg, 0.21 mmol) in ~methylene chloride ;(2; ml~ a~;0 C under a dry nitrogen ~- atmosph~re ~was:~ added- 2,6^!utidine :;(28 ~lL, 0.24 mmol) followed by ~tri11ic ~anh~ydride i~(39~ ~L, ~0.23 mmol). After stirring for 10 SUBSTITUTE SHE~T
, ~, : - :
: ~ :
. -, , minutes at 0 C, a solution of diisopropylethylamine (41 IlL, 0.24 mmol) and a-(S)-~2-(4-n-propylphenyl)ethyl)glycine-(L)-Leucine, N-Phenylamide 9 (95 mg, 0.24 mmol) in methylene chloride (1 mL) was added. The solution was stirred at room temperature overnight, diluted with methylene chloride (20 mL), and washed 5 successively with water (2 x 5 mL), saturated sodium bicarbonate (2 x 5 mL), and saturated salt solution (5 mL). The solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The product was purified by HPLC on silica gel eluted with 2% acetone in methylene chloride (103 mg, 85% yield).
n-C3H7 n-c3H7 ¢1 ¢~
'hCH202C ~ O H2, Pd/C HO2C ~
CH--NH~NHJ~ NHPh CH--NH~NHJ~
O ~ O ~
r~CH3 rCH3 10 CH3 5bk CH3 N~ Rl-Carbcxyethvl~-a-(S~-(2-(4-n-propylphenvl!ethyl!glvcine-(L)-!eucine. N-~h~lamide (5bk!
A solution of N-[1 (R)-benzyloxycarbonylethyl]-a-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide 10 (103 mg, 0.18 mmol) in ethyl acetate (t 0 mL) containing Pearlman's catalyst (15 mg) was stirred under 1 atmosphere of I hydrogen gas overnight. The mixture was filtered and the solvent eYaporated in vacuo to give 5bk (70 mg, 82% yield):
MS: m/e 483 (M+1) 1H NMR (CD30D, 200 MHz):~ ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37-7.28 (m, 3H), 7.09-7.05 (m, 4H), 5.15 ~dd, 1H, J = 7.0, 2.0 Hz), 4.67 (t, 1H, J
6.~0 Hz), 4.00 (t, 1H, J = 6.0 Hz), 3.75 (m, lH), 2.68 (br. m, 2H), SUBS~ITuTE SHEET
- 69 - ;.;;~ -2.51 (t, ~H, J = 7.0 Hz), 2.12 (m, 2H), 1.80-1.58 (m, 6H), 1.51 (d, 3H, J = 7.0 Hz), 1.31 (br. m, 4H), 1.01 (dd, 6H, J = 6.0 Hz), 0.90 tt, 3H, J = 7.0 Hz).
The following additional compounds were prepared 5 according to the method of Example 4.
~N-(l (R)-Carboxy-ethyl)-a-(S!-[2-(4-eropylehenyl!ethyl]]glycine-~ ar~ jne. N-phenylamide (5bv) MS: m/e 525 (M+1) lO 1H NMR (CD30D, 400 MHz): ~ 7.57 (d, 2H, J = 8 Hz), 7.25 (t, 2H, J =
~8 Hz), 7.11-7~01 (m, 5H), 4.52 ~dd, 1H, J = 8.5, 4.5 Hz), 3.27-3.18 (m, ~3H), 3.15 (q, lH, J = 7 Hz), 2.63 (t, 2H, J = 7.5 Hz), 2.51 (t, 2H, J =:7 Hz3, 2~02-1~80 (m, 4H), 1~78-1~66 (m, 2H), 159 (hextet, 2H, J
= 7 Hz), 1.27 (d, 3 H, J = 7 Hz), 0.90 (t, 3H, J = 7 Hz).
Example 5 J
HO2C~ 1~ O
CH3--NH~NHJ` NHPh O ~
~CH3 5~q CH3 Employing the procedure outlined in Method E, 30 dipeptide 14 was prepared and converted to compound 5bq using methodology described in Example 4 for the preparation of 5bk.
SUBSTITUTE SHEET
WO 92/21360 PCI /US92tO3809 ~,CH3 CH3~ Cbz-NH~OCH3 )2CuCNLi2 Cbz-NH OCH3 ., ~
N-Benzyloxycarbony~ c-(S)-(2-(3.4-dimethyiphenyl)ethyl)~iycine. methvl este~ (1'1 ) A~ solutbn of n-butyl lithium in hexanes (1.6N, 2.5 mL) was~added~to~i~3,4~-dimetll)rliodobenzene (870 mg, 4 mmol) in a 25 mL round ~bottom~ flask th~at had been cooled to -78 C under a dry nitrogen~atmosphere. ~'~The~solution was slowly~ warmed to 40 C
and~ stirred;~for~ hour.- The solution was; cooled to 0 C and slowly tran,sfe~rred `via~ cannula to a dry flas k under dry nitrogen atmosphere~ containing copper(l) cyanide~ (179 ~mg, 2 mmol) in 5 mL THF.~ The mixture was stirred until homogeneous and the solvent evaporated with a stream of nitrogen ~gas. The residue was redissolved in THF and stirred for 1 hour at 0 C to yield a greenish solution.
Approximately half of the THF cuprate solution (~1.4 mmol) was diluted in dry THF (20 mL) and cooled to 0 C. This solution was slowly added via a syringe pump over a period of 1 hour to a solution of N-carbobenzyloxy-a - ( S ) - ~ 2 -iodoet~,yl)lglyci~ne, methy! ester (277 mg, 0.70 mmol) in THF (5 mL). The~solution was ~stirred at room temperature for 5 hours.
