AU2357600A - 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesionmediated by vla-4 - Google Patents

3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesionmediated by vla-4 Download PDF

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AU2357600A
AU2357600A AU23576/00A AU2357600A AU2357600A AU 2357600 A AU2357600 A AU 2357600A AU 23576/00 A AU23576/00 A AU 23576/00A AU 2357600 A AU2357600 A AU 2357600A AU 2357600 A AU2357600 A AU 2357600A
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dioxo
compound
cyclobut
amino
pharmaceutical salt
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Louis John Lombardo
Joan E. Sabalski
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Wyeth LLC
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American Home Products Corp
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Description

WO 00/35855 PCTIUS99/29369
-I
3,4-DIAMINO-3-CYCLOBUTENE-1,2-DIONE DERIVATIVES WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4 5 Field of the Invention This invention relates to novel N-substituted 3,4-diamino-3-cyclobutene-1,2 dione derivatives which inhibit leukocyte adhesion mediated by interaction of the a 1 integrin (VLA-4) with its counterreceptor VCAM-1, and their use for the treatment of inflammatory and autoimmune diseases. 10 Background of the Invention VLA-4 (also referred to as A., integrin and CD49d/CD29), first identified by Hemler and Takada (Hemler and Takada, European Patent Application, Publication No. 330, 506, published August 30, 1989) is a member of the p, integrin family of 15 cell surface receptors, each of which comprises two subunits, an a 4 chain and a p, chain. There are at least nine p, integrins, all sharing the same [3, chain and each having a distinct a chain. These nine receptors all bind a different complement of the various cell matrix molecules such as fibronectin, laminin and collagen. VLA-4, for example, binds to fibronectin. VLA-4 is unique among p, integrins in that it also 20 binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for fibronectin and VCAM-1 I binding activities and each activity has been shown to be inhibited independently (Elices, et al., Cell, 60:577-584 (1990)). 25 Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells 30 involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release WO 00/35855 PCT/US99/29369 - 2 chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer (Springer, Nature, 346:425-434 (1990)) and Osborn (Osborn, Cell, 62:3-6 (1990)). 5 Inflammatory brain disorders, such as multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium / leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators 10 that cause extensive tissue damage resulting in impaired nerve conduction and paralysis. In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown 15 that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to injured tissue causing still further insult (Vedder, et al., Surgey, 106:509 (1989)). Other inflammatory conditions mediated by an adhesion mechanism include asthma (Pretolani, et al., J. Exp. Med., 180:795 (1994); Abraham, et al., Clin. Invest., 93:776 (1994); Mulligan, et al., Immunology, 150:2407 20 (1993)), Alzheimer's disease, atherosclerosis (Cybulsky, et al., Science, 251:788 (1991); Li, et al., Atheroscler. Thromb., 13:197 (1993)), AIDS dementia (Sasseville, et al., Am. J. Path., 144:27 (1994)), diabetes (Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993); Burkly, et al., Diabetes, 43:526 (1994); Baron, et al., J Clin. Invest., 93:1700 (1994)), inflammatory bowel disease (Hamann, et al., 25 Immunology, 152:3238 (1994)). multiple sclerosis (Yednock, et al., Nature, 356:63 (1992); Baron, et al., J. Exp. Med., 177:57 (1993)), rheumatoid arthritis (van Dinther Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993); Elices, et al., J. Clin. Invest., 93:405 (1994); Postigo, et al., J. Clin. Invest., 89:1445 (1991)), tissue transplantation (Paul, et al., Transpl. Proceed., 25:813 (1993), and tumor metastasis (Okahara, et al., 30 Can. Res., 54:3233 (1994); Paavonen, et al., Int. J. Can., 58:298 (1994); Schadendorf, et al., J. Path., 170:429 (1993)).
WO 00/35855 PCT/US99/29369 -3 Because of the significance of VLA-4 in inflammatory and autoimmune conditions, it is desirable to test for the presence of VLA-4 in biological samples and for compounds which inhibit cell adhesion. Individually, each receptor/ligand interaction is rapidly reversible; however, 5 during the process of cell adhesion, multiple cx3p integrin receptors on one cell engage multiple VCAM-1 ligands on another cell, and together provide a strong and stable adhesive bond. In order to prevent cell adhesion, small molecule inhibitors of a 4 3 1 integrin must achieve a high degree of receptor occupancy for disruption of a significant number of these adhesive interactions. Furthermore, due to the 10 multivalency of the adhesive interaction, inhibitory compounds exhibit a very steep titration curve, since inhibition begins with 85-90% receptor occupancy and is complete when 95-100% of the receptors are occupied. With such a narrow dynamic range there is considerable assay to assay variation in cell-based adhesion studies. An assay which can detect the presence of a single VCAM-1 molecule with a single 15 receptor and thus prevent assay to assay variation is desired. N-substituted 3,4-diamino-3-cyclobutene-1,2-dione derivatives have been taught. Japanese Patent JP05229999 A2 930907 discloses cyclobutenediones which are symmetrically disubstituted with ax-amino acids. U.S. Patent No. 5,168,103 issued December 1, 1992, and assigned to 20 American Home Products, describes cyclobutenedione derivatives having formula (2) 0 0 R N (N - X H 2 2 where A is alkylene or alkenylene. These compounds are taught to be useful as N methyl-D-aspartate antagonists. 25 WO 00/35855 PCT/US99/29369 -4 Description of Invention This invention provides novel compounds of Formula I 0 0 1 0 O ( H2)z RN OH(CH2)x OH 5 R 2
R
3 (C H 2)y 0 5 0 I wherein R is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or 10 R and R 2 may be taken together to form a saturated or unsaturated heterocycloalkyl;
R
3 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; A is aryl or heteroaryl; and x, y and z are independently 0, 1, 2, 3, 15 or a pharmaceutical salt thereof. In some preferred embodiments of the present invention R' is alkyl of 1 to 10 carbon atoms, aralkyl of 7 to 11 carbon atoms, or heteroaralkyl of 7 to 11 members having 1 to 3 heteroatoms. In still more preferred embodiments of the present 20 invention R ' is straight chain alkyl of 4 to 8 carbon atoms, benzyl, benzhydryl, phenethyl, pyridylmethyl or pyridylethyl.
R
2 is preferably hydrogen, alkyl of 1 to 10 carbon atoms or aralkyl of 7 to 11 carbon atoms. More preferably R 2 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or naphthylmethyl. 25 Alternatively, when R' and R 2 are taken together, they preferably form a substituted heterocycloalkyl of 5 to 7 members having 1 to 3 heteroatoms selected from N, O and S. A is preferably substituted or unsubstituted aryl. When A is substituted the substituent is preferably selected from -NR 4 COR', -OCONR 6
R
7 or -O(CH,)mNR 6
R
7 WO 00/35855 PCT/US99/29369 -5 wherein R 4 is hydrogen or alkyl of 1 to 3 carbon atoms, R is substituted or unsubstituted aryl, heteroaryl or heterocycloalkyl, R 6 and R 7 are independently, hydrogen or alkyl of 1 to 3 carbon atoms, or R 6 and R 7 , taken together may form a substituted heterocycloalkyl, and m is an integer from I to 6. 5 In some embodiments of the present invention it is preferred that x and y are 0 and z is 1. R' is preferably hydrogen in some aspects of the invention. For purposes of defining preferred substituted heterocycloalkyl, preferred substituents are alkyl of 1 to 3 carbon atoms, aryl, -COR" or -COOR' wherein R' is alkyl of 1 to 3 carbon atoms, aryl of 5 or 6 carbon atoms or aralkyl of 6 or 7 carbon 10 atoms, and R' is hydrogen, alkyl of 1 to 3 carbon atoms, aryl of 5 or 6 carbon atoms or aralkyl of 6 or 7 carbon atoms. In some embodiments of the present invention R' is alkyl, aralkyl or heteroaralkyl, A is phenyl, x and y are 0, and z is 1. 15 More preferred compounds of the present invention are the following compounds: [2-(Benzylamino)-3,4-dioxo-cyclobut-1 -enyl]-L-phenylalanine; [2-(benzhydrylamino)-3,4-dioxo-cyclobut- 1 -enyl]-L-phenylalanine; 2- { 2-[2- (1H-Indol-3-yl)-ethylamino]-3,4-dioxo-cyclobut- 1 -enylamino } -L 20 phenylalanine; { 3,4-Dioxo-2- [ (pyridin-3-ylmethyl)-amino]-cyclobut- 1 -enyl }-L-phenyl alanine; [2-(Benzyl-hexyl-amino)-3,4-dioxo-cyclobut- I1-enyl]-L-phenylalanine; (2-Dibenzylamino-3,4-dioxo-cyclobut- I -enylamino)-L-phenylalanine; 25 (S)-2-(2-Dihexylamino-3,4-dioxo-cyclobut- 1-enylamino)-3-phenyl-propionic acid; (S)-2-[2-(Hexyl-naphthalen-2-ylmethyl-amino)-3,4-dioxo-cyclobut- I -enyl amino]-3-phenyl-propionic acid; (S)-2- {(2-[(4-Dimethylamino-benzyl)-hexyl-amino]-3,4-dioxo-cyclobut- 1 30 enylamino } -3-phenyl-propionic acid; N-[3,4-Dioxo-2-(4-phenyl-piperazin-1-yl)-cyclobut- 1-en-1-yl]-L-phenyl alanine; WO 00/35855 PCT/US99/29369 -6 (S)-2-[2-(4-Acctyl-piperazin- I -yl)-3,4-dioxo-cyclobut- I -enylaminoj-3 phenyl-propionic acid; (S)-3-(4-Benzoylamino-phenyl)-2-(2-dihexylamino-3,4-dioxo-cyclobut- 1 enylamino)-propionic acid; 5 (S)-3-( 1 -Benzyl- 1H-imidazol-4-yl)-2-(2-dihexylamino-3,4-dioxo-cyclobut-1 enylamino)-propionic acid; N-(2-Dihexylamino-3,4-dioxo-cyclobut- 1-enylamino)-O-(3-dimethylamino propyl)-L-tyrosine; N- [2- [Methyl[2-(4-pyridinyl)ethyl] amino]-3,4-dioxo- I -cyclobuten- I1-yl]-4 10 [(4-pyridinylcarbonyl)amino]-L-phenylalanine; N-[2-[Methyl(2-phenylethyl)amino]-3,4-dioxo- I -cyclobuten- 1 -yl]-4-[(4 pyridinylcarbonyl)amino]-L-phenylalanine; N-[2-(Dihexylamino)-3,4-dioxo- I -cyclobuten- 1 -yl]-4- [(4-pyridinylcarbonyl) amino]-L-phenylalanine; 15 N-[2-(Methyl-pyridin-3-ylmethyl-amino)-3,4-dioxo-cyclobut- 1 -enyl]-4 [(pyridine-4-carbonyl)-amino]-L-phenylalanine; N-[2-(Dihexylamino)-3,4-dioxo- I -cyclobuten- I1-yl]-4-[(3-pyridinylcarbonyl) amino]-L-phenylalanine; N-[2-[Methyl[2-(4-pyridinyl)ethyl] amino]-3,4-dioxo- I -cyclobuten- 1-yl]-4 20 [(3-pyridinylcarbonyl)amino]-L-phenylalanine; N-[2-(Methyl-pyridin-3-ylmethyl-amino)-3,4-dioxo-cyclobut- 1 -enyl]-4 [(pyridine-3-carbonyl)-amino]-L-phenylalanine; N-{ 2-[Methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-cyclobut- I -enyl }-L phenylalanine; 25 N-[2-(Dihexylamino)-3,4-dioxo- 1-cyclobuten-1-yl]- {4- [4-(N- carboxy benzoyl)piperidinylcarbonyl]amino }-L-phenylalanine methyl ester; (2S)-3-(4-Dimethylcarbamoyloxy-phenyl)-2-[2-(methyl-phenethyl-amino) 3,4-dioxo-cyclobut- 1-enylamino]-propionic acid; (2S)-2-(2-Dihexylamino-3,4-dioxo-cyclobut- 1 -enylamino)-3-(4-dimethyl 30 carbamoyloxy-phenyl)-propionic acid; (2S)-3-(4-Dimethylcarbamoyloxy-phenyl)-2-[2-(methyl-pyridin-3-ylmethyl amino)-3,4-dioxo-cyclobut- I -enylamino]-propionic acid; WO 00/35855 PCT/US99/29369 -7 (2S)-3-(4-Dimethylcarbamoyloxy-phenyl)-2- { 2-[methyl-(2-pyridin-4-yl ethyl)-amino]-3,4-dioxo-cyclobut- I -enylamino }-propionic acid; (2S)-3-[4-(4-methylpiperazinyl)carbamoyloxy-phenyl] -2-[2-(methyl phenethyl-amino)-3,4-dioxo-cyclobut- I -enylamino]-propionic acid: 5 (2S)-3-[4-(4-methylpiperazinyl)carbamoyloxy-phenyl)-2- { 2-[ methyl-(2 pyridin-4-yl-ethyl)-amino]-3,4-dioxo-cyclobut- 1 -enylamino } -propionic acid; and (2S)-3-[4-(4-methylpiperazinyl)carbamoyloxy-phenyl)-2- { 2-dihexylamino] 3,4-dioxo-cyclobut- 1-enylamino }-propionic acid; or a pharmaceutical salt thereof. 10 "Alkyl" as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from I to 8 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. Alkyl may be substituted and unsubstituted. 15 "Aryl" as used herein means mono or bicyclic aromatic ring having from 5 to 12 carbon atoms. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary aryl groups include phenyl and naphthyl. Aryl may be substituted or unsubstituted. 20 "Aralkyl" as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined. Exemplary aralkyl groups include benzyl and phenethyl. The aralkyl may be substituted or unsubstituted. "Halogen" is chlorine, fluorine, iodine or bromine. 25 "Heteroaryl" whether used alone or as part of a group such as "heteroaralkyl" means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Exemplary heteroaryls include pyridyl, pyrazinyl, pyridazinyl. pyrimidinyl, indolyl, imidazolyl, pyrazolyl and pyrrolyl. 30 Preferred heteroaryl groups include 1H-indoly-3-yl, pyridin-3-yl, pyridin-4-yl, and 1H imidazol-4-yl. The heteroaryl may be substituted or unsubstituted.