The reaction~,was quenched with 10% ammonium chloride solution (5 mL) and extracted with rnethylene chloride (3 x 20 mL). The solution~was dried over anhydrous magnesium sulfate and the solvent and~excess;~iodoxylené evaporated under~ high vacuum. The product'was~purified~by~ flash column chromatography on silica gel~éluted~ h~20% ethyl acetate in hexanes (78 mg, 31% yield).
,," ~ "
~ SUBSTITUTE 5HEET
" .. . .
- 7 1 - ~ . J
1H NMR (CDCI3, 200 MHz): â 7.36 (bs, 5H), 7.05 (d, 1H, J _ 7.0 Hz), 6.08-6.94 (m, 2H,), 536 (d, 1H, J = 8Hz), 5.13 (s, 2H,), 4.05 (bm, 1H, ), 3.73 (s, 3H,), 2.6 (t, 2H, J = 9.0 Hz),.2.23 (s, 6H), 2.15 (m, 1H, J=8 Hz), 1.95 (m, 1H, J=8 Hz), OH- ~CH3 ;; 10 ~ ,~
Cbz-NH~OCH3 Cbz-NH
~ ~ 15~
N-Be~nzyloxvcarbonvl-a-(S!-(2-(3.4-dimethvlphenvl!~thyl!alvcine A solution of N-carbobenzyloxy~ ( S ) - ( 3, 4 -20 dimethylphenethyl)glycine, methyl ester 11 (209 mg, 0.59 mmol), wa~ disolved in 6 mL of methanol and 3 mL of water. The solution was degased and flushed~with nitrogen. One equivalent (24 mg) of LiO`H was added to the solution, the flask sealed and stirred overnight at room temperature. The solution was acidified with 25 1.1 equivalents of acetic acid (39 mg) and the solvent evaporated in vacuo. The residue was washed with water and filtered. The precipitate was dried in vacuo (204 mg, 100% yield). The product was used without further purification.
i , , 30 1H NMR (CD30D, 20`0 MHz): ~ 7.36 (br m, 5H), 7.0-6.8 (m, 3H, J, 7.0 Hz), 5.08 (s, 2H), 5.13 (s, 2H), 4.08 (br m, lH), 2.56 (t, 2H, ~, 9.0 Hz),.2.19 (s, 6H), 2.1;5-1.9 (bm, 2H) ~ "
SU~STITUTE S tEET
~, . , ; , ` .
,~ ~
WO 92/21360 PCr/US92/03809 ~,CH3 ¢~CH3 H2N~NHPh EDC, HOBt, ~ o S ~ \~CH3 ~ ~ - NHPh Cbz-NH ~OH CH3 ~
O 12 13 rCH3 lO N-Ben~zyloxycàrbonyl--(S)-~2-(3 4-dime _-(L)-leucine. N-ph~y~de (13) ` ` A ~ ~ solution of N-Carbobenzyloxy-a - ( S ) - ( 3, 4 -dimethylphenethyl)glycine 12 (207 mg, 0~.55 mmol), (L)-leucine, l5 N-phenylamide ~ 12~5~m~g, 0.61 mmol), N-hydmxybenztriazole (87 mg,~ 0~6 mmol),~and N-methyl morpholine (130 ,uL, 1.1 mmol) in THF~(3~~mL)~was ~stirred at room temperature for 10 minutes.
ED~C~ (158 ~mg;,~0.83 mmol) was added and the solution stirred for 4 ~hours. Methylene chloride (25 mL) was added and the solution 20 ~ washed successively with 2~1 HCI (3 x 5 -mL) ~and saturated sodium bicarbo~nate solution (3 x 5 mL). After ~ drying over anhydrous magne~ium sulfate, the soJvent was evaporated in vacuo and the product purified by flash column chromatography on silica gel eluted with 2% ethyl acetate in methylen~ chloride (148 mg, 53%
25 yield).
lH NMR~(CD3OD, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.42-7.28 (m, 7H), 7.16-6.83 ~m, 4H), 5.15 (S, 2H), 4.60 (t, lH, J = 6.0 Hz), 4.16 ' (t, 1H, Jl= 6.0 Hz), 2.6 (br. m, 2H), 2.2 (S, 6H), 2.2-1.8 (m, 2H), 1.8-30 1.6 (br~m, 2H),1.31 (br m, 1H), 1.01 (s, 6H, J, 6.0 Hz).
SUBSTITUTE SHEET
", .,, ;~
WO 92/21360 PCl/US92/03809 CH~ CH3 ;:
¢~' H2, Pd/C ¢~
~ O ~/bOH
Cb~-NH J~NHPh H N~NHJ`NHPh O ~ O ~ ,.
1 3 1H3CH3 14 ~CH3 - 1~ a-(S)-(2-(3.4-dimethylehenyl!ethyl)Qly~ine-(L)-leUCine._ N-phenylamide (1 4) To a solution of 3 ml of methanol and N-carbobenzyloxy-a-(S)-(3,4-dimethylphenethyl)glycine-(L)-leucine, N-phenylamide 15 (148 mg) was added 10 mg of 10% palladium on carbon in a 10 ml round bottom flask titted with a stirring bar and rubber septum. ;
Ths flask was flushed with hydrogen via syringe attached to a balloon reservoir. Stirring was continued for 1 hr, during which the starting material was converted to product and the reaction 2~ mixture became homogeneousr Filtration through a 2 micron filter removed the palladium catalyst and the methanol solvent - ~ was removed under reduc~ed pressure. The product was recovered (89 mg, 98% yield) and used in the subsequent step without purification.
1 H NMR (CD30D, 200 MHz): ~ 7.56 ~d, 2H, J = 7.7 Hz), 7.42-7.28 (m, 2H), 7.18-7.1 (m, H), 6.8 (S, 3H), 4.63 ~t, lH, J = 6.0 Hz), 3.42 (t, lH, J = 6.0 Hz), 2.6 (t, 2H, J = 6 Hz, ), 2.2 (S, 6H), 2.1-1.8 (m, 2H), 1.8-1.6 (br m, 2H),1.31 (br m, 1H), 1.01 (m, 6H, ).
SU8STITUTE SHE~T' ~, ~
'-? ' " ` ` `
PhcH2o~ ¢~CH3 J Ch3 OH J
O -- PhCH202C ~ O
,~ NHJ~ Tf20 1 NHJ~
2 ~ NHPh 2, 6 - I U t CH3 NH ~ NHPh O
14 ~CH3 15 ~CH3 N-~1 (R)-Benzyloxycarbonvl-ethvl]-a-(S~-(2-(3.4-dimethylehenyl)ethyl~lycine-~L)-leucine. N-phenylamide (15! -~
To a solution of benzyl (L)-lactate (52 mg, 0.28 mmol) 15 in methylene chloride (5 mL) at 0 ~ under a dry nitrogen atmosphere was added 2~,6-lutidine (35 ,uL, 0.30 mmol), stirred for 5~minutes and then followed by triflic anhydride (48 ~LL, 0.28 mmol). After stirring for 10 minutes at 0 C, a solution of diisopropylethylamine (51 ~L, 0.2~ mmol) and a-(S)-(3,4-20 dimethylphenethyl)glycine-(L)-leucine, N-phenylamide 14 (104 mg, 0.26 mmol) in methylene chloride (5 mL) was added. Th~
solution was stirred at room tsmperature overnight, diluted with methylene chloride (20 mL), and washsd suceessively with water (2 x 5 mL), saturated sodium bicarbonate ~2 x 5 mL). The solution 25 was dried over anhydrous sodium sulfate and evaporated in vacuo.
The product was purified by HPLC on silica gel eluted with 3%
ethyl acetate in methylene chloride (47 mg, 32% yield).
1H NMR ~CD3OD, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37-7.28 (m, 30 7H), 7.15-7.1 (d, 4H, J = 7.0), 7.0-6.85 (ml3H), 5.13 ~s, 2H), 4.6 (bs, 1H), 3.45 (t, 1H, J = 6.0 Hz), 2.6 (t., 2H, J,6 Hz), 2.2 (s, 6H), 1.95-1.6 (m, 6H), 1.3 (d, 3H, J,7 Hz), 0.98 (m, 6H).
; : SUBSTITUTE SHEET
WO 92/21360 PCl/US92/03B09 ~`
H~, Pearlman's ¢~CH3 J catalyst J
hCH202C ~ O _ ,, HO2C f o CH3--NH~ J~NHPh 3 ~ _ NHPh O ~
CH3 5bq ~CH3 N-[1 (R)-Carboxy-ethyll-a-(S)-(2-(3.4- - ~:
dimethylphenyl)e~hyl)~ly~ine-rL)-l~ucine. N-phenyiamide (5bq) :-`
To ~ a solution of 47 mg of aminoester in 1 mL of methanol was added:2:mg of Pearlman's catalyst. After 3 hours of vigorous stirring under an atmosphere of hydrogen, the mixture was filtered through 2 micron nylon filter pack and concentrated in vacuo to give 41 9 of 5bq as a colorless solid~
1 H NMR (CD30D, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37 7.28 (m, 2H), 7.15-7.1 (d, 1H, J = 7~0), 7.0-6.85 (m,3H), 4.7 (bs, lH), 4.0 (bm, 1H), 3.60 (t, 1H, J = 6.0 Hz), 2.6 (t., 2H, J=6 Hz), 2.2 (s, 6H), 2.2-2.0 (m, 4H), 1.75 ~m, 5H), 1.3 (d, 3H, J=7 Hz), 0.98 (m, 6H).
i ~; SU8STITUTE SHEIET
To a solution of benzyl (L)-lactate (52 mg, 0.28 mmol) 15 in methylene chloride (5 mL) at 0 ~ under a dry nitrogen atmosphere was added 2~,6-lutidine (35 ,uL, 0.30 mmol), stirred for 5~minutes and then followed by triflic anhydride (48 ~LL, 0.28 mmol). After stirring for 10 minutes at 0 C, a solution of diisopropylethylamine (51 ~L, 0.2~ mmol) and a-(S)-(3,4-20 dimethylphenethyl)glycine-(L)-leucine, N-phenylamide 14 (104 mg, 0.26 mmol) in methylene chloride (5 mL) was added. Th~
solution was stirred at room tsmperature overnight, diluted with methylene chloride (20 mL), and washsd suceessively with water (2 x 5 mL), saturated sodium bicarbonate ~2 x 5 mL). The solution 25 was dried over anhydrous sodium sulfate and evaporated in vacuo.
The product was purified by HPLC on silica gel eluted with 3%
ethyl acetate in methylene chloride (47 mg, 32% yield).