WO 00/35855 PCT/US99/29369 - 8 "Heteraralkyl" means an heteroaryl-alkyl group in which the heteroaryl and alkyl are as previously described. Exemplary heteroaralkyls include pyridylmethyl, pyridylethyl, thienylethyl, thienylmethyl, indolylmethyl, and furylmethyl. The heteraralkyl may be substituted or unsubstituted. 5 Heterocycloalkyl refers to a monocycloalkyl having from 5 to 10 members including one or more heteroatoms selected from N, O or S. The heterocycloalkyl may be saturated or unsatured and may be substituted or unsubstituted. 10 Suitable substituents, unless otherwise noted are unsubstituted and include, but are not limited to, alkyl of 1 to 3 carbon atoms, halogen, -CN, -NO 2 , perhaloalkyl of 1 to 3 carbon atoms, aryl, aralkyl, -NR'COR 5 , -CO,R 4 , -OR 4 , -OCONR 6
R
7 or
-O(CH
2 )mNR 6
R
7 wherein R 4 is hydrogen, alkyl of 1 to 3 carbon atoms, or aralkyl of 7-10 carbon atoms, R 5 is aryl, heteroaryl or heterocycloalkyl, R 6 and R 7 are 15 independently, hydrogen or alkyl of 1 to 3 carbon atoms, or R 6 and R 7 , taken together may form a heterocycloalkyl, and m is an integer from I to 6. Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents thereof. 20 Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. Pharmaceutically acceptable salts are the acid addition salts which can be 25 formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like. 30 The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. The individual isomers can be prepared directly or by WO 00/35855 PCT/US99/29369 -9 asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture. Novel compounds of Formula I are prepared by the sequential addition of appropriate amine nucleophiles to 3,4-diethoxy-3-cyclobutene- 1,2-dione in alcoholic 5 solvent, followed by hydrolysis of the precursor carboxylic acid ester to the parent acid by treatment with aqueous base as shown in the following reaction schemes. Scheme 1 X X + o\o + EtOH C Et Et H 2 N 3 Method 1 OCEtOH3 Eto O t H2 Et O)t N1 H 0 *HCI H 0 10 R NH X X R2 LiOH 0 0 11 111'THF EtOH RO O OCH 3 H0 R O OH EtOH N N H2p N N 12 H 1 2 H Method 2 R Method 3 R 0 15 In the case where the product of Method I contains X = OH, the corresponding carbamates are prepared as in Scheme 2.
WO 00/35855 PCT/US99/29369 - 10 Scheme 2 C i I NO 0 dt Et CI IN OCH 3 Hf OH Method 4 0 Et/ oC ( N OHON3N SOCH3 EtO N HN NCH 3 Et . OCH Et O N 0H pyridine H 0 CH 2CI2 Method 5 5 The carbamate products are then further elaborated via Method 2 above. The method of preparing compounds of Formula I as described above are exemplified in the following specific examples. These examples are illustrative and are not meant to be limiting to this disclosure in any way/ Other methods of 10 preparing compounds of the present invention may be apparent to those skilled in the art. Reactants and reagents used are either commercially available or can be prepared according to standard literature procedures.
WO 00/35855 PCT/US99/29369 -11 Example 1 (Method 1) [2-Ethoxy-3.4-dioxo-cyclobut- I -enyll -L-phenylalanine methyl ester To a stirred solution of L-phenylalanine methyl ester HCI (2.0 mmol, 431 mg) in 5 absolute ethanol (20 mL) was added triethylamine (2.2 mmol, 202 mg; 278 p.L) and the resulting solution was stirred at room temperature for 15 minutes. Subsequently, neat 3,4-diethoxy-3-cyclobutene-1,2-dione (2 mmol, 340 mg; 296 p-tL) was added dropwise and the resulting solution was stirred at room temperature overnight, during which a white solid precipitated out of solution. The volatiles were removed in vacuo 10 and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (Na2SO) and purified by flash chromatography (SiO,: 1) 20% EtOAc/hexane; 2) 30c% EtOAc/hexane; 3) 40% EtOAc/hexane) to afford the title compound as a colorless oil (551 mg; 85%). 15 'H NMR (DMSO-d 6 , 300 MHz) 6 9.1 (br d, 1H), 7.24 (min, 6H), 4.88 (min, 1H), 4.55 (min, 3H), 4.16 (m, 2H), 3.23 (dd, 1H), 2.96 (min, 1H), 1.30 (min, 2H). Example 2 (Method 2) [2-(Benzylamino)-3.4-dioxo-cvclobut-1-envll-L-phenvlalanine methyl ester 20 To a stirred solution of [2-ethoxy-3,4-dioxo-cyclobut-l1-enyl]-L-phenylalanine methyl ester (0.33 mmol, 100 mg) in absolute ethanol (3 mL) was added neat benzylamine (0.36 mmol, 39 mg; 40 gL) dropwise at room temperature. The resulting solution was stirred at room temperature overnight, during which a white 25 solid precipitated out of solution. The volatiles were removed in vacuo and the residue was taken up in EtOAc and partitioned between EtOAc and water. The organics were dried (NaSO 4 ), concentrated in vacuto and purified by flash chromatography (SiO,: EtOAc/hexane) to afford the title compound as a white solid (113 mg; 94%). 30 'H NMR (DMSO-d 6 , 400 MHz) 8 7.85 (br s, 1H), 7.66 (br s, 1H), 7.37 (min, 2H), 7.26 (min, 6H), 7.13 (min, 2H), 5.1 (m, 1H), 4.68 (min, 2H), 3.68 (s, 3H), 3.16 (dd, 1H, J = 13.9, 5.4 Hz), 3.03 (min, 1H).
WO 00/35855 PCT/US99/29369 - 12 Example 3 (Method 3) [2-(Benzvylamino)-3.4-dioxo-cyclobut- 1 -envll-L-phenylalanine N N O Al H H OH 5 To a stirred solution of [2-(benzylamino)-3,4-dioxo-cyclobut-l-enyl]-L-phenyl alanine methyl ester (0.16 mmol, 60 mg) in THF (5 mL) was added aqueous LiOH (1.0 M; 0.16 mmol; 160 iL) and the resulting solution was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue 10 partitoned between 0.1M acetic acid and EtOAc. The organics were dried (NaSO 4 ) and concentrated in vacuo to afford the title compound as a white solid, mp = 215 216oC (33 mg; 59%). 'H NMR (DMSO-d 6 , 400 MHz) 5 13.1 (br s, IH), 7.89 (br s, 1H), 7.59 (br s, 1H), 15 7.37 (m, 2H), 7.26 (m, 6H), 7.14 (m, 2H), 4.91 (m, 1H), 4.68 (m, 2H), 3.17 (m, 1H), 3.01 (m, 1H). MS (El, m/e (%)) 350 (17, M'), 259 (16), 91 (100). 20 Example 4 (Method 2) [2-(benzhydrylamino)-3,4-dioxo-cyclobut- I -envll-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester and diphenyl 25 methylamine in 88% yield. 'H NMR (DMSO-d 6 , 400 MHz) 5 8.38 (br s, 1H), 7.68 (br s, 1H), 7.39 (m, 4H), 7.26 (m, 9H), 7.12 (m, 2H), 6.33 (m, 1H), 5.01 (m, 1H), 3.69 (s, 3H), 3.16 (dd, 1H, J = 13.4; 5.6 Hz), 3.05 (dd, 1H, J = 13.4; 5.6 Hz).
WO 00/35855 PCT/US99/29369 - 13 Example 5 (Method 3) [2-(benzhydrylamino)-3.4-dioxo-cyclobut- I -enyll-L-phenylalanine -0 I N N H H 5 Following the procedure of Method 3 above, the title compound was obtained in 76% yield as a white solid, mp = 187-188 0 C. 'H NMR (DMSO-d 6 , 400 MHz) 8 13.2 (br s, 1H), 8.41 (br s, 1H), 7.62 (be s, 1H), 7.38 (m, 4H), 7.30 (m, 2H), 7.24 (m, 7H), 7.13 (d, 2H, J = 7.02 Hz), 6.34 (m, 1H), 10 4.90 (M, 1H), 3.16 (dd, 1H, J = 13.7; 4.9 Hz), 3.05 (m, 1H). MS ((+)FAB, m/e (%)) 449 (14, (M+Na) ), 427 (45, (M+H)*), 217 (33), 167 (100). IR (KBr, cmi') 3200, 1790, 1730, 1640, 1575, 1530, 1440, 710. Anal. Calc'd for C6H,,N20, * 0.25 HO 2 0: C, 72.45; H, 5.26; N, 6.50. 15 Found: C, 72.69; H, 5.22; N, 6.67. Example 6 (Method 2) 2- f 2-[2-( 1H-Indol-3-yl)-ethylamino]-3.4-dioxo-cyclobut- 1 -enylamino } -L phenylalanine methyl ester 20 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-l1-enyl]-L-phenylalanine methyl ester and tryptamine in 86% yield. 25 'H NMR (DMSO-d , 400 MHz) 8 10.88 (s, 1H), 7.68 (br s, 1H), 7.57 (d, 2H, J = 7.8 Hz), 7.33 (d, 1H, J = 7.8 Hz), 7.23 (m, 3H), 7.12 (m, 3H), 7.07, (dt, 1H, J = 7.03; 1.1 Hz), 6.96 (dt, 1H, J =7.03; 1.1 Hz), 5.0 (m, 1H), 3.79 (m, 2H), 3.67 (s, 3H), 3.13 (M, 1H), 3.02 (m, 1H), 2.91 (m, 2H).
WO 00/35855 PCT/US99/29369 - 14 Example 7 (Method 3) 2- 2-[2-( 1H-Indol-3-vl)-ethylamino]-3.4-dioxo-cyclobut- I -enylviamino }-L phenylalanine 0 0 I H N 5~ OH H H 5 Following the procedure of Method 3 above, the title compound was obtained in 61% yield as a white solid. 10 'H NMR (DMSO-d 6 , 400 MHz) 8 13.3 (br s, 1H), 10.8 (s, 1H), 7.58 (d, 2H, J = 7.8 Hz), 7.32 (d, 1H, J = 8.1 Hz), 7.10 - 7.30 (m, 6H), 7.06 (m, IH), 6.97 (m, 1H), 4.90 (m, 1H), 3.79 (m, 2H), 3.38 (q, 1H, J = 7.0 Hz), 3.14 (dd, 1H, J = 13.9; 4.7 Hz), 3.01 (dd, 1H, J = 13.9; 4.7 Hz), 2.92 (m, 2H). MS (El, m/e (%)) 403 (4, M'), 385 (16), 294 (60), 143 (100). 15 Anal. Calc'd for C2 3 H2,N 3 04 * 0.4 HO: C, 67.27; H, 5.35; N, 10.23. Found: C, 67.58; H, 5.82; N, 9.78. Example 8 (Method 2) 20 2- {3,4-Dioxo-2-[(pyridin-3-vlmethyl)-aminol-cyclobut- 1 -enylamino } -3-phenvl-pro pionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-L-phenylalanine methyl ester and 3 25 pyridylmethylamine in 81% yield, mp=191-192oC. 'H NMR (DMSO-d 6 , 400 MHz) 8 8.51 (d, 2H, J = 5.1 Hz), 7.87 (br s, 1H), 7.68 (br s, 2H), 7.40 (dd, 1H, J = 4.7, 7.6 Hz), 7.24 (m, 3H), 7.13 (d, 2H, J = 7.2 Hz), 5.01 (br s, 1H), 4.72 (d, 2H, 5.7 Hz), 3.68 (s, 3H), 3.17 (dd, 1H, J = 5.2, 13.7 Hz), 3.03 (m, 1H).
WO 00/35855 PCT/US99/29369 - 15 MS (EI, m/e (%)) 365 (6, M'), 337 (7), 274 (15), 242 (40), 214 (18), 186 (13), 146 (44), 44 (100). IR (KBr, cm-') 3175, 2960, 1800, 1745, 1650, 1570, 1480, 1430, 1310, 1280. 5 Anal. Calc'd for C,H N 3 0 4 : C, 65.74; H, 5.24; N, 11.50. Found: C, 65.22; H, 5.15; N, 11.27. Example 9 (Method 3) f 3.4-Dioxo-2-[(pyridin-3-vlmethyl)-amino]-cyclobut- 1 -envyl }-L-phenylalanine OH N N H H 10 N Following the procedure of Method 3 above, the title compound was obtained in 9% yield as a white solid, mp = 259-261oC. 15 'H NMR (DMSO-d 6 , 300 MHz) 8 13.25 (br s, 1H), 8.53 (br d, 2H) 7.93 (br s, 1H), 7.69 (br d, 2H), 7.41 (m, IH), 7.20 (m, 5H), 4.91 (m, 1H), 4.73 (m, 2H), 3.18 (dd, 1H), 3.03 (m, 1H). MS ((+) FAB, m/e (%)) 352 (10, (M+H)*), 232 (17), 179 (23), 157 (100). 20 Example 10 (Method 2) [2-(Benzvl-hexvl-amino)-3.4-dioxo-cyclobut- I -envl]-L-phenvlalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-L-phenylalanine methyl ester and 25 benzyl(hexyl)-amine in 57% yield as a light yellow oil which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 -16 Example 11 (Method 3) [2-(Benzvl-hexvl-amino)-3.4-dioxo-cyclobut- I -envyll-L-phenylalanine N -N OH H) O 5 Following the procedure of Method 3 above, the title compound was obtained in 41% yield as a yellow foam, mp = 61-65oC. 'H NMR (DMSO-d 6 , 400 MHz) 8 13.1 (s, 1H), 7.79 (br s, 1H), 7.35 (dd, 3H, J = 10.6, 6.9 Hz), 7.21 (m, 6H), 5.14 (m, 1H), 4.67 (br s, 2H), 3.38 (br m, 2H), 3.26 (dd, 10 2H, J = 14, 4.0 Hz), 2.98 (dd, 1H, J = 14.1, 11.2 Hz), 1.38 (br s, 2H), 1.15 (m, 6H), 0.82 (t, 3H, J = 6.8 Hz). MS ((+)FAB, m/e (%)) 457 (76, (M + Na)*), 435 (100, (M + H)*), 389 (13), 192 (35). IR (KBr, cm') 3290, 2940, 1800, 1740, 1675, 1570, 1520, 700. 15 Anal Calc'd for C 2 6 H3oN04 * 0.25 H,O; C, 71.13; H, 7.00; N, 6.38. Found: C, 71.31; H, 7.00; N, 6.20. Example 12 (Method 2) (2-Dibenzylamino-3,4-dioxo-cyclobut-1-envlamino)-L-phenylalanine methyl ester 20 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester and dibenzyl amine in 44% yield as a light yellow solid which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 17 Example 13 (Method 3) (2-Dibenzvlamino-3,4-dioxo-cyclobut- 1 -enyvlamino)-L-phenvylalanine S OH H 0 Following the procedure of Method 3 above, the title compound was obtained in 79% 5 yield as a yellow solid. 'H NMR (DMSO-d 6 , 400 MHz) 5 13.13 (s, 1H), 8.01 (d, 1H, J = 9.0 Hz), 7.35 (m, 6H), 7.20 (m, 8H), 5.19 (m, 1H), 4.55 (br s, 4H), 3.26 (dd, 2H, J = 3.9, 14.0 Hz), 2.97 (m, 1H). MS (EI, m/e (%)) 440 (20, M'), 349 (16), 91(100). 10 IR (KBr, cm 1 ) 3450-3250 (br), 2925, 1800, 1740, 1680, 1570, 1520, 1445, 1265, 700. Anal. Calc'd for C, 7
H
2 4 20 4 : C, 73.62; H, 5.49; N, 6.36. Found: C, 72.48; H, 5.41; N, 6.01. 15 Example 14 (Method 2) (S)-2-(2-Dihexvlamino-3.4-dioxo-cvclobut- I -envlamino)-3-phenyl-propionic acid methyl ester 20 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-L-phenylalanine methyl ester and dihexylamine in 62% yield as a light yellow solid which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 18 Example 15 (Method 3) (S)-2-(2-Dihexvlamino-3,4-dioxo-cyclobut- I -enylamino)-3-phenvl-propionic acid /^L/'/^^ N OH NN ~ HO0 5 Following the procedure of Method 3 above, the title compound was obtained in 86% yield as a colorless oil. 'H NMR (DMSO-d 6 , 400 MHz) 8 13.1 (br s, 1H), 7.58 (d, 1H, J = 9.2 Hz), 7.2 (m, 5H), 5.09 (m, 1H), 3.44 (br s, 4H), 3.24 (dd, 1H, J = 4.0, 13.8 Hz), 3.0 (dd, 1H, J = 10 11.3, 14.1 Hz), 1.43 (br s, 4H), 1.20 (m, 12H), 0.84 (t, 6H, J = 7.0 Hz). MS (EI, m/e (%) 428 (100, M'), 372 (36), 337 (55), 224 (30). Example 16 (Method 2) (S)-2-[2-(Hexvl-naphthalen-2-vlmethyl-amino)-3,4-dioxo-cyclobut- 1-envlaminol-3 15 phenyl-propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester and (2 naphthalenyl-methyl)hexylamine in 63% yield as a colorless oil which was carried on 20 immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 19 Example 17 (Method 3) (S)-2-[2-(Hexvl-naphthalen-2-vlmethyl-amino)-3.4-dioxo-cyclobut- I -envlamino]-3 phenvl-propionic acid 0 I S OH H O 5 Following the procedure of Method 3 above, the title compound was obtained in 80% yield as a light yellow solid, mp = 62-70'C. 'H NMR (DMSO-d 6 , 400 MHz) 5 13.15 (br s, 1H), 7.91 (m, 2H), 7.80 (s, 1H), 7.52 10 (m, 2H), 7.29 (m, 2H) 7.21 (m, 6H), 5.17 (m, IH), 4.84 (br s, 2H), 3.24 (dd, 2H, J = 3.7, 14.3 Hz), 2.99 (m, 1H), 1.48-1.2 (m, 3H), 1.13 (s, 6H), 0.78 (t, 3H, J= 6.7 Hz). MS (El, m/e (%)) 484 (5, M'), 439 (4), 219 (28), 44 (100). Example 18 (Method 2) 15 (S)-2- { 2-[(4-Dimethylamino-benzvl)-hexyl-amino]-3,4-dioxo-cyclobut-1 envlamino }-3-phenvl-propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester and (4-dimethyl 20 aminobenzyl)hexylamine in 59% yield as a colorless oil which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 20 Example 19 (Method 3) (S)-2- {2-[ (4-Dim ethylamino-benzvl)-hexyl-amino]-3.4-dioxo-cyclobut- 1 envlamino }-3-phenvl-propionic acid yield as a white solid, mp = 77-80oC. 'H NMR (DMSO-ds, 400 MHz) 8 13.07 (s, 1H), 7.78 (br s, 1H), 7.23 (m, 5H), 7.02 10 (br s, 2H), 6.65 (d, 2H, J = 7.9 Hz), 5.16 (br s, 1H), 4.49 (br s, 2H), 3.26 (dd, 1H, J = 3.7, 13.8 Hz), 3.0 (m, 1H), 2.87 (s, 6H), 1.48 (br s, 3H), 1.15 (m, 7H), 0.82 (t, 3H, J = 6.8 Hz). MS ((+)FAB, m/e (%)) 500 (100, [M+Na]+), 478 (34, [M+H] ), 455 (17), 357 (32). 15 Example 20 (Method 2) N-[3,4-Dioxo-2-(4-phenvl-piperazin- 1-vll-cyclobut- 1-en- 1-vll-L-phenvlalanine methyl ester N ~H0 5 Following the procedure of Method 2 above, the title compound was obtained in 97from 20 [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester and 1-phenyl piperazine in 63% yield as a white solid which was carried on immediately to the77-80C. subsequent reaction. 'H NMR (DMSO-d 6 , 400 MHz) 8 13.07 (s, 1H), 7.78 (br s, 1H), 7.23 (in, 5H), 7.02 10 (br s, 2H), 6.65 (d, 2H, J = 7.9 Hz), 5.16 (br s, 1H), 4.49 (br s, 2H), 3.26 (dd, 1H, J 3.7, 13.8 Hz), 3.0 (in, I H), 2.87 (s, 6H), 1.48 (br s, 3H), 1. 15 (in. 7H), 0. 82 (t, 3H. J = 6.8 Hz). MIS ((+)FAB, mle (%)) 500 (100, [M+Na]+), 478 (34, [M+H]'), 455 (17), 357 (32). 15 Example 20 (Method 2) N-[3,4-Dioxo-2-(4-nhenyl-piperazin- 1 -yl)-cyclobut- 1-en-i -yl]-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from 2() [2-ethoxy-3,4-dioxo-cyclobut-1I-enyl]-L-phenylalanine methyl ester and I1-phenyl piperazine in 63% yield as a white solid which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 -21 Example 21 (Method 3) N-[3.4-Dioxo-2-(4-phenvl-piperazin- I -vl)-cyclobut- 1-en- 1-yl]-L-phenvlalanine 0 I OH rN H O 5 Following the procedure of Method 3 above, the title compound was obtained in 65% yield as a white solid, mp = 165-167oC. 'H NMR (DMSO-d 6 , 400 MHz) 8 13.1 (br s, 1H), 8.01 (d, 1H, J = 9.0 Hz) 7.29-7.16 (m, 7H), 6.98 (d, 2H, J = 8.1 Hz), 6.82 (t, 1H, J = 7.2Hz), 5.08 (m, 1H), 3.77 (br s, 10 4H), 3.24 (dd, 2H, J =4.0, 14.0Hz), 3.19 (t, 3H, J = 5.0 Hz), 2.98 (dd, 1H, J= 11.0, 13.8 Hz). MS (EI, m/e (%)) 405 (48, M'), 361 (6), 304 (5), 44 (100). Example 22 (Method 2) 15 (S)-2-[2-(4-Acetyl-piperazin- 1 -vl)-3.4-dioxo-cyclobut- 1-enylaminol-3-phenvl propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- 1 -enyl]-L-phenylalanine methyl ester and 1 20 acetylpiperazine in 71% yield as a white solid which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 22 Example 23 (Method 3) (S)-2-[2-(4-Acetyl-piperazin-1 -vl)-3.4-dioxo-cyclobut- I -envlamino]-3-phenvl propionic acid O N H