1H NMR ~CD3OD, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37-7.28 (m, 30 7H), 7.15-7.1 (d, 4H, J = 7.0), 7.0-6.85 (ml3H), 5.13 ~s, 2H), 4.6 (bs, 1H), 3.45 (t, 1H, J = 6.0 Hz), 2.6 (t., 2H, J,6 Hz), 2.2 (s, 6H), 1.95-1.6 (m, 6H), 1.3 (d, 3H, J,7 Hz), 0.98 (m, 6H).
; : SUBSTITUTE SHEET
WO 92/21360 PCl/US92/03B09 ~`
H~, Pearlman's ¢~CH3 J catalyst J
hCH202C ~ O _ ,, HO2C f o CH3--NH~ J~NHPh 3 ~ _ NHPh O ~
CH3 5bq ~CH3 N-[1 (R)-Carboxy-ethyll-a-(S)-(2-(3.4- - ~:
dimethylphenyl)e~hyl)~ly~ine-rL)-l~ucine. N-phenyiamide (5bq) :-`
To ~ a solution of 47 mg of aminoester in 1 mL of methanol was added:2:mg of Pearlman's catalyst. After 3 hours of vigorous stirring under an atmosphere of hydrogen, the mixture was filtered through 2 micron nylon filter pack and concentrated in vacuo to give 41 9 of 5bq as a colorless solid~
1 H NMR (CD30D, 200 MHz): ~ 7.56 (d, 2H, J = 7.7 Hz), 7.37 7.28 (m, 2H), 7.15-7.1 (d, 1H, J = 7~0), 7.0-6.85 (m,3H), 4.7 (bs, lH), 4.0 (bm, 1H), 3.60 (t, 1H, J = 6.0 Hz), 2.6 (t., 2H, J=6 Hz), 2.2 (s, 6H), 2.2-2.0 (m, 4H), 1.75 ~m, 5H), 1.3 (d, 3H, J=7 Hz), 0.98 (m, 6H).
i ~; SU8STITUTE SHEIET
Claims (18)
1. A compound of formula I
I
or a pharmaceutically acceptable salt thereof wherein:
R1 is substituted C1-6 alkyl, wherein the substituent is selected from the group consisting of:
(a) hydrogen, (b) carboxy, O
(c) CNH2, (d) C6-10 aryl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) pyridyl, (4) furyl, (5) pyrryl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, (21) purinyl, (22) carbazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, (26) benzthiazolyl, and (27) benzoxazolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, amino, C1-6alkylamino, aminoC1-6alkyl, carboxyl, carboxylC1-6alkyl, and C1-6alkylcarbonyl;
(e) Rb wherein Ra and Rb are each independently hydrogen; C6-10aryl and mono and di-substituted C6-10aryl as defined above (d); or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
(f) , wherein Ra and Rb are each independently hydrogen; C6-10aryl and mono and di-substituted C6-10aryl as defined above (d); or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactim or benzolactim ring wherein the lactim portion thereof is a ring of up to 8 atoms, said lactim or benzolactim have a single hetero atom;
(g) amino and substituted amino wherein the substituent is selected from C1-6 alkyl and C6-10 aryl where aryl is defined in (d);
R2 is CHRcRd wherein Rc is (a) H, (b) C1-3alkyl, or (c) hydroxyl;
Rd is C6-10arylC1-2alkyl or C6-10aryl substituted C1-2alkyl wherein the substituent is C1-3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of:
(1) phenyl, (2) naphthyl, (3) pyridyl, (4) pyrryl, (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyi, (21) purinyl, (22) carboxazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, (26) benzthiazolyl, and (27) benzoxazolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, amino, C1-6alkylamino, aminoC1-6alkyl, carboxyl, carboxylC1-6alkyl, and C1-6alkylcarbonyl;
R3 is (a) H, (b) C 1-10alkyl, (c) C6-10aryl or C6-10aryl C1-3alkyl, wherein the aryl group is selected from the group consisting of (1) phenyl, and (2) substituted phenyl, wherein the substitutent is carboxy, carboxyC1-3alkyl, aminocarbonyl, C1-6alkylaminocarbonyl;
AA is an amino acid of formula II
II
wherein Re and Rf are individually selected from:
(a) hydrogen, (b) C1-6alkyl, (c) mercapto C1-6alkyl, (d) hydroxy C1-6alkyl, (e) carboxy C1-6alkyl, (f) amino substituted C1-6alkyl (g) aminocarbonyl C1-6alkyl, (h) mono- or di-C1-6alkyl amino C1-6alkyl, (i) guanidino C1-6alkyl, (j) substituted phenyl C1-6alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (k) substituted indolyl C1-6 alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (l) substituted imidazolyl C2-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (m) substituted pyridyl C1-6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (n) substituted pyridylamino C1-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, X is R5 - N - R6 wherein R5 and R6 are each individually selected from the group consisting of:
(a) H, (b) C1-10alkyl, (c) C6-10aryl or C6-10arylC1-6alkyl, wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) pyridyl, (4) pyrryl, (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, (21) purinyl, (22) carbazolyl, (23) isoxazolyl, (24) benzthiazolyl, (25) benzoxazolyl, (26) thiazolyl, and (27) oxazolyl.
I
or a pharmaceutically acceptable salt thereof wherein:
R1 is substituted C1-6 alkyl, wherein the substituent is selected from the group consisting of:
(a) hydrogen, (b) carboxy, O
(c) CNH2, (d) C6-10 aryl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) pyridyl, (4) furyl, (5) pyrryl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, (21) purinyl, (22) carbazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, (26) benzthiazolyl, and (27) benzoxazolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, amino, C1-6alkylamino, aminoC1-6alkyl, carboxyl, carboxylC1-6alkyl, and C1-6alkylcarbonyl;
(e) Rb wherein Ra and Rb are each independently hydrogen; C6-10aryl and mono and di-substituted C6-10aryl as defined above (d); or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
(f) , wherein Ra and Rb are each independently hydrogen; C6-10aryl and mono and di-substituted C6-10aryl as defined above (d); or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactim or benzolactim ring wherein the lactim portion thereof is a ring of up to 8 atoms, said lactim or benzolactim have a single hetero atom;
(g) amino and substituted amino wherein the substituent is selected from C1-6 alkyl and C6-10 aryl where aryl is defined in (d);
R2 is CHRcRd wherein Rc is (a) H, (b) C1-3alkyl, or (c) hydroxyl;
Rd is C6-10arylC1-2alkyl or C6-10aryl substituted C1-2alkyl wherein the substituent is C1-3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of:
(1) phenyl, (2) naphthyl, (3) pyridyl, (4) pyrryl, (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyi, (21) purinyl, (22) carboxazolyl, (23) isoxazolyl, (24) thiazolyl, (25) oxazolyl, (26) benzthiazolyl, and (27) benzoxazolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, amino, C1-6alkylamino, aminoC1-6alkyl, carboxyl, carboxylC1-6alkyl, and C1-6alkylcarbonyl;
R3 is (a) H, (b) C 1-10alkyl, (c) C6-10aryl or C6-10aryl C1-3alkyl, wherein the aryl group is selected from the group consisting of (1) phenyl, and (2) substituted phenyl, wherein the substitutent is carboxy, carboxyC1-3alkyl, aminocarbonyl, C1-6alkylaminocarbonyl;
AA is an amino acid of formula II
II
wherein Re and Rf are individually selected from:
(a) hydrogen, (b) C1-6alkyl, (c) mercapto C1-6alkyl, (d) hydroxy C1-6alkyl, (e) carboxy C1-6alkyl, (f) amino substituted C1-6alkyl (g) aminocarbonyl C1-6alkyl, (h) mono- or di-C1-6alkyl amino C1-6alkyl, (i) guanidino C1-6alkyl, (j) substituted phenyl C1-6alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (k) substituted indolyl C1-6 alkyl, wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (l) substituted imidazolyl C2-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (m) substituted pyridyl C1-6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, (n) substituted pyridylamino C1-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy, X is R5 - N - R6 wherein R5 and R6 are each individually selected from the group consisting of:
(a) H, (b) C1-10alkyl, (c) C6-10aryl or C6-10arylC1-6alkyl, wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) pyridyl, (4) pyrryl, (5) furyl, (6) thienyl, (7) isothiazolyl, (8) imidazolyl, (9) benzimidazolyl, (10) tetrazolyl, (11) pyrazinyl, (12) pyrimidyl, (13) quinolyl, (14) isoquinolyl, (15) benzofuryl, (16) isobenzofuryl, (17) benzothienyl, (18) pyrazolyl, (19) indolyl, (20) isoindolyl, (21) purinyl, (22) carbazolyl, (23) isoxazolyl, (24) benzthiazolyl, (25) benzoxazolyl, (26) thiazolyl, and (27) oxazolyl.
2. A compound according to Claim 1 wherein R1 is substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(a) hydrogen, (b) carboxy, (c) -?-NH2, (d) C6-10aryl or C6-10aryl C1-6alkyl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrirnidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (9) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, and C1-6alkylcarbonyl;
(e) - N-?-Ra Rb wherein Ra and Rb are each independently is hydrogen, C6-10 aryl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10 aryl as defined above; or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and benzyl; or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
(a) hydrogen, (b) carboxy, (c) -?-NH2, (d) C6-10aryl or C6-10aryl C1-6alkyl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrirnidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (9) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, and C1-6alkylcarbonyl;
(e) - N-?-Ra Rb wherein Ra and Rb are each independently is hydrogen, C6-10 aryl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10 aryl as defined above; or substituted C1-6alkyl wherein the substitutent is selected from hydroxy, halo, and benzyl; or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
3. A compound according to Claim 2 wherein R2 is CHRcRd wherein Rc is (a) H, (b) C1-3alkyl, or (c) hydroxyl;
Rd is C6-10aryl C1-2alkyl or C6-10aryl substituted C1-2 alkyl, wherein the substituent is C1-3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (9) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, and C1-6alkylcarbonyl.
Rd is C6-10aryl C1-2alkyl or C6-10aryl substituted C1-2 alkyl, wherein the substituent is C1-3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and mono and di-substituted C6-10aryl as defined above in items (1) to (9) wherein the substitutents are independently selected from C1-6alkyl, C1-6alkyloxy, halo, hydroxy, and C1-6alkylcarbonyl.
4. A compound according to Claim 3 wherein R3 is (a) H, (b) C1-10alkyl, (c) phenyl, substituted phenyl, wherein the substitutent is carboxy, carboxy C1-3alkyl, amino carbonyl.
5. A compound according to Claim 4 wherein AA is an amino acid selected from glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxy-lysine, homohistidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, homoserine, and citrulline.