OH
3 5 Following the procedure of Method 3 above, the title compound was obtained in 39% yield as a white solid, mp = 155-158 0 C. 1 H NMR (DMSO-d , 400 MHz) 6 13.1 (br s, 1H), 7.96 (d, 1H, J = 9.2 Hz) 7.24 (m, 10 5H), 5.07 (m, IH), 3.66 (br s, 2H), 3.57 (br s, 3H), 3.50 (d, 3H, J = 4.2 Hz), 3.23 (dd, 1H, J = 4.2, 13.8 Hz), 2.97 (dd, 1H, J = 11.0, 13.8 Hz), 2.03 (s, 3H). MS (EI, m/e (%)) 371 (21, M'), 270 (10). Example 24 (Method 1) 15 [2-Ethoxy-3,4-dioxo-cyclobut- 1-envyl]-L-(4-benzoylamino)phenylalanine methyl ester Following the procedure of Method 1 above, the title compound was obtained from L-(4-benzoylamino)phenylalanine methyl ester hydrochloride and 3,4-diethoxy-3 20 cyclobutene-1,2-dione in 64% yield. 'H NMR (DMSO-d 6 , 300 MHz) 8 10.2 (s, 1H), 9.1 (br dd, 1H), 7.93 (dd, 2H), 7.69 (d, 2H), 7.53 (m, 3H), 7.2 (d, 2H), 4.59 (m, 3H), 3.7 (s, 3H), 3.21 (dd, 1H), 2.93 (br m, 1H), 1.31 (m, 3H). 25 WO 00/35855 PCT/US99/29369 - 23 Example 25 (Method 2) (S)-3-(4-Benzovlamino-phenvl)-2-(2-dihexylamino-3.4-dioxo-cyclobut- I envlamino)-propionic acid methyl ester 5 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L-(4-benzoylamino)phenylalanine methyl ester and dihexylamine in 70% yield as a white solid which was carried on immediately to the subsequent reaction. 10 Example 26 (Method 3) (S)-3-(4-Benzovlamino-phenvl)-2-(2-dihexylamino-3.4-dioxo-cyclobut- 1 envlamino)-propionic acid H 0 N Y-0 \OO N N OH HO 15 Following the procedure of Method 3 above, the title compound was obtained in 61% yield as a white solid, mp = 95-100C. 'H NMR (DMSO-d 6 , 400 MHz) 6 13.1 (br s, 1H), 10.17 (s, 1H), 7.91 (m, 2H), 7.68 (d, 2H, J = 8.6 Hz), 7.6 - 7.48 (m, 4H), 7.19 (d, 2H, J = 8.6 Hz), 5.09 (m, 1H), 3.45 20 (br m, 4H), 3.22 (dd, 1H, J = 3.8, 13.9 Hz), 2.98 (dd, 1H, J = 11.2, 13.8 Hz), 1.43 (br s, 4H), 1.20 (s, 12H), 0.80 (t, 6H, J = 6.7 Hz). MS ((+)FAB, m/e (%)) 570 (51, [M+Na]+), 548 (25, [M+H]+), 210 (10), 105 (100). Anal. Calc'd for C32H41N305 * 0.4 H-0: C, 69.26; H, 7.59; N, 7.57. 25 Found: C, 69.14; H, 7.55; N, 7.52.
WO 00/35855 PCT/US99/29369 - 24 Example 27 (Method 1) [2-Ethoxy-3.4-dioxo-cyclobut- I -enyl]-L-(im-benzvyl)histidine methyl ester Following the procedure of Method 1 above, the title compound was obtained from 5 L-(im-benzyl)histidine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene 1,2-dione in 58% yield. 'H NMR (DMSO-d 6 , 300 MHz) 6 9.0 (br dd, 1H), 7.67 (s, 1H), 7.31 (m, 3H), 7.16 (d, 2H), 6.91 (br s, 1H), 5.12 (s, 2H), 4.6 (m, 3H), 3.62 (d, 3H), 3.05 (dd, 1H), 2.9 (m, 10 1H), 1.3 (m, 3H). Example 28 (Method 2) (S)-3-(1-Benzvl- 1H-imidazol-4-vl)-2-(2-dihexylamino-3.4-dioxo-cyclobut-1 envlamino)-propionic acid methyl ester 15 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-L-(im-benzyl)histidine methyl ester and dihexylamine in 94% yield as a white solid which was carried on immediately to the subsequent reaction. 20 Example 29 (Method 3) (S)-3-(1-Benzvl-IH-imidazol-4-vl)-2-(2-dihexvlamino-3,4-dioxo-cyclobut- 1 envlamino)-propionic acid N N OH H O0 25 Following the procedure of Method 3 above, the title compound was obtained in 45% yield as a white solid, mp = 75-80oC.
WO 00/35855 PCT/US99/29369 - 25 H NMR (DMSO-d 6 , 400 MHz) 8 7.87 (d, J = 8.8 Hz, 1H); 7.66 (s, 1H), 7.29 (m, 3H), 7.16 (dd, J = 6.4, 1.8 Hz, 2H), 6.92 (s, 1H), 5.13 (s, 2H), 5.04 (q, J = 8.3, 5.8 Hz, 1H), 3.55 (br, 4H), 3.01 (m, 2H), 1.49 (br s, 4H), 1.21 (s, 13H), 0.82 (s, 6H). MS ((+)FAB, m/e (%)) 509 (100, [M + H] 0 ), 185 (30), 172 (40). 5 Anal. Calc'd for C29H40404 * 0.5 H,O: C, 67.28; H, 7.98; N, 10.82. Found: C, 67.53; H, 8.10; N, 10.47. Example 30 (Method 1) 10 [2-Ethoxy-3.4-dioxo-cyclobut- 1-envyl-O-(3-dimethylaminopropyl)-L-tyrosine methyl ester Following the procedure of Method 1 above, the title compound was obtained from O-(3-dimethylaminopropyl)-L-tyrosine methyl ester hydrochloride and 3,4-diethoxy 15 3-cyclobutene- 1,2-dione in 71% yield. 'H NMR (DMSO-d 6 , 300 MHz) 6 9.1 (br d, 1H), 7.12 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.6 (m, 2H), 3.93 (t, 2H), 3.69 (s, 3H), 3.1 (m, 1H), 2.88 (m, IH), 2.31 (t, 2H), 2.12 (s, 6H), 1.8 (m, 2H), 1.3 (m, 3H). 20 Example 31 (Method 2) N-(2-Dihexvlamino-3,4-dioxo-cyclobut- 1 -envlamino)-O-(3-dimethylamino-propyvl) L-tyrosine methyl ester 25 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-O-(3-dimethylaminopropyl)-L-tyrosine methyl ester and dihexylamine in 23% yield as a white solid which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 26 Example 32 (Method 3 (modified)) N-(2-Dihexvlamino-3,4-dioxo-cyclobut- I -enylamino)-O-(3-dimethylamino-propvl) L-tyrosine I 0O N, N OH H O 5 Following a modification procedure of Method 3 above, the lithium salt of the title compound was obtained in 66% yield as a light yellow solid. The modified procedure requires removing the volatiles in vacuo from the reaction mixture following completion of ester hydrolysis (usually 3 hours at room temperature), followed by 10 partitioning the reaction mixture between EtOAc and water. The aqueous phase is then lyophilized to afford the lithium salt as an amorphous powder. 'H NMR (DMSO-d , 400 MHz) 6 7.08 (d, 1H, J = 6.6 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.68 (d, 2H, J = 8.6 Hz), 4.28 (m, 1H), 3.87 (t, 2H, J = 6.4 Hz), 3.3 (br s, 4H), 3.05 15 (d, 2H, J = 5.1 Hz) 2.31 (t, 2H, J = 7.1 Hz), 2.11 (s, 6H), 1.78 (t, 2H, J = 6.9 Hz), 1.43 (br s, 4H), 1.19 (br m, 12H), 0.82 (t, 6H, J = 7.0 Hz). MS ((+)FAB, m/e (%)) 536 (100, [M + Li]'), 530 (50, [M+H]+). IR (KBr, cm') 3400, 2960, 2930, 2880, 1800, 1575, 1520, 1240. 20 Example 33 (Method 1) [2-Ethoxy-3,4-dioxo-cyclobut- 1 -envl]-4-[(4-pvridinvlcarbonyl)amino]l-L phenvlalanine methyl ester Following the procedure of Method 1 above, the title compound was obtained from 25 4-[(4-pyridinylcarbonyl)amino]-L-phenylalanine methyl ester hydrochloride and 3,4 diethoxy-3-cyclobutene- 1,2-dione in 71% yield.
WO 00/35855 PCT/US99/29369 - 27 'H NMR (DMSO-d , 300 MHz) 8 10.47 (s, 1H), 9.12 (br dd, 1H), 8.78 (dd, 2H), 7.83 (d, 2H), 7.69 (d, 2H), 7.23 (d, 2H), 4.9 (br m, 1H), 4.59 (m, 2H), 3.7 (s, 3H), 3.22 (dd, 1H), 2.94 (m, 1H), 1.31 (m, 3H). 5 Example 34 (Method 2) N-[2-[Methyl[2-(4-pyridinvl)ethyl] amino]-3.4-dioxo- 1 -cyclobuten- 1-vll-4-[(4 pyridinylcarbonvl)amino]l-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from 10 [2-ethoxy-3,4-dioxo-cyclobut- 1-enyl]-4-[(4-pyridinylcarbonyl)amino]-L-phenyl alanine methyl ester and methyl-[2-(4-pyridinyl)ethyl]amine in 41% yield as a yellow foam which was carried on immediately to the subsequent reaction. Example 35 (Method 3 (modified)) 15 N- [2- [Methyl[2-(4-pyridinvyDethyl] amino] -3.4-dioxo- I -cyclobuten- 1-vl]-4-[(4 pyridinylcarbonyl)amino]-L-phenvlalanine H N Y Na N N OH
CH
3 0 Following the procedure of Method 3 (modified) above, the title compound was 20 obtained as its corresponding lithium salt in 73% yield as a yellow solid. 'H NMR (DMSO-d 6 , 400 MHz) 8 10.45 (s, 1H), 8.74 (dd, J = 1.5, 4.6 Hz, 2H), 8.40 (d, J = 4.8 Hz, 2H), 7.81 (d, J = 6.1 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.40 (br m, 1H), 7.20 (d, J = 5.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 4.40 (m, 1H), 3.70 (br s, 2H), 25 3.10 (m, 6H), 2.81 (m, 2H). MS ((+)FAB, m/e (%)) 506 (100, [M + Li]'), 500 (50, [M+H]+). IR (KBr, cm') 3400, 1575, 1530, 1410, 1320.