6. A compound according to Claim 4 wherein AA is .
wherein Re and Rf are independently selected from:
(a) hydrogen;
(b) C1-4alkyl;
(c) mercapto C1-3alkyl;
(d) hydroxy C1-4alkyl, (e) carboxy C1-4alkyl;
(f) amino C1-4alkyl;
(g) aminocarbonyl C1-4alkyl;
(h) mono - or di-C1-6alkyl amino C1-4alkyl;
(i) guanidino C1-4alkyl;
(j) substituted phenyl C1-4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1-3 alkyl;
(k) substituted indolyl C1-4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1-3 alkyl;
(l) substituted imidazolyl C2-6alkyl wherein the substituent is hydrogen, hydroxy, carboxy, or C1-4 alkyl;
(m) substituted pyridyl C1-6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy; and (n) substituted pyridylamino C1-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy.
wherein Re and Rf are independently selected from:
(a) hydrogen;
(b) C1-4alkyl;
(c) mercapto C1-3alkyl;
(d) hydroxy C1-4alkyl, (e) carboxy C1-4alkyl;
(f) amino C1-4alkyl;
(g) aminocarbonyl C1-4alkyl;
(h) mono - or di-C1-6alkyl amino C1-4alkyl;
(i) guanidino C1-4alkyl;
(j) substituted phenyl C1-4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1-3 alkyl;
(k) substituted indolyl C1-4 alkyl, wherein the substituent is hydrogen, hydroxy, carboxy, or C1-3 alkyl;
(l) substituted imidazolyl C2-6alkyl wherein the substituent is hydrogen, hydroxy, carboxy, or C1-4 alkyl;
(m) substituted pyridyl C1-6 alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy; and (n) substituted pyridylamino C1-6alkyl wherein the substitutent is hydrogen, hydroxy, carboxy, C1-4 alkyl, or C1-4alkyloxy.
7. A compound according to Claim 6 wherein X is - N - R6 wherein R5 and R6 are each individually selected from the group consisting of (a) H, (b) C1-10alkyl, or (c) C6-10aryl, or C6-10arylC1-6alkyl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) thienyl, (4) imidazolyl, (5) benzimidazolyl, (6) pyrimidyl, (7) benzofuryl, (8) benzothienyl, (9) indolyl, and (10) pyridyl.
8. A compound according to Claim 7 wherein, Rd is C1-4alkylC6-10arylC1-2alkyl; and R3 is (a) H, or (b) C1-10alkyl; and
9. A compound according to Claim 8 wherein, R1 is C6-10aryl C1-6alkyl; and Rb is H.
10. A compound of formula I according to Claim 9 which is:
(a) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(b) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-isoleucine, N-phenylamide;
(c) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, N-phenylamide;
(d) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;
(e) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-benzyl ether, N-phenylamide;
(f) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide;
(g) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(2-phenyl-ethyl)glycine, N-phenylamide;
(h) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine, N-phenylamide;
(i) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-valine, N-phenylamide;
(j) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-serine, N-phenylamide Hydrochloride;
(k) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-asparagine, N-phenylamide;
(l) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide hydrochloride;
(m) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, N-phenylamide;
(n) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid, N-phenylamide ;
(o) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride;
(p) N-[1(R)-Carboxy-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(q) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(r) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(S)-arginine, N-phenylamide;
(s) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(t) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-methylphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(u) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(2'-thienyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(v) N-(1(R)-Carboxy-ethyl)-.alpha.-(S)-(2-(4-ethylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(w) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(x) N-(1(R)-Carboxy-ethyl)-.alpha.-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(y) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(2-cyclohexyl-ethyl)glycine, N-phenylamide;
(z) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(cyclohexyl)glycine, N-phenylamide;
(aa) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(cyclohexylmethyl)glycine, N-phenylamide;
(ab) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-.beta.-naphthylalanine, N-phenylamide;
(ac) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-.alpha.-naphthylalanine, N-phenylamide;
(ad) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, .alpha.,.delta.-bis- N-phenylamide];
(ae) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-cyclohexylamide;
(ae) N-[(1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-(4-hydroxyphenyl-ethyl)glycine, N-phenylamide;
(af) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide;
(ag) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, N.delta.-benzylamide, N.alpha.-phenylamide];
(ah) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-Ornithine, N-phenylamide;
(ai) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-arginine, N-phenylamide;
(aj) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-(3-phenylpropyl)glycine, N-phenylamide;
(ak) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-n-octylglycine, N-phenylamide;
(al) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4- N-(4-carboxyphenyl)amide ;
(am) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4- N-(~-trifluoromethylphenyl)amide;
(an) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide;
(ao) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl) amide;
(ap) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(aq) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-arginine, N-phenylamide;
(ar) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(3,4-dimethylphenyl-ethyl))glycine-(L)-leucine, N-phenylamide.