WO 00/35855 PCT/US99/29369 -28 Anal. Calc'd for C 27
H
2 4 NOLi * 3.5 H,O: C, 56.98; H, 5.49; N, 12.31. Found: C, 56.96; H, 5.34; N, 11.82. Example 36 (Method 2) 5 N-[2-[Methyl(2-phenylethyl)aminol-3.4-dioxo- 1 -cyclobuten-1 -yll-4-[(4 pyridinylcarbonvyl)aminol-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4- [(4-pyridinylcarbonyl)amino]-L 10 phenylalanine methyl ester and methyl-(2-phenethyl)amine in 93% yield as a colorless foam which was carried on immediately to the subsequent reaction. Example 37 (Method 3 (modified)) N-[2-[Methyl (2-phenvlethyl) aminol-3,4-dioxo- 1 -cyclobuten- I -vll-4-[(4 15 pyridinylcarbonvyl)aminol-L-phenylalanine H N o H
CH
3 O Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 90% yield as a white solid. 20 'H NMR (DMSO-d , 400 MHz) 6 10.45 (s, 1H), 8.73 (m, 2H), 7.80 (d, J = 5.7 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.32-7.08 (m, 8H), 4.38 (d, J = 4.6 Hz, IH), 3.67 (br s, 2H), 3.08 (m, 5H), 2.79 (m, 2H). MS ((+)FAB, m/e (%)) 521 (100, [M + Na]+), 505 (85, [M+Li]+), 499 (60, [M+H]*). 25 IR (KBr, cm') 3400, 1810, 1660, 1580, 1530, 1410, 1330.
WO 00/35855 PCT/US99/29369 - 29 Example 38 (Method 2) N-[2-(Dihexvlamino)-3.4-dioxo- 1 -cyclobuten- I -vll-4-[(4-pyridinylcarbonvl)amino] L-phenvlalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from 5 [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4-[(4-pyridinylcarbonyl)amino]-L-phenyl alanine methyl ester and dihexylamine in 87% yield as a light yellow foam which was carried on immediately to the subsequent reaction. Example 39 (Method 3 (modified)) 10 N-[2-(Dihexvlamino)-3,4-dioxo- I -cyclobuten- I -vll]-4- [ (4-pvridinylcarbonvl)amino l L-phenvlalanine H N Y 0 N OH H 0 Following the procedure of Method 3 (modified) above, the title compound was 15 obtained as its corresponding lithium salt in 92% yield as a white solid. 'H NMR (DMSO-d 6 , 400 MHz) 6 10.46 (s, 1H), 8.75 (dd, J = 4.4, 1.8 Hz, 2H), 7.83 (dd, J = 4.4, 1.8 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 6.2 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 4.33 (q, J = 5.5 Hz, 1H), 3.65 (br s, 2H), 3.25 (br s, 2H), 3.11 (d, J = 20 5.7 Hz, 3H), 1.43 (br s, 4H), 1.15 (br s, 11 Hz), 0.78 (s, 6H). MS ((+)FAB, m/e (%)) 555 (100, [M+Li]*), 549 (97, [M+H]*). IR (KBr, cm
'
) 3330, 2910, 1800, 1660, 1580, 1520, 1410, 1300. Anal. Calc'd for C 3 1
H
3 9
N
4 0 5 Li * 2 H,O: C, 62.99; H, 7.33; N, 9.48. 25 Found: C, 62.65; H, 7.23; N, 9.31.
WO 00/35855 PCT/US99/29369 - 30 Example 40 (Method 2) N-[2-(Methyl-pyridin-3-vlmethyl-amino)-3,4-dioxo-cyclobut- 1 -envl]l-4-[(pyridine-4 carbonvl)-amino]-L-phenylalanine methyl ester 5 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4-[(4-pyridinylcarbonyl)amino]-L-phenyl alanine methyl ester and methyl-(3-pyridinylmethyl)amine in 88% yield as a colorless foam which was carried on immediately to the subsequent reaction. 10 Example 41 (Method 3 (modified)) N-[2-(Methyl-pyridin-3-ylmethyl-amino)-3,4-dioxo-cyclobut- I -envl]l-4-f(pyridine-4 carbonvyl)-aminol]-L-phenylalanine 0 IN N,\ O N H O N CH 0H O 15 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 85% yield as a yellow solid. 1 H NMR (DMSO-d 6 , 400 MHz) 6 10.47 (s, 1H), 8.77 (dd, J = 4.4, 1.8 Hz, 2H), 8.50 (min, 2H), 7.84 (min, 2H), 7.70 (br m, 1H), 7.58 (d, J = 8.6 Hz, 3H), 7.39 (dd, J = 7.6, 20 4.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 4.7 (d, J = 15.2 Hz, 1H), 4.68 (br m, 1H), 4.54 (br s, 1H), 3.18 (dd, J = 13.6, 4.3 Hz, 1H), 3.01 (s, 3H), 2.94 (dd, J = 13.6, 8.3 Hz, 1H). MS ((+), (-) ESI, m/e (%)) 486 (82, [M+H]+), 484 (58, [M-H]). IR (KBr, cm') 3400, 1800, 1620, 1580, 1530, 1410, 1325. 25 WO 00/35855 PCT/US99/29369 -31 Example 42 (Method 1) [2-Ethoxy-3.4-dioxo-cvclobut- I -enyll-4- [ (3-pyridinylcarbonyl)amino]-L phenylalanine methyl ester 5 Following the procedure of Method 1 above, the title compound was obtained from 4-[(3-pyridinylcarbonyl)amino]-L-phenylalanine methyl ester hydrochloride and 3,4 diethoxy-3-cyclobutene-1,2-dione in 74% yield. 10 'H NMR (DMSO-d 6 , 300 MHz) 8 10.4 (s, 1H), 9.1 (br dd, 1H), 9.08 (d, 1H) 8.75 (dd, 1H), 8.27 (dt, 1H), 7.68 (d, 2H), 7.56 (dd, 1H), 7.23 (d, 2H), 4.9 (m, 1H), 4.58 (m, 2H), 3.68 (s, 3H), 3.23 (dd, 1H), 2.96 (m, 1H), 1.32 (m, 3H). 15 Example 43 (Method 2) N- [2-(Dihexvlamino)-3,4-dioxo- I -cyclobuten- I -yvl -4- [(3-pvridinylcarbonvyl)amino] L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from 20 [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4- [ (3-pyridinylcarbonyl)amino]-L phenylalanine methyl ester and dihexylamine in 95% yield as a yellow foam which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 32 Example 44 (Method 3 (modified)) N-[2-(Dihexvlamino)-3.4-dioxo- 1-cyclobuten- 1-vll-4-[(3-pyridinylcarbonyl)amino] L-phenvlalanine NN N OH N ):tO N. 0 H 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 53% yield as a white solid. 'H NMR (DMSO-d 6 , 400 MHz) 6 10.38 (s, 1H), 9.06 (dd, J = 2.4, 1.8 Hz, 1H), 8.72 10 (dd, J = 4.7, 1.7 Hz, 1H), 8.25 (dt, J = 2.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.54 (m, 1H), 7.09 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 4.45 (m, 1H), 3.28 (br s, 4H), 3.11 (dd, J = 13.6, 4.8 Hz, 1H), 2.99 (dd, J = 13.8, 7.2 Hz, 1H), 1.40 (br s, 4H), 1.16 (br s, 12H), 0.74 (s, 6H). 15 MS ((+)FAB, m/e (%)) 555 (43, [M+Li]f), 549 (100, [M+H] ). IR (KBr, cm-) 3375 (br), 2900, 1800, 1660, 1575, 1530, 1410, 1325. Example 45 (Method 2) N-[2-[Methyl[2-(4-pyridinvyl)ethyl] aminol-3,4-dioxo- I -cyclobuten- I -vll-4-[(3 20 pyridinylcarbonyl)amino]-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4-[(3-pyridinylcarbonyl)amino]-L phenylalanine methyl ester and methyl-[2-(4-pyridinyl)ethyl]amine in 54% yield as a 25 yellow foam which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 33 Example 46 (Method 3 (modified)) N-[2-[Methyl[2-(4-pvridinvyl)ethyll aminol-3.4-dioxo- I -cyclobuten- 1 -vI-4-[(3 pyridinvlcarbonvl)amino]-L-phenvlalanine H N N o 0 N N OH H
CH
3 O 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 81% yield as a pale yellow solid. 'H NMR (DMSO-d 6 , 400 MH) 6 10.39 (s, 1H), 9.04 (d, J = 1.8 Hz, 1H), 8.71 (dd, J = 10 4.8, 1.8 Hz, 1H), 8.39 (d, J = 4.6 Hz, 2H), 8.24 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.52 (m, 1H), 7.43 (br s, 1H), 7.19 (d, J = 5.3 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 4.42 (d, J = 4.4 Hz, 1H), 3.70 (br s, 2H), 3.10 (m, 5H), 2.81 (m, 2H). MS ((+)ESI, m/e (%)) 506 (25, [M+Li]'), 500 (100, [M+H]+). IR (KBr, cm') 3400 (br), 1810, 1660, 1580, 1535, 1410, 1320. 15 Anal. Calc'd for C 27
H
24
N
5
O
5 Li * 2.5 H 2 0: C, 58.90; H, 5.49; N, 12.72. Found: C, 58.68; H, 5.25; N, 12.46. Example 47 (Method 2) 20 N-[2-(Methyl-pyridin-3-vlmethyl-amino)-3.4-dioxo-cyclobut- I -envl]l-4-[(pyridine-3 carbonvl)-aminol-L-phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-4-[(3-pyridinylcarbonyl)amino]-L 25 phenylalanine methyl ester and methyl-(3-pyridinylmethyl)amine in 66% yield as a colorless foam which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 34 Example 48 (Method 3 (modified)) N-[2-(Methyl-pyridin-3-vlmethyl-amino)-3.4-dioxo-cyclobut- I -envl]l-4-[(pyridine-3 carbonvyl)-amino]-L-phenvlalanine N 0\ O N N OH ~H I!% ' H3 H N CHs 0 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 73% yield as a white solid. 'H NMR (DMSO-d 6, 400 MHz) 5 10.4 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 8.73 (dd, J = 10 4.8, 1.8 Hz, 1H), 8.5 (m, 2H), 8.28 (dt, J = 2.0 Hz, 1H), 7.72 (br m, 1H), 7.57 (m, 4H), 7.39 (dd, J = 7.7, 4.8 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 4.76 (d, J = 14.9 Hz, 1H), 4.66 (br m, 1H), 4.55 (br s, 1H), 3.18 (dd, J = 13.6, 4.3 Hz, 1H), 3.01 (s, 3H), 2.94 (dd, J = 13.8, 8.2 Hz, 1H). MS ((-), (+)ESI, m/e (%)) 486 (18, [M+H]'), 484 (100, [M-H]) 15 IR (KBr, cm') 3275 (br), 1800, 1660, 1580, 1530, 1410, 1315. Anal. Calc'd for C 2 6
H
2 ,,NsOsLi * 2.8 HO: C, 57.62; H, 5.13; N, 12.92. Found: C, 57.56; H, 4.74; N, 12.73. 20 Example 49 (Method 2) N- {2-[Methyl-(2-pyridin-4-vl-ethyl)-amino]-3.4-dioxo-cyclobut- 1 -envl } -L phenylalanine methyl ester Following the procedure of Method 2 above, the title compound was obtained from 25 [2-ethoxy-3,4-dioxo-cyclobut- I -enyl]-L-phenylalanine methyl ester and methyl-[2 (4-pyridinyl)ethyl]amine in 55% yield as a clear oil which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 35 Example 50 (Method 3 (modified)) N- { 2-[Methyl-(2-pyridin-4-vl-ethvl)-amino]-3.4-dioxo-cyclobut- I -envyl }I -L phenylalanine N N N O H H 5 CH 3 O Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 87% yield as a white solid. 10 'H NMR (DMSO-d6, 400 MHz) 5 8.4 (d, J = 5.7 Hz, 2H), 7.42 (br m, 1H), 7.2 (d, J = 5.7 Hz, 2H), 7.11 (m, 5H), 4.39 (d, J = 4.6 Hz, 1H), 3.68 (br s, 2H), 3.18 (m, 5H), 2.78 (mn, 2H). MS ((+)FAB, m/e (%)) 402 (45, [M+Na]*), 380 (100, [M+H]'). IR (KBr, cm-) 3375, 1800, 1580, 1530, 1410. 15 Anal. Calc'd for C21H 2 oN 3 0,Li * 1.5 HO0: C, 61.21; H, 5.63; N, 10.20. Found: C, 61.00; H, 5.44; N, 10.05. Example 51 (Method 1) 20 [2-Ethoxy-3,4-dioxo-cyclobut-l-envll- {4- [4-(N carboxvbenzovyl)piperidinvlcarbonyl]amino I}-L-phenvlalanine methyl ester Following the procedure of Method 1 above, the title compound was obtained from { 4-[4-(N-carboxybenzoyl)piperidinylcarbonyl] amino }-L-phenylalanine methyl 25 ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1,2-dione in 37% yield.
WO 00/35855 PCT/US99/29369 - 36 Example 52 (Method 2) N-12-(Dihexylamino)-3,4-dioxo- 1 -cyclobuten-1 -yll- {4- [4-(N carboxvbenzoyl)piperidinvlcarbonvll amino I -L-phenvlalanine methyl ester 5 Following the procedure of Method 2 above, the title compound was obtained from [2-ethoxy-3,4-dioxo-cyclobut- 1-enyl]- { 4- [4-(N-carboxybenzoyl)piperidinyl carbonyl]-amino}-L-phenylalanine methyl ester and dihexylamine in 50% yield as a clear oil which was carried on immediately to the subsequent reaction. 10 Example 53 (Method 3) N-[2-(Dihexvlamino)-3,4-dioxo- 1-cyclobuten-1-yl]- { 4- [4-(N-carboxybenzoyl) piperidinylcarbonyll amino I -L-phenvlalanine methyl ester 00 I o H OY N OH HO 15 Following the procedure of Method 3 above, the title compound was obtained in 75% yield as a light yellow solid, mp = 75-80 0 C. 'H NMR (DMSO-d 6 , 400 MHz) 6 13.01 (br s, 1H), 9.83 (s, 1H), 7.57 (d, 1H, J = 9.0 Hz), 7.47 (d, 2H, J = 8.3 Hz), 7.33 (m, 4H), 7.12 (d, 2H, J = 8.6 Hz), 5.07 (s, 2H), 20 5.03 (m, 1H), 4.04 (d, 2H, J = 13.2 Hz), 3.5 (br m, 4H), 3.28 (br s, under H,O, 1H), 3.16 (dd, 1H, J = 3.8 Hz), 2.93 (dd, 1H, J = 11.0 Hz), 2.85 (br m, 2H), 1.76 (m, 2H), 1.48 (m, 6H), 1.20 (br s, 13H), 0.82 (t, 6H, J = 6.7 Hz). MS ([M+H]', m/e (%)) 689 (30), 555 (25), 186 (65), 91 (100). IR (KBr, cm') 3320, 2930, 1810, 1675, 1580, 1520, 1235. 25 Anal. Calc'd for C 39
H
52
N
4 0 7 . C, 68.00; H, 7.61; N, 8.13. Found: C, 67.60; H, 7.79; N, 7.95.
WO 00/35855 PCT/US99/29369 - 37 Example 54 (Method 1) [2-Ethoxy-3.4-dioxo-cyclobut- I -enyll-L-tyrosine methyl ester Following the procedure of Method 1 above, the title compound was obtained from 5 L-tyrosine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1,2-dione in 95% yield. Example 55 (Method 4) (2S)-3-(4-Dimethylcarbamoyloxy-phenyl)-2-ethoxy-3.4-dioxo-cyclobut- 1 10 enylamino]-propionic acid methyl ester To a solution of [2-ethoxy-3,4-dioxo-cyclobut-l-enyl]-L-tyrosine methyl ester (1.6 mmol, 500 mg) in pyridine (15 mL) was added neat dimethylcarbamyl chloride (4.7 mmol, 505 mg; 433 gtL) dropwise and the resulting solution was heated at 40oC for 15 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and 1N HC1. The organics were washed with additional 1N HC1, water, and brine and dried (Na 2 SO,). Purification by flash chromatography (SiO,: 60% EtOAc/hexane) afforded the title compound as a yellow foam (282 mg; 45% yield). 20 Example 56 (Method 2) (2S)-3-(4-Dimethylcarbamoyloxy-phenvyl)-2-[2-(methyl-phenethyl-amino)-3,4-dioxo -cyclobut-1-enylamino]-propionic acid methyl ester 25 Following the procedure of Method 2 above, the title compound was obtained from (2S)-3-(4-dimethylcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo-cyclobut- 1 enylamino]-propionic acid methyl ester and methyl-(2-phenethyl)amine in 75% yield as a colorless foam which was carried on immediately to the subsequent reaction. 30 'H NMR (DMSO-d 6 , 400 MHz) 8 7.85 (d, 1H, J = 9.0 Hz), 7.22 (mn, 8H), 7.01 (d, 2H, J = 8.6 Hz), 5.12 (m, 1H), 3.72 (br m, 1H), 3.68 (s, 3H), 3.21 (dd, 1H, J = 4.5 Hz), 3.09 (s, 3H), 2.99 (s, 4H), 2.88 (s, 3H), 2.81 (m, 2H).
WO 00/35855 PCT/US99/29369 -38 Example 57 (Method 3 (modified)) (2S)-3-(4-Dimethylcarbamoyloxy-phenyl)-2-[2-(methyl-phenethyl-amino)-3.4-dioxo -cyclobut- I -envlamino]-propionic acid I /ON~ Ni N OH H 5
CH
3 0 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 82% yield as a white solid. 10 'H NMR (DMSO-d 6 , 400 MHz) 5 7.33 (br m, 1H), 7.26 (m, 5H), 7.1 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 4.36 (d, 1H, J = 4.8 Hz), 3.65 (br m, 2H), 3.12 (dd, 2H, J = 5.1 Hz), 3.07 (s, 3H), 2.98 (s, 3H), 2.86 (s, 3H), 2.79 (m, 2H). MS ((+)FAB, m/e (%)) 488 (55, [M + Na]+), 472 (60, [M + Li]'), 466 (100, [M + H]+). 15 IR (KBr, cm') 3410, 2910, 1810, 1725, 1580, 1530, 1410, 1210. Anal. Calc'd for C 25
H,
6 N30 6 Li * 1.5 HO0. C, 60.24; H, 5.86; N, 8.43. Found: C, 60.40; H, 5.65; N, 8.27. 20 Example 58 (Method 2) (2S)-2-(2-Dihexylamino-3,4-dioxo-cyclobut- I -envlamino)-3-(4-dimethylcarbamovl oxy-phenvl)-propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from 25 (2S)-3-(4-dimethylcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo-cyclobut- 1 enylamino]-propionic acid methyl ester and dihexylamine in 40% yield as a yellow oil which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 39 Example 59 (Method 3) (2S)-2-(2-Dihexylamino-3,4-dioxo-cyclobut- I -enylamino)-3-(4-dimethylcarbamoyl oxy-phenvl)-propionic acid 0 YN QiO OJ 0 N OH HH QH 0 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 70% yield as a light yellow solid. 1 H NMR (DMSO-d6, 400 MHz) 8 7.11 (d, 1H, J = 6.4 Hz), 7.045 (min, 2H), 6.87 (inm, 10 2H), 4.28 (min, 1H), 3.5 (br m, 4H), 3.12 (d, 2H, J = 5.3 Hz), 2.99 (s, 3H), 2.87 (s, 3H), 1.43 (br m, 4H), 1.18 (br m, 12H), 0.82 (t, 6H, J = 6.9 Hz). MS ((+)ESI, m/e (%)) 533 (30, (M+NH4')+), 516 (100, (M+H)+). IR (KBr, cm-) 3400, 2910, 1800, 1730, 1580, 1520, 1380, 1220. 15 Anal. Calc'd for C 28 H40 30 6 Li * 1.25 H 2 0: C, 61.77; H, 7.87; N, 7.72. Found: C, 61.67; H, 7.42; N, 7.45. Example 60 (Method 2) (2S)-3-(4-Dimethvlcarbamovyloxy-phenyl)-2-[2-(methvl-pyridin-3-ylmethyl-amino) 20 3,4-dioxo-cyclobut- I -enylaminol-propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from (2S)-3-(4-dimethylcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo-cyclobut- 1 enylamino]-propionic acid methyl ester and methyl-(3-pyridinylmethyl)amine in 82% 25 yield as a colorless foam which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 - 40 Example 61 (Method 3 (modified)) (2S)-3-(4-Dimethylcarbamovloxy-phenvl)-2-[2-(methyl-pyridin-3-vlmethyl-amino) 3.4-dioxo-cyclobut- 1 -enylviamino]-propionic acid I QO OyN H OH N H3 H 0 N N 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 88% yield as a light yellow solid. 'H NMR (DMSO-d , 400 MHz) 8.50 (m, 2H), 7.67 (br m, 1H), 7.61 (d, 1H, J = 7.7 10 Hz), 7.38 (dd, 1H, J = 4.7 Hz), 7.12 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.3 Hz), 4.0 (m, 2H), 4.51 (br s, 1H), 3.18 (dd, 1H, J = 4.3 Hz), 3.02 (s, 3H), 2.99 (s, 3H), 2.94 (m, 1H), 2.88 (s, 3H). MS ((+)ESI, m/e (%)) 459 (19, [M+Li] ), 453 (100, [M+H]*). IR (KBr, cm') 3410, 2920, 1810, 1730, 1580, 1530, 1410, 1220. 15 Anal. Calc'd for C, 3
H
23
N
4 0 6 Li * 1.5 HO. C, 56.90; H, 5.40; N, 11.54. Found: C, 56.63; H, 5.17; N, 11.41. Example 62 (Method 2) 20 (2S)-3-(4-Dimethylcarbamovloxy-phenvl)-2- {2-[methyl-(2-pyridin-4-vl-ethyl) amino] -3,4-dioxo-cyclobut- I -envylamino I -propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from (2S)-3- (4-dimethylcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo-cyclobut- 1 25 enylamino]-propionic acid methyl ester and methyl-[2-(4-pyridinyl)ethyl]amine in 77% yield as a colorless foam which was carried on immediately to the subsequent reaction.
WO 00/35855 PCT/US99/29369 -41 Example 63 (Method 3 (modified)) (2S)-3-(4-Dimethylcarbamovloxy-phenvl)-2- { 2-[methyl-(2-pyridin-4-vl-ethyl) amino] -3.4-dioxo-cyclobut- I -enylamino I -propionic acid ON" N OH NH
CH
3 O 5 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 88% yield as a yellow solid. 'H NMR (DMSO-d , 400 MHz) 8 8.41 (d, 2H, J = 5.5 Hz), 7.41 (m, 1H), 7.21 (d, 2H, 10 J = 5.7 Hz), 7.09 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 4.37 (m, 1H), 3.70 (br m, 2H), 3.09 (m, 5H), 2.98 (s, 3H), 2.86 (s, 3H), 2.80 (br m, 2H). MS ((+)ESI, m/e (%)) 473 (20, [M+Li]'), 467 (100, [M+H]+). IR (KBr, cm') 3410, 2930, 1800, 1770, 1580, 1530, 1410, 1210, 1160. 15 Anal. Calc'd for C 2 4
H
25
N
4
O
6 Li * 2.0 H2
O
. C, 56.69; H, 5.75; N, 11.02. Found: C, 56.82; H, 5.43; N, 10.89. Example 64 (Method 5) (2S)-3-[4-(4-methylpiperazinvl)carbamoyvloxy-phenvll-2-ethoxy-3,4-dioxo-cyclobut 20 1-envlaminol-propionic acid methyl ester To a solution of phosgene (1.9M solution in toluene; 7.8 mmol; 4.1 mL) in CHC1, (80mL) at 0OC was added a solution of [2-ethoxy-3,4-dioxo-cyclobut-1-enyl]-L tyrosine methyl ester (7.8 mmol, 2.5 g) and pyridine (8.0 mmol, 633 mg; 647 L) in 25 CH 2 C1 2 (10 mL) dropwise over 15 minutes. The resulting solution was stirred at 0oC for 30 minutes and a solution was N-methylpiperazine (11.7 mmol, 1.2 g; 1.3 mL) and pyridine (11.7 mmol, 929 mg; 950 L) in CH 2 C1, (10 mL) was then added dropwise over 30 minutes. The resulting solution was warmed to room temperature WO 00/35855 PCT/US99/29369 - 42 and stirred overnight. The reaction mixture was concentrated in vacuto and the residue was partitioned between EtOAc and water. The organics were dried (Na 2
SO
4 ), concentrated, and purified by falsh chromatography (SiO,: 5% Et 3 N / EtOAc) to afford the title compound as a colorless foam (1.3g; 37%). 5 Example 65 (Method 2) (2S)-3-[4-(4-methylpiperazinyl)carbamoyloxy-phenvll-2-[2-(methyl-phenethyl amino)-3,4-dioxo-cyclobut- I -enylamino]-propionic acid methyl ester 10 Following the procedure of Method 2 above, the title compound was obtained from (2S)-3-[4-(4-methylpiperazinyl)carbamoyloxy-phenyl]-2-ethoxy-3,4-dioxo-cyclobut 1-enylamino]-propionic acid methyl ester and methyl-(2-phenethyl)amine in 95% yield as a colorless foam which was carried on immediately to the subsequent reaction. 15 Example 66 (Method 3) (2S)-3-[4-(4-methylpiperazinvl)carbamoyloxy-phenyvll-2- [2-(methyl-phenethyl amino)-3,4-dioxo-cyclobut- I -enylaminol-propionic acid
NCH
3 N 0 N N OH O NH
CH
3 0 20 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 90% yield as a white solid. 'H NMR (DMSO-d 6 , 400 MHz) 8 7.32-7.16 (m, 6H), 7.09 (d, 2H, J = 8.6 Hz), 6.90 25 (d, 2H, J = 8.6 Hz), 4.32 (m, 1H), 3.65 (br m, 2H), 3.51 (br s, 2H), 3.38 (br s, 2H), 3.08 (m, 5H), 2.79 (br m, 2H), 2.31 (m, 4H), 2.19 (s, 3H). MS (FAB, mle (%)) 543 (35, (M+Na)+), 527 (40, (M+Li)) 521 (100). IR (KBr, cm'") 3410, 2930, 1810, 1725, 1580, 1530, 1410, 1210.
WO 00/35855 PCT/US99/29369 - 43 Anal. Calc'd for C,,H 3
N
4 0 6 Li * 2.0 H,O. C, 59.78; H, 6.27; N, 9.96. Found: C, 60.04; H, 6.07; N, 9.77. 5 Example 67 (Method 2) (2S)-3-[4-(4-methylpiperazinvl)carbamoyloxy-phenvl)-2- { 2-[methyl-(2-pyridin-4-vl ethyl)-aminol-3,4-dioxo-cyclobut- I -envlamino }-propionic acid methyl ester Following the procedure of Method 2 above, the title compound was obtained from 10 (2S)-3-[4-(4-methylpiperazinyl)lcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo cyclobut-1-enylamino]-propionic acid methyl ester and methyl-[2-(4 pyridinyl)ethyl]amine in 62% yield as a yellow foam which was carried on immediately to the subsequent reaction. 15 Example 68 (Method 3 (modified)) (2S)-3-[4-(4-methylpiperazinyl)carbamovloxy-phenvl)-2- { 2-[methyl-(2-pyridin-4-yl ethyl)-amino]-3,4-dioxo-cyclobut- I -enylamino I }-propionic acid rl--NC H 3
SOHOH
3 NN N OH NH
CH
3 0 20 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 80% yield as a off-white solid. 1 H NMR (DMSO-d , 400 MHz) 5 8.41 (d, 2H, J = 5.9 Hz), 7.39 (m, 1H), 7.21 (d, 2H, J = 5.7 Hz), 7.09 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.38 (m, 1H), 3.69 (br 25 m, 2H), 3.51 (br s, 2H), 3.35 (br s, 4H, under H 2 0 peak), 3.09 (m, 4H), 2.82 (m, 2H), 2.30 (m, 4H), 2.19 (s, 3H). MS ((+)FAB, m/e (%)) 534 (100, [M+2Li]f), 528 (50, [M+Li]+). IR (KBr, cm") 3400 (br), 2920, 1810, 1720, 1580, 1530, 1410.
WO 00/35855 PCT/US99/29369 - 44 Example 69 (Method 2) (2S)-3- [4-(4-m ethylpiperazinyl)carbamoyloxy-phen1)-2- {2-dihexvlamino]-3.4 dioxo-cyclobut- I -enylviamino I -propionic acid methyl ester 5 Following the procedure of Method 2 above, the title compound was obtained from (2S)-3-[4-(4-methylpiperazinyl)lcarbamoyloxy-phenyl)-2-ethoxy-3,4-dioxo cyclobut- I -enylamino]-propionic acid methyl ester and dihexylamine in 85% yield as a colorless foam which was carried on immediately to the subsequent reaction. 10 Example 70 (Method 3 (modified)) (2S)-3-[4-(4-methylpiperazinvl)carbamoyloxy-phenyl)-2- { 2-dihexylamino]-3.4 dioxo-cyclobut- I -enylamino }-propionic acid l NCH 3 N,.) QyO N' CV,,, ~ OH 0 N N OH H 0 15 Following the procedure of Method 3 (modified) above, the title compound was obtained as its corresponding lithium salt in 84% yield as a white solid. 'H NMR (DMSO-d , 400 MHz) 8 7.11 (d, 1H, J = 6.4 Hz), 7.05 (m, 2H), 6.88 (m, 2H), 4.29 (m, 1H), 3.65 (br m, 2H), 3.55 (br s, 3H), 3.34 (br s, 4H, under HO peak), 20 3.12 (d, 2H, J = 5.3 Hz), 2.31 (m, 4H), 2.19 (s, 3H), 1.43 (br m, 4H), 1.18 (br m, 11H), 0.82 (t, 6H, J - 6.9 Hz). MS ((+)FAB, m/e (%)) 577 (100, [M+Li]), 531 (20), 186 (45), 127 (80). IR (KBr, cm-) 3410, 2920, 1810, 1580, 1520, 1410. 25 Anal. Calc'd for C 3
,H
4 5
N
4 06Li * 1.5 H,O. C, 61.68; H, 8.02; N, 9.28. Found: C, 61.43; H, 7.78; N, 9.04.
WO 00/35855 PCT/US99/29369 - 45 The foregoing compounds were tested for VLA-4 binding activity using the following monvalent FACS assay. The IC,, for a compound reflects 50% receptor occupancy. The assay can accurately measure the activity of compounds with ICso ranging from 0.5nM to ImM. 5 Monovalent FACS Assay for af, Integrin/VCAM-1 Binding The VLA-4 binding activity of exemplary compounds was measured by measuring the inhibition of the interaction of soluble VCAM-1 with Jurkat cells 10 (ATCC #TIB-153) which express high levels of a 4 f, integrin (VLA-4) using a modification of the fluorescence activated cell sorter (FACS) assay described by Yednock, et al., J. Biol. Chem., 1995, 270:28740. VCAM-1 interacts with the cell surface in an ( 4 1 integrin-dependent fashion. Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovine 15 serum, penicillin, streptomycin and glutamine as described by Yednock, supra. Recombinant soluble VCAM-1 (rsVCAM-1) was produced in a baculovirus expression system as a chimeric fusion protein containing the seven immunoglobulin domains of VCAM-1 on the N-terminus and the human IgG, heavy chain constant region on the C-terminus as described by Yednock, supra. Supernatant containing 20 approximately 10ug/ml rsVCAM-1 was collected after 72 hours and used in the assay without purification. Jurkat cells (approximately 107 cells/ml) were treated with 1.5mM MnCl 2 and 5ptg/ml 15/7 for 30 minutes on ice to activate 0, integrin. Mn 2 activates the receptor to enhance ligand binding, and 15/7 is a monoclonal antibody that recognizes an 25 activated/ligand occupied conformation of a 4 f, integrin and locks the molecule into this conformation thereby stabilizing the VCAM-1/ 4 f3, integrin interaction. Yednock, et al., supra. Antibodies similar to 15/7 have been prepared and may be used in this assay. For example, see, Luque, et al., 1996, J. Bio. Chem., 271: 11067. Aliquots of 25 pl cells were incubated for 30 minutes at room temperature 30 with compounds using a standard 5-point serial dilution. 15 ptl of rsVCAM-Fc- WO 00/35855 PCT/US99/29369 - 46 containing baculovirus supernatant was added to the cells and incubated for 30 minutes on ice as described in Yednock, et al., supra. Cells were washed twice and resuspended in 100 tl of a 1:100 dilution of FITC-conjugated goat anti-human IgG to detect the human Ig-VCAM-1 construct 5 diluted in assay media containing 2.5%7 mouse serum to block potential cross reactivity with cell surface bound 15/7. Cells were incubated on ice for 30 minutes in the dark. Cells were washed twice and analyzed with a standard FACS analysis as described in Yednock, et al., supra. on a FACScan flow cytometer (Becton Dickinson, Mountain View, CA). 10 Data is shown in Table 1. Table 1 Example IC50 (FACS) 4M 3 58 pM 5 101 pM 7 52 pM 9 116 pM 11 4.4 pM 13 4.4 pM 15 1.5 pM 17 36 pM 19 13 pM 21 86 pM 23 40 pM 26 150 nM 29 631 nM 32 12 nM 35 15 nM 37 2.2 nM 39 1.3 nM 41 26 nM 44 6.5 nM WO 00/35855 PCT/US99/29369 - 47 Example 1C50 (FACS) 4M 46 40 nM 48 160 nM 50 9 PM 53 71 nM 57 0.9 nM 59 0.6 nM 61 8.3 nM 63 1.6 nM 66 0.5 nM 68 1.3 nM 70 0.2 nM Thus, compounds of the present invention exhibit high affinity for VLA-4, and can effectively inhibit the interaction of VLA-4 with VCAM. The compounds are useful 5 for the treatment of inflammatory and autoimmune diseases including, but not limited to multiple sclerosis, meningitis, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel syndrome, rheumatoid arthritis, tumor metastasis, tissue transplantation, and myocardial ischemia. 10 The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and salts with organic acids such as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with 15 alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium. The compounds of the present invention can also be used in the form of esters at the C-terminus; carbamates, amides and the like at the N-terminus or other conventional "pro-drug" forms which, when administered, convert to the active moiety in vivo. 20 WO 00/35855 PCT/US99/29369 - 48 Compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile 5 water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. These compounds may be administered orally as well 10 as by intravenous, intramuscular, or subcutaneous routes. When administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions, formulations may contain, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, or elixirs containing, for example, from about 20 to 50% ethanol, and the like. When administration is 15 parenterally, formulation may be, for example, sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% by weight of active ingredient in combination with a carrier, and more preferably between about 5% and 60% by weight of active ingredient. 20 The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard filled or liquid-filled capsules. Oral administration of the compounds is preferred. 25 The dosage requirements can be determined by one skilled in the art and will vary with the particular composition employed, the route of administration, the severity of the symptoms presented and the particular subject being treated.

Claims (39)

1. A compound of the formula: 0 0o R1 O O (Q H 2)z N N-(CH 2 )x- OH R
2 R3 (CH 2 )y -1 5 O wherein R' is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R 2 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or R' and R 2 may be taken together to form a saturated or unsaturated heterocyclic ring; 10 R 3 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; A is aryl or heteroaryl; and x, y and z are independently 0, 1, 2, 3, or a pharmaceutical salt thereof. 15 2. The compound of Claim 1 wherein A is phenyl, R' is alkyl, R 2 and R 3 are H, x and y are 0 and z is 1.
3. The compound of Claim 2 wherein A is substituted phenyl. 20
4. The compound of Claim 1 wherein A is phenyl, R' is heteroaralkyl, R 2 and R 3 are H, x and y are 0 and z is 1.
5. The compound of Claim 1 wherein A is substituted aryl and the substituent is OCONR 6 R 7 . 25
6. A compound of Claim 1 which is [2-(benzylamino)-3,4-dioxo-cyclobut-1 enyl]-L-phenylalanine; or a pharmaceutical salt thereof. WO 00/35855 PCT/US99/29369 - 50
7. A compound of Claim 1 which is [2-(benzhydrylamino)-3,4-dioxo-cyclobut 1-enyl]-L-phenylalanine; or a pharmaceutical salt thereof.
8. A compound of Claim 1 which is 2- { 2-[2-(1H-Indol-3-yl)-ethylamino]-3,4 5 dioxo-cyclobut-1-enylamino}-L-phenylalanine; or a pharmaceutical salt thereof.
9. A compound of Claim 1 which is { 3,4-dioxo-2-[(pyridin-3-ylmethyl)-amino] cyclobut- 1-enyl }-L-phenylalanine; or a pharmaceutical salt thereof.
10 10. A compound of Claim 1 which is [2-(benzyl-hexyl-amino)-3,4-dioxo cyclobut-1-enyl]-L-phenylalanine; or a pharmaceutical salt thereof.
11. A compound of Claim 1 which is (2-dibenzylamino-3,4-dioxo-cyclobut-1 enylamino)-L-phenylalanine; or a pharmaceutical salt thereof. 15
12. A compound of Claim 1 which is (S)-2-(2-dihexylamino-3,4-dioxo-cyclobut 1-enylamino)-3-phenyl-propionic acid; or a pharmaceutical salt thereof.
13. A compound of Claim 1 which is (S)-2-[2-(hexyl-naphthalen-2-ylmethyl 20 amino)-3,4-dioxo-cyclobut-1-enylamino]-3-phenyl-propionic acid; or a pharmaceutical salt thereof.
14. A compound of Claim 1 which is (S)-2-{ 2-[(4-dimethylamino-benzyl)-hexyl amino]-3,4-dioxo-cyclobut- 1-enylamino }-3-phenyl-propionic acid; or a 25 pharmaceutical salt thereof.
15. A compound of Claim 1 which is N-[3,4-dioxo-2-(4-phenyl-piperazin-1-yl) cyclobut-1-en-1-yl]-L-phenylalanine; or a pharmaceutical salt thereof. 30
16. A compound of Claim 1 which is (S)-2-[2-(4-acetyl-piperazin-1-yl)-3,4 dioxo-cyclobut-1-enylamino]-3-phenyl-propionic acid; or a pharmaceutical salt thereof. WO 00/35855 PCT/US99/29369 -51
17. A compound of Claim I which is (S)-3-(4-benzoylamino-phenyl)-2-(2 dihexylamino-3,4-dioxo-cyclobut- I -enylamino)-propionic acid; or a pharmaceutical salt thereof. 5
18. A compound of Claim 1 which is (S)-3-(1-benzyl-I1H-imidazol-4-yl)-2-(2 dihexylamino-3,4-dioxo-cyclobut- I -enylamino)-propionic acid; or a pharmaceutical salt thereof.
19. A compound of Claim I which is N-(2-dihexylamino-3,4-dioxo-cyclobut-1 10 enylamino)-O-(3-dimethylamino-propyl)-L-tyrosine; or a pharmaceutical salt thereof.
20. A compound of Claim 1 which is N-[2-[methyl[2-(4-pyridinyl)ethyl]amino] 3,4-dioxo- 1-cyclobuten- 1-yl]-4-[(4-pyridinylcarbonyl)amino]-L-phenylalanine; or a pharmaceutical salt thereof. 15
21. A compound of Claim I which is N-[2-[methyl(2-phenylethyl)amino]-3,4 dioxo- I -cyclobuten- 1-yl]- 4 -[(4-pyridinylcarbonyl)amino]-L-phenylalanine; or a pharmaceutical salt thereof. 20
22. A compound of Claim 1 which is N-[2-(dihexylamino)-3,4-dioxo-1-cyclo buten-1l-yl]-4-[(4-pyridinylcarbonyl)amino]-L-phenylalanine; or a pharmaceutical salt thereof.
23. A compound of Claim 1 which is N-[2-(methyl-pyridin-3-ylmethyl-amino) 25 3,4-dioxo-cyclobut-1-enyl]-4-[(pyridine-4-carbonyl)-amino]-L-phenylalanine; or a pharmaceutical salt thereof.
24. A compound of Claim I which is N-[2-(dihexylamino)-3,4-dioxo-1-cyclo buten- 1-yl]-4-[(3-pyridinylcarbonyl)amino]-L-phenylalanine; or a pharmaceutical 30 salt thereof.
25. A compound of Claim 1 which is N-[2-[methyl[2-(4-pyridinyl)ethyl] amino] 3,4-dioxo- 1-cyclobuten-1-yl]-4-[(3-pyridinylcarbonyl)amino]-L-phenylalanine; or a pharmaceutical salt thereof. WO 00/35855 PCT/US99/29369 - 52
26. A compound of Claim 1 which is N-[2-(methyl-pyridin-3-ylmethyl-amino) 3,4-dioxo-cyclobut- 1-enyl]-4-[(pyridine-3-carbonyl)-amino]-L-phenylalanine; or a pharmaceutical salt thereof. 5
27. A compound of Claim 1 which is N-{2-[methyl-(2-pyridin-4-yl-ethyl) amino]-3,4-dioxo-cyclobut-1-enyl }-L-phenylalanine; or a pharmaceutical salt thereof. 10
28. A compound of Claim 1 which is N-[2-(dihexylamino)-3,4-dioxo-1-cyclo buten-1-yl]- { 4- [4-(N- carboxybenzoyl)-piperidinylcarbonyl]amino }-L-phenyl alanine methyl ester; or a pharmaceutical salt thereof.
29. A compound of Claim 1 which is (2S)-3-(4-dimethylcarbamoyloxy-phenyl) 15 2-[2-(methyl-phenethyl-amino)-3,4-dioxo-cyclobut- I -enylamino]-propionic acid; or a pharmaceutical salt thereof.
30. A compound of Claim 1 which is (2S)-2-(2-dihexylamino-3,4-dioxo-cyclo but-1-enylamino)-3-(4-dimethylcarbamoyloxy-phenyl)-propionic acid; or a 20 pharmaceutical salt thereof.
31. A compound of Claim 1 which is (2S)-3-(4-dimethylcarbamoyloxy-phenyl) 2-[2-(methyl-pyridin-3-ylmethyl-amino)-3,4-dioxo-cyclobut- 1 -enylamino]-propionic acid; or a pharmaceutical salt thereof. 25
32. A compound of Claim 1 which is (2S)-3-(4-dimethylcarbamoyloxy-phenyl) 2- { 2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-cyclobut- I -enylamino } propionic acid; or a pharmaceutical salt thereof. 30
33. A compound of Claim 1 which is (2S)-3-[4-(4-methylpiperazinyl)carbamoyl oxy-phenyll -2- [2- (methyl-phenethyl-amino)-3,4-dioxo-cyclobut- I -enylamino] propionic acid; or a pharmaceutical salt thereof. WO 00/35855 PCT/US99/29369 - 53
34. A compound of Claim 1 which is (2S)-3-[4-(4-methylpiperazinyl)carbamoyl oxy-phenyl)-2- { 2 -[methyl-( 2 -pyridin-4-yl-ethyl)-amino]-3,4-dioxo-cyclobut- I -enyl amino }-propionic acid; or a pharmaceutical salt thereof. 5
35. A compound of Claim 1 which is (2S)-3-[4-(4-methylpiperazinyl)carbamoyl oxy-phenyl) -2- { 2-dihexylamino]-3,4-dioxo-cyclobut-l1-enylamino } -propionic acid; or a pharmaceutical salt thereof. 10
36. A method for inhibiting leukocyte adhesion in a patient suffering from a condition associated with leukocyte adhesion comprising administering to the patient a therapeutically effective amount of a compound of the formula: 1 0 0 (H2)z R N (CH2)x OH R2C (CH2)y 0 wherein R 1 is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; 15 R 2 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or R' and R 2 may be taken together to form a saturated or unsaturated heterocyclic ring; R 3 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; A is aryl or heteroaryl; and 20 x, y and z are independently 0, 1, 2, 3, or a pharmaceutical salt thereof.
37. A method of treating a patient suffering from an inflammatory diseases comprising administering to the patient a therapeutically effective amount of a 25 compound of the formula: R1. ((i2)z R ' O) (OH2 N ~-(CH2)x OH R 2 R 3 (CH2)y-1 0 WO 00/35855 PCT/US99/29369 - 54 wherein R' is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R 2 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or R and R 2 may be taken together to form a saturated or unsaturated heterocyclic ring; 5 R 3 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; A is aryl or heteroaryl; and x, y and z are independently 0, 1, 2, 3, or a pharmaceutical salt thereof. 10
38. The method of Claim 36 wherein the inflammatory disease is selected from the group consisting multiple sclerosis, meningitis, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel syndrome, rheumatoid arthritis, tumor metastasis, tissue transplantation, and myocardial ischemia. 15
39. A pharmaceutical composition comprising a compound of the formula: 1 O t (9 H2)z R - (CH 2 )x OH R2 ' 3 (C H2)y R R0 wherein R' is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R 2 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or R' and R 2 may be taken together to form a saturated or unsaturated 20 heterocyclic ring; R 3 is H, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; A is aryl or heteroaryl; and x, y and z are independently 0, 1, 2, 3, and a pharmaceutically acceptable carrier. 25
AU23576/00A 1998-12-14 1999-12-10 3,4-diamino-3-cyclobutene-1,2-dione derivatives which inhibit leukocyte adhesionmediated by vla-4 Abandoned AU2357600A (en)

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