(a) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(b) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-isoleucine, N-phenylamide;
(c) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-alanine, N-phenylamide;
(d) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-phenylalanine, N-phenylamide;
(e) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-serine-O-benzyl ether, N-phenylamide;
(f) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-tryptophan, N-phenylamide;
(g) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(2-phenyl-ethyl)glycine, N-phenylamide;
(h) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-norleucine, N-phenylamide;
(i) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-valine, N-phenylamide;
(j) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-serine, N-phenylamide Hydrochloride;
(k) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-asparagine, N-phenylamide;
(l) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-threonine, N-phenylamide hydrochloride;
(m) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-lysine, N-phenylamide;
(n) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-glutamic acid, N-phenylamide ;
(o) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-tyrosine, N-phenylamide hydrochloride;
(p) N-[1(R)-Carboxy-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-phenylamide;
(q) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(r) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(S)-arginine, N-phenylamide;
(s) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(3-hydroxyphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(t) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-methylphenyl)-ethyl)glycine-(S)-leucine, N-phenylamide hydrochloride;
(u) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(2'-thienyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(v) N-(1(R)-Carboxy-ethyl)-.alpha.-(S)-(2-(4-ethylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(w) N-[1(R)-Carboxy-5-(1-oxo-isoindolin-2-yl)pentyl]-.alpha.-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(x) N-(1(R)-Carboxy-ethyl)-.alpha.-(S)-(2-(4-chlorophenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(y) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(2-cyclohexyl-ethyl)glycine, N-phenylamide;
(z) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(cyclohexyl)glycine, N-phenylamide;
(aa) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)]glycine-.alpha.-(S)-(cyclohexylmethyl)glycine, N-phenylamide;
(ab) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-.beta.-naphthylalanine, N-phenylamide;
(ac) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-.alpha.-naphthylalanine, N-phenylamide;
(ad) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, .alpha.,.delta.-bis- N-phenylamide];
(ae) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-cyclohexylamide;
(ae) N-[(1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-(4-hydroxyphenyl-ethyl)glycine, N-phenylamide;
(af) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-phenylglycine, N-phenylamide;
(ag) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-[(L)-glutamic acid, N.delta.-benzylamide, N.alpha.-phenylamide];
(ah) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-Ornithine, N-phenylamide;
(ai) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-arginine, N-phenylamide;
(aj) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-(3-phenylpropyl)glycine, N-phenylamide;
(ak) N-[1(R)-Carboxy-ethyl)]-.alpha.-(S)-(2-phenyl-ethyl)glycine-.alpha.-(S)-n-octylglycine, N-phenylamide;
(al) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4- N-(4-carboxyphenyl)amide ;
(am) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(4- N-(~-trifluoromethylphenyl)amide;
(an) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(3-pyridyl)amide;
(ao) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-phenyl-ethyl)glycine-(L)-leucine, N-(benzothiazol-2-yl) amide;
(ap) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-n-propylphenyl)ethyl)glycine-(L)-leucine, N-phenylamide;
(aq) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(4-propylphenyl)ethyl)glycine-(L)-arginine, N-phenylamide;
(ar) N-[1(R)-Carboxy-ethyl]-.alpha.-(S)-(2-(3,4-dimethylphenyl-ethyl))glycine-(L)-leucine, N-phenylamide.
11. A pharmaceutical composition for treating a matrix metalloendoproteinase-mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of compound of formula I according to Claim 1.
12. A pharmaceutical composition for treating a matrix metalloendoproteinase-mediated disease comprising a pharmaceutical carrier and a non-toxic effective amount of compound of formula I according to Claim 10.
13. A pharmaceutical composition for treating degenerative disease comprising a pharmaceutical carrier and a non-toxic effective amount of compound of formula I according to Claim 1.
14. A pharmaceutical composition for treating degenerative disease comprising a pharmaceutical carrier and a non-toxic effective amount of compound of formula I according to Claim 10.
15. A method of treating matrix metalloendoproteinase-mediated disease comprising the administration to a subject in need of such a therapeutically effective amount of a compound of formula I according to Claim 1.
16. A method of treating matrix metalloendoproteinase-mediated disease comprising the administration to a subject in need of such a therapeutically effective amount of a compound of formula I according to Claim 10.
17. A method of treating degenerative disease comprising the administration to a subject in need of such a therapeutically effective amount of a compound of formula I
according to Claim 1.
according to Claim 1.
18. A method of treating degenerative disease comprising the administration to a subject in need of such a therapeutically effective amount of a compound of formula according to Claim 10.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US70582691A | 1991-05-28 | 1991-05-28 | |
| US705,826 | 1991-05-28 | ||
| US87390592A | 1992-04-24 | 1992-04-24 | |
| US873,905 | 1992-04-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2102890A1 true CA2102890A1 (en) | 1992-11-29 |
Family
ID=27107579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002102890A Abandoned CA2102890A1 (en) | 1991-05-28 | 1992-05-01 | Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0586537A4 (en) |
| JP (1) | JPH06508135A (en) |
| CA (1) | CA2102890A1 (en) |
| WO (1) | WO1992021360A1 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5326760A (en) * | 1992-06-29 | 1994-07-05 | Glaxo, Inc. | Aminobutanoic acid compounds having metalloprotease inhibiting properties |
| US5773428A (en) * | 1993-08-05 | 1998-06-30 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
| US6013792A (en) * | 1993-08-05 | 2000-01-11 | Syntex (U.S.A.), Inc. | Matrix metalloprotease inhibitors |
| HU222818B1 (en) * | 1993-08-05 | 2003-11-28 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitor indole derivatives, preparation thereof and pharmaceutical compositions containing these compounds |
| US5470834A (en) * | 1993-10-06 | 1995-11-28 | Florida State University | Sulfoximine and suldodiimine matrix metalloproteinase inhibitors |
| US5455262A (en) * | 1993-10-06 | 1995-10-03 | Florida State University | Mercaptosulfide metalloproteinase inhibitors |
| US5403952A (en) * | 1993-10-08 | 1995-04-04 | Merck & Co., Inc. | Substituted cyclic derivatives as novel antidegenerative agents |
| US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
| DE69502378T2 (en) * | 1994-01-20 | 1998-10-01 | British Biotech Pharm | METALOPROTEINAS INHIBITORS |
| AU2361295A (en) * | 1994-04-28 | 1995-11-29 | Merck & Co., Inc. | N-carboxyalkyl derivatives as antidegenerative active agents |
| US5919940A (en) * | 1995-01-20 | 1999-07-06 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| WO1996033733A1 (en) * | 1995-04-25 | 1996-10-31 | Fuji Yakuhin Kogyo Kabushiki Kaisha | Novel remedy for skin deficiencies |
| US6281352B1 (en) | 1995-11-14 | 2001-08-28 | Dupont Pharmaceuticals Company | Macrocyclic compounds as metalloprotease inhibitors |
| PT874830E (en) * | 1995-12-08 | 2003-06-30 | Agouron Pharma | METHYLOPROTEINAS INHIBITOR PHARMACEUTICAL COMPOSITION CONTAINING THIS INHIBITOR AND THE PHARMACEUTICAL UTILIZATION AND USEFUL METHOD FOR THEIR PREPARATION |
| US6500948B1 (en) | 1995-12-08 | 2002-12-31 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof |
| ATE225343T1 (en) * | 1995-12-20 | 2002-10-15 | Hoffmann La Roche | MATRIX METALLOPROTEASE INHIBITORS |
| ATE220660T1 (en) | 1996-09-10 | 2002-08-15 | British Biotech Pharm | CYTOSTATIC HYDROXAMIC ACID DERIVATIVES |
| US6462023B1 (en) | 1996-09-10 | 2002-10-08 | British Biotech Pharmaceuticals, Ltd. | Cytostatic agents |
| US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| US6008243A (en) * | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| US5985900A (en) * | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| HRP980443A2 (en) | 1997-08-18 | 1999-10-31 | Carl P. Decicco | Novel inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis |
| AU2001250571A1 (en) * | 2000-04-28 | 2001-11-12 | P.N. Gerolymatos S.A. | Treatment of pathological conditions influenced by the action of matrix metalloproteinases (mmps) using clioquinol |
| AU2003233154A1 (en) | 2002-06-10 | 2003-12-22 | Pfizer Inc. | Metabolites of prinomastat and their sythesis |
| OA12937A (en) * | 2002-10-09 | 2006-10-13 | Pfizer Prod Inc | Thiazole compounds for the treatment of neurodegenerative disorders. |
| EP1636220A1 (en) * | 2003-05-12 | 2006-03-22 | Pfizer Products Inc. | Isoxazole and isothiazole compounds for the treatment of neurodegenerative disorders |
| WO2004101523A1 (en) | 2003-05-17 | 2004-11-25 | Korea Research Institute Of Bioscience And Biotechnology | Novel 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same |
| WO2006117660A2 (en) * | 2005-05-04 | 2006-11-09 | Clio Pharmaceutical Corporation | Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8311286D0 (en) * | 1983-04-26 | 1983-06-02 | Searle & Co | Carboxyalkyl peptide derivatives |
| US4568666A (en) * | 1984-10-18 | 1986-02-04 | G. D. Searle & Co. | Carboxylalkyl peptide derivatives |
| US4771037A (en) * | 1986-01-21 | 1988-09-13 | Ici Americas Inc. | N-carboxyalkyl compounds |
-
1992
- 1992-05-01 JP JP5500416A patent/JPH06508135A/en not_active Withdrawn
- 1992-05-01 EP EP92912475A patent/EP0586537A4/en not_active Withdrawn
- 1992-05-01 WO PCT/US1992/003809 patent/WO1992021360A1/en not_active Application Discontinuation
- 1992-05-01 CA CA002102890A patent/CA2102890A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06508135A (en) | 1994-09-14 |
| EP0586537A4 (en) | 1997-06-25 |
| EP0586537A1 (en) | 1994-03-16 |
| WO1992021360A1 (en) | 1992-12-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2102890A1 (en) | Substituted n-carboxyalkylpeptidyl derivatives as antidegenerative active agents | |
| RU2170232C2 (en) | Phosphinic acid amides and method of prophylaxis or treatment of patients associated with unfavorable metalloprotease activity | |
| US5387610A (en) | Peptide derivatives of collagenase inhibitor | |
| FI84472C (en) | FOERFARANDE FOER FRAMSTAELLNING AV KOLLAGENASINHIBITORER PAO BASIS AV HYDROXIAMINOSYRA. | |
| KR100352316B1 (en) | Sulfonylamino substituted hydroxamic acid derivatives as metalloprotease inhibitors | |
| US5672583A (en) | Carboxy-peptidyl derivatives as antidegenerative active agents | |
| US5679700A (en) | Substituted phosphinic acid-containing peptidyl derivatives as antidegenerative agents | |
| SK63194A3 (en) | Peptide derivatives | |
| FR2609289A1 (en) | NOVEL COMPOUNDS WITH ACTIVITY OF COLLAGENASE INHIBITORS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME | |
| CZ287780B6 (en) | Peptide derivatives, their use and pharmaceutical preparation in which they are comprised | |
| JPH10512241A (en) | Hydroxamic acid-containing inhibitors of matrix metalloproteases | |
| US5508266A (en) | Gem-disubstituted amino acid derivatives | |
| JP3647914B2 (en) | Cyclic amino acid derivatives | |
| US5506244A (en) | Cyclic amino acid derivatives | |
| US5403952A (en) | Substituted cyclic derivatives as novel antidegenerative agents | |
| US5629343A (en) | N-(mercaptoacyl) peptidyl derivatives as antidegenerative agents | |
| US6090785A (en) | Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative agents | |
| US5932551A (en) | Substituted N-carboxyalkylpeptidyl derivatives as antidegenerative active agents | |
| EP0159396B1 (en) | Carboxyalkyl peptide derivatives | |
| WO1995029689A1 (en) | N-carboxyalkyl derivatives as antidegenerative active agents | |
| IE65539B1 (en) | Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of using same | |
| CA2196182A1 (en) | Aldehyde derivatives as upsteine protease inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |