AU765427B2 - Inhibitors of phospholipase enzymes - Google Patents
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- AU765427B2 AU765427B2 AU27825/99A AU2782599A AU765427B2 AU 765427 B2 AU765427 B2 AU 765427B2 AU 27825/99 A AU27825/99 A AU 27825/99A AU 2782599 A AU2782599 A AU 2782599A AU 765427 B2 AU765427 B2 AU 765427B2
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- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Description
WO 99/43654 PCT/US99/03898 INHIBITORS OF PHOSPHOLIPASE ENZYMES Background of the Invention S The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A, enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way.
Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized L. Smith, Biochem. 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX- 1 and COX- 2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A, enzymes (hereinafter PLA2). The reaction catalyzed by PLA, is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA 2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation Wasserman, Hospital Practice, 15:49-58 (1988)].
Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For WO 99/43654 PCT/US99/03898 example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-l/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA 2 has been suggested as a useful mechanism for a therapeutic agent, to interfere with the inflammatory response.
[See, J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)].
A family of PLA, enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined.
These secreted PLA 2 s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA,s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA, has been determined.
This non-pancreatic PLA 2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA, is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA, is regulated by protein kinase C and G proteins Burch and J. Axelrod, Proc. Natl. Acad. Sci. 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA, to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA, has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was 2 ii;i i-lr^u I lr.tirirr r..sri;i~i; r, ;Ir...rr~-",llrY ;i iii i ibL WO 99/43654 PCT/US99/03898 reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophvs. Acta., 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA,.
A cytosolic phospholipase A, (hereinafter "cPLA2") has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA, enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
It is now desirable to identify pharmaceutically useful compounds which inhibit the actions of these phospholipase enzymes for use in treating or preventing inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such antiinflammatory agents for therapeutic use in a variety of disease states.
Numerous pieces of evidence have supported the central role of cPLA, in lipid mediator biosynthesis: cPLA 2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel Gelb, 1993); activation of cPLA 2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA 2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995). Although these data are compelling, the most definitive evidence for the central role of cPLA 2 in eicosanoid and PAF production came from mice made deficient in cPLA 2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF. The cPLA 2 deficient mice have also been informative of the role of cPLA 2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997). Thus, despite the size of the phospholipase A 2 superfamily, cPLA, is essential for prostaglandin, leukotriene, and PAF production.
Clark, J. Lin, Kriz, R. Ramesha, C. Sultzman, L. Lin, A. Y., Milona, and Knopf, J. L. (1991). A novel arachidonic acid-selective cytosolic PLA, contains a Ca 2 -dependent translocation domain with homology to PKC and GAP. Cell 3 e i -4- 1043-105 1. Hanel, A. and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A, enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958.
Lin, Lin, A. and DeWitt, D. L. (I 992a) EL-i I- induces the accumulation of cPLA2 and the release of PGE, in human fibroblasts. J. Biol. Chem. 267, 2345 1-23454. Lin, Lin, A. and Knopf, J. L. (1992b) Cytosolic phospholipase A, is coupled to hormonally regulated release of arachidonic acid. Proc. Natl. Acad. Sci. USA 89, 6147-615 1.
Lin. Wartinann, Lin, A. Knopf, J. Seth, and Davis, R. J. (1993) cPLA 2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278.
Glover, de Carvaiho, Bayburt, Jonas, Chi, Leslie, and Gelb, M. (1995) Translocation of the 85-kDa phospholipase A 2 from cytosol to the nuclear envelo pe ~:in rat basophilic leukemia cells stimulated with calcium ionophore or IgEtantigen. J. Biol.
~:Chem. 270, 15359-15367. Schievella, A. Regier, M. Smith, W. and Lin, L.-L.
(1995). Calcium-mediated translocation of cytosolic phospholipase A, to the nuclear envelope and endoplasmic reticulum. J. Biol. Chem. 270, 30749-30754.
Uozumi, Kume, Nagase, Nakatani, Ishii, Tashiro, Komagata, Mai, Ikuta, Ouchi, Miyazaki, Shimizu, T. (1997). Role of cytosolic phospholipase A 2 in allergic response and parturition. Nature 390, 6 18-622. Bonventre, J. V., Huang, Reza Talheri, O'Leary, Li, Moskowitz, M. and Sapirstein, A.
(1997) Reduced fertility and postischaemnic brain injury in mice deficient in cytosolic phospholipase A 2 Nature 390, 622-625.
4aa The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.
Summary of the Invention 0 This document discloses both indole and indoline compounds of the formula shown below. The claims defining the invention are limited to certain indole compounds defined by the following: R R 3 I R 3 RI- R4 R1 R4 TN or N R2 R 2
R
5 Rs o o o *o o o o« r r w:adynno delete\SpecM23l33 changes 1S-07-03.doc WO 99/43654 PCT/US99/03898 wherein: R, and R, are independently selected from H, halogen, -OH, -C,-CI 0 alkyl, preferably alkyl, -S-C,-Co alkyl, preferably alkyl, C,-CIO alkoxy, preferably alkoxy, -CN, -NO 2 -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -Sbenzyl; or a ring moiety of the groups b) or below, directly bonded to the indole ring or bonded to the indole ring by a or -(CH 2 bridge; a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI 0 alkyl, preferably alkyl, C,-CI 0 alkoxy, preferably C 1
-C
6 alkoxy, -NO 2 -CN, -CF 3 or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected frim halogen, C,-CI 0 alkyl, preferably alkyl, C 1 -Co alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -NH2, -CN, -CF 3 or -OH; _or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from I to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C 1
-C
6 alkyl, C,-Co alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NO, -CN,
CF
3 or -OH; or d) a moiety of the formulae: R6
R
6 I KI RN N R7 z R7 R7 *~nii; ui irinpiri~ WO 99/43654 PCT/S99/03898
H
6 z O O 6 N I R7 R7 z R< RiR
R
6 R7,S or O Z is O or S; R, is selected from the relevant members of the group H, C,-Co alkyl, preferably C-C, alkyl, CI-Clo alkoxy, preferably C 1 alkoxy, phenyl, -O-phenyl, -Sphenyl, benzyl, -O-benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 alkyl, preferably C 1
-C
6 alkyl, C,-Co alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NO 2 -CN,
CF
3 or -OH; R, is selected from the relevant members of the group -OH, -CF 3 C,-Clo alkyl, preferably C 1 alkyl, Ci-Clo alkoxy, preferably C 1 alkoxy, -(CH 2
),-NH
2
-NH-
alkyl), alkyl)2, alkyl), alkyl),, phenyl, -O-phenyl, benzyl, or -O-benzyl; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 alkyl, preferably alkyl, C 1 -Co alkoxy, preferably C 1
-C
6 alkoxy, -NO, -NH 2 -CN, or -CF,; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, 6 WO 99/43654 PCT/US99/03898 pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, alkyl, preferably C-C 6 alkyl, Ci-C10 alkoxy, preferably C,-C, alkoxy, -CHO, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C 1 alkyl, alkoxy, preferably C,-C, alkoxy, -CHO, -NO, -NH 2 -CN, -CF 3 or -OH; n is an integer from 0 to 3; R, is selected from H, halogen, -CN, -CHO, -CF3, -OH, C 1 alkyl, preferably C,- C6 alkyl, C,-Clo alkoxy, preferably alkoxy, -CHO, -CN, -NO 2
-NH
2
-NH-C-C,
alkyl, -N(C-C 6 alkyl) 2 -N-SO,-C 1
-C
6 alkyl, or -S0 2
-C
1
-C
6 alkyl; R, is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, -(CH 2 ),-tetrazole, 0~
OO
or N (C 1
-C
6 lower alkyl) N (C 1
-C
6 lower alkyl), or O S-OH -PaHI 00 o-p-OH" 7 WO 99/43654 PCTIUS99/03898 or a moiety selected from the formulae wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 -C(Z)-NH-S0 2 or -C(Z)-NH-S0 2
-(CH
2 M' is selected from the group of -COOH, -(CH 2 tetrazole, R8 R8 R R8..7 -N
N
15R1R1
R
9 0 S R 8 a R 8
N/IR
R8q
KF,
HN/ R j/R9 \j R9 R0R 10
R
10
S
0 ~0 0 N0-P-OH
S
R0 OH
R
8 or
R
10
R
8 in each appearance, is independently selected from H, -COOH,
(CH
2 )n-C(O)-CO0H, tetrazole, WO 99/43654 WO 9943654PCTIUS99/03898 0 0 0
P-OHS
0 ,orOH R9 is selected from H, halogen, -CF 3 -OH, -COOH, -(CH 2
),-COOH,
-(CH
2
-C
1
-C
6 alkyl, -O-C 1
-C
6 alkyl, -O-(CH 2
-O-CH,-C=C-COOH,
-O-C=C-CH,-COOH, -NH(C,-C 6 alkyl), -N(CI-C 6 alkyl) 2
-N-C(O)-(CH
2 ).-COOH. -N-SO,-
(CH
2
-C(O)-N-(CH
2
),,-COOH;
Ri is selected from the group of H, halogen, -CF3 -OH, -(CH 2 )n-COOH, -(H)C(O-OH 3'-6akl 0C-6 ly,--C-6aky)(H"
N(,
alkyl), -N(CI-C 6 alkyl) 2 1
-C
6 alkyl)-(OH) 2
R
8
R
IR
R9R XR N (>C-C 6 lower aikyl N (>C-C 6 lower haloalkyl: 9 WO 99/43654 WO 9943654PCT/US99/03898 0
N
N S0R N 110 (Cl-C 6 lower alkyl) AR a R 8 NR8 N ,R 8 S ,R 8 a R 8 Ior
R
11 is selected from H, C 1
-C
6 lower alkyl, C 1
-C
6 cycloalkyl, -CF 3 -COOH, -(CH 2 COOH, -(CH 2 ).-C(0)-CO0H,
-(CH
2 )n with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 3
R
8
R
9 RIO, and/or R 11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 00 0 0 O1%/ 7 -P-OH 0\/P 0 OH orN 0 0.0
N-
S N1 N
NN
S 0 N (Cl-C 6 lower alkyl,' n is an integer from 0 to 3; WO 99/43654 PCT/US99/03898
R
4 is selected from H, -CF, C,-C 6 lower alkyl, C 1
-C
6 lower alkoxy, C 3
-C
1 0 cycloalkyl, -C 1
-C
6 alkyl-C 3
-C
0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2
M:
L
2 indicates a linking or bridging group of the formulae
-(CH
2 or -(CH 2 )n-S-(CH 2
C(O)C(O)X;
where X is O or N
M
2 is selected from: a) the group of lower alkyl, lower alkoxy, C 3
-C
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from I to 3 substituents selected from halogen, C,-Co alkyl, preferably alkyl, C,-Clo alkoxy, preferably C 1 alkoxy, -NO, -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Clo alkyl, preferably alkyl, Cl-C,, alkoxy, preferably C 1 alkoxy, -NO 2 -NH2, -CN, or -CF3; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Clo alkyl, preferably alkyl, alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NH 2 -CN, -CF 3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents 11 WO 99/43654 PCTIUS99/03898 selected from halogen, CI-Cl 0 alkyl, preferably C 1
-C
6 alkyl, C,-C 10 alkoxy, preferably CI-C 6 alkoxy, -CHO, -NO 2 -CN, -CF3 or -OH; R, is selected from C -C 6 lower alkyl, C 1 6 lower alkoxy, 3
-C
0 cycloalkyl,
-(CH
2 2 3
-C
10 cycloalkyl, -(CH 2 2 ~C 1 c ycloalkyl, or the groups of: a) -(CH 2 ),,-phenyl-O-phenyl, -(CH 2 ).-phenyl-CH 2 -phenyl, -(CH 2 ),,-O-phenyl- CH,-phenyl, -(CH 2 ),,-phenyl-(O-CI{ 2 -phenyl) 2
-CH
2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: 0 Y, S 0 (H2n"S, H )M"0 11*1 C2rNW, C20,, Y
(CH
2 )nwherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3
-C
6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, CI-C, 0 alkyl, preferably C 1
-IC
6 alkyl, CI-CI 0 alkoxy, preferably
C,-C
6 alkoxy, -N2, -NH 2 -CN, or -CF 3 or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, 12 WO 99/43654 PCT/US99/03898 pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, alkyl, preferably C,-C 6 alkyl, C 1 -Co alkoxy, preferably C,-C, 6 alkoxy, -CN, -CF3, or by one phenyl ring, the phenyl ring being optionally substituted by by from 1 to 3 substituents selected from halogen, C 1
-C
0 alkyl, preferably C-C, 6 alkyl, CI-Clo alkoxy, preferably C-C, 6 alkoxy, -NH2 -CN, -CF 3 or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from I to 3 substituents selected from halogen, C -C 0 alkyl, preferably C-C, 6 alkyl, C,-Co alkoxy, preferably C-C, 6 alkoxy, -CHO, -NO 2 -NH, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-CI
0 alkyl, preferably C,-C, 6 alkyl, C,-Clo alkoxy, preferably C 1
-C,
6 alkoxy, -CHO, -NO 2 NH2 -CN, -CF 3 or -OH; d) a moiety of the formulae -(CH 2
-(CH
2 or wherein A is the moiety:
D
sCC
B
wherein D is H, C-C, 6 lower alkyl, C 1
-C,
6 lower alkoxy, -CF 3 or -(CH 2 )n-CF 3 B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CFz, -OH, -C,-C 6 alkyl, alkoxy,
C,
6 2
-NH(C-C,
6 6
-NO
2 or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms .selected from O, N or S, such as, for example, morpholino; 13 dbtii .I.r WO 99/43654 PCT/US99/03898 or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
Another R 3 is wherein L' is as defined above, more preferably wherein L' is a chemical bond, and M' is the moiety: R9 and R 9 is as defined in the broad genus above.
Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R 3 and R, are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position.
In a further preferred group herein, R, is in the indole or indoline 5-position and is benzyloxy, R, and R 4 are hydrogen and R 3 and R 5 are as defined above.
Among the more preferred compounds of this invention are those of the following formulae: R1 R3 R1 R3 R4 oR4 N or R2 I R2
I
Rs wherein: WO 99/43654 WO 9943654PCTIUS99/03898 RI is selected from H, halogen, -C,3 -OH, alkyl, preferably -C 1
-C
6 alkyl, -S-
C)-C
10 alkyl, preferably -S-C 1
-C
6 alkyl, C 1
-C
10 alkoxy, preferably C 1
-C
6 alkoxy, -CN, -NO 2 phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R6 R 6 R 0 070
R
6 S7 R7 or 0 0
R
6 is selected from H, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, phenyl, -0-phenyl, benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 1,_6 alkyl, C 1
-C
6 alkoxy, -NO 2
-NH
2 -CN, -CF 3 or
OH;
R
7 is selected from -OH, -C3 1
C
6 alkyl, C 1
-C
6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(C 1
C
6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NO 2
-NH
2
-CF
3 or -OH; is selected from H. halogen, -CE 3 -OH, -C 1
-C
10 alkyl, preferably -C 1
-C
6 alkyl, C,- CIO alkoxy, preferably 1,_6 alkoxy, -CHO, -CN, -NO 2
-NH-C
1
-C
6 alkyl, -N(C 1
-C
6 alkyl) 2 -N-S0 2
-C,-C
6 alkyl, or -S0 2
-C,-C
6 alkyl;
R
3 is selected from -COOH, -C(O)-COOH, -(CH 2
-(CH
2
),,-COOH,
-CH=CH-COOH,
-(CH
2 ),,-tetrazole, S WO 99/43654 PCTAJS99/03898 WO0 /35 CTU9/39 0" N 4(C1C6 lower alkyl) or 0~Q N
N'
N (C 1
-C
6 lower alkyl), or o1 n-OH
-~OH
o 0 or a moiety selected from the formulae wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 -C(Z)-NH-S0 2 or -C(Z)-NH-S0 2
-(CH
2 M' is selected from the group of -COOH, -(CH 2 0 -COOH, -(CH 2 tetrazole, R R9 -N
N
WO 99/43654 WO 9943654PCTIUS99/03898 R8/7 HN N 0 11 0-P-OH O 0 H or
R
<RIO
R
8 in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH,
(CH
2 )n-C(0)-C00H, tetrazole, 0 11 I) -P-OH 0 O 0
S
,orOH9
R
9 is selected from H, halogen, -C3 -OH, -COOH, -(CH 2
),,-COOH,
-(CH
2
-C
1
-C
6 alkyl, -O-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), or -N(C 1
-C
6 alkyl) 2 RIO is selected from the group of H, halogen, -CF3 -OH, -(CH 2
),,-COOH,
-(CH
2
-C
1
-C
6 alkyl, -O-C 1
-C
6 alkyl, -NH(Cl-C 6 alkyl), -N(C,-C 6 alkyl) 2 0 ,R9
N-I
TW%\R
9 -(CH2)
R
8 ~NR9
R
8 Nj
->R
-(CHI)n WO 99/43654 PCT/US99/03898 N' '(C1-C 6 tower alkyl) L V o ,R 8 N ,R8 N ,R8 Z R, Z 'R9 (CH2)n 'R9 S ,Rs R8 (CH2,/ (C2)n/ or
R
1 is selected from H, C,-C, 6 lower alkyl, C,-C, 6 cycloalkyl, -CF 3 -COOH, -(CH 2 COOH, -(CH 2 )n-C(O)-COOH,
R
8 R 8 N- J Rg Rg R
(CH
2 n with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 3
R
9 Rio, and/or shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 00 0
P-OH
ZOH 0H orN
S
n is an integer from 0 to 3; R4 is selected from H, -CF, C -C6 lower alkyl, C-C, 6 lower alkoxy, C -CIo cycloalkyl, -C,-C 6 alkyl-C-Co cycloalkyl, -CHO, halogen, or a moiety of the formula -L2_M 2 18 WO 99/43654 PCT/IS99/03898
L
2 indicates a linking or bridging group of the formulae -(CH 2
-(CH
2 )n-C(O)-(CH 2
-(CH
2 or
M
2 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3
-C,
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Co alkyl, preferably CI-C, 6 alkyl, C,-C 0 alkoxy, preferably C,-C, 6 alkoxy, -NO, -NH2, -CN, or -CF 3 or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Clo alkyl, preferably C,-C, 6 alkyl, C,-Co alkoxy, preferably C,-C, 6 alkoxy, -NO -NH 2 -CN, or -CF 3 or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, preferably C,-C,6 alkyl, C 1 -Clo alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO, -CN, -CF3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C, 0 alkyl, preferably C,-C, 6 alkyl, alkoxy, preferably C,-C, 6 alkoxy, -CHO, -NO 2 -CN,
CF
3 or -OH; R, is selected from C,-C 6 lower alkyl, C 1
-C
6 lower alkoxy, -(CH 2 )n-C 3
-C
10 cycloalkyl,
-(CH
2 )n-S-(CH 2 )n-C 3
-C,
0 cycloalkyl, -(CH 2 2 3
-C
0 cycloalkyl, or the groups of: a) -(CH 2 ),-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-
CH
2 -phenyl, -(CH 2 ),-phenyl-(O-CH,-phenyl) 2 -CH-phenyl-C(O)-benzothiazole or a moiety of the formulae: 0 0 Y O I (CH2) I, (CH) S WO 99/43654 PCT/US99/03898 0 /J O ,(CH2)n y /(CH2) 0 y /(CH2)r S (CH2) /(CH2)n"
(CH
2 )n, wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3
-C
cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -CN, -NH 2 NO, or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0, preferably S or O; or b) a moiety of the formulae -(CH 2
-(CH
2 or -(CH 2 wherein A is the moiety:
DC
B
wherein D is H, C-C 6 lower alkyl, C 1
-C
6 lower alkoxy, -CF 3 or -(CH 2
)-CF
3 B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -OH, alkyl, C,-C 6 alkoxy, -NH, or -NO,; or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position (R 4 is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
In an another preferred group of this invention R, is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R 2 and R, are hydrogen, and R 3 and R, are as defined above.
ri- I.TI-- I-~liin WO 99/43654 PCT/US99/03898 A further preferred group of this invention consists of R, and R,at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C,-C 6 alkoxy, cyano, sulfonyl and halo, R 2 and R 4 are hydrogen, and R 3 and R, are as defined above.
Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R 3 and R 5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position.
In a further preferred group herein, R, is in the indole or indoline 5-position and is benzyloxy, R 2 and R 4 are hydrogen and R 3 and R 5 are as defined above.
A preferred group of compounds of this invention have the following formulae:
R
1 R3 K R4
N
R2 I wherein: R, is selected form H, halogen, -OH, -C 1
-C
6 alkyl, C,-C 6 alkoxy, -NO 2
-NH,,
CN, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: 2 O
R
7 R7
R
6 R N By-
R
6 R 6
S
0 0 0 R6 R7 O0 R6 R7 O
O
,or WO 99/43654 PCT/US99/03898
R
6 is selected from H, CI-C 6 alkyl, C 1 -C 6 alkoxy, phenyl, -0-phenyl. benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, CI-C 6 alkoxy, -NH 2 CF3 or -OH;
R
7 is selected from -CF3 C -C 6 alkyl, C 1
-C
6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(C 1
-C
6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen,C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NH 2 -N21 C 31 or -OH; R, is selected from H, halogen, -CN, -CHO, -CF -O H, CICl alkyl, preferably C,- C6 alkyl, CI-Cl 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -CN, -NO 2
-NH
2 -NH-C 1
-C
6 alkyl, alkyl) 2 -N-S0 2
-C,-C
6 alkyl, orS 2
-C,-C
6 alkyl;
R
3 is selected from -COOH, -C(O)-COOH, -(CH 2 ,C(O)-COOH, -(CH 2
-COOH,
-CH=CH-COOH, -(CH 2 ,-tetrazole, 2K 1 or N (C 1
-C
6 lower a lkyl) C S0N
NN
Nl (C 1
-C
6 lower alkyl)
P-OH
o ,or 0 or a moiety selected from the formulae wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 22 WO 99/43654 WO 9943654PCTIUS99/03898
-C(Z)-N(R
6
-C(Z)-N(R
6
)-(CH
2 6 6 -C(Z)-NH-S0 2 or -C(Z)-NH-S0 1 M' is selected from the group of -COOH, -(CH 2
-(CH
2 1
-C(O)-COOH,
tetrazole, HN N 7R 0 11 0P-OH 11"~0 O 0 S O or R8 0 Rpin each appearance, is independently selected from
(CH
2 )n-C(O)-COOH, tetrazole, H, -COOH, 0 11 7-P-OH 0 ,or
H
R
9 is selected from H, halogen, -CF 3 -OH, -COOH, -(CH 2
),,-COOH,
-(CH
2 )n-C(O)-COOH, -C 1
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C,-C 6 alkyl) 2 RIO is selected from the group of H, halogen, -C 3 -OH, -COOH, -(CH 2 1
-COOH,
-(CH
2 )n-C(O)-COOH, -C 1
-C
6 alkyl, -O-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1 6 alkyl) 2 23 WO 99/43654 PCTIUS99/03898 R8 8
HR
9 or 0 N S N (C 1
-C
6 lower alkyl) 0 000 00
S.S
N (C 1
-C
6 lower alkyl' (C 1
-C
6 lower haloalkyl,;
R
1 is selected from H, C I -C 6 lower alkyl, C 1
-C
6 cycloalkyl, -CF 3 -COOH, -(CH 2 COOHK -(CH 2 ).-C(0)-CO0H,
R
8
R
N-j H> R9
-(CH
2 )n with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 3
R
8
R
9 1 RIO, and/or R 11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: -0 /0-P-OH S0 0 'OH or n is an integer from 0 to 3; WO 99/43654 PCT/US99/03898 R, is selected from H, lower alkyl, lower alkoxy, cycloalkyl, alkyl-C 3
-C
0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2
-M
2
L
2 indicates a linking or bridging group of the formulae
-(CH
2
-(CH
2
A-C(O)-(CH
2
-(CH
2 )n-O-(CH 2 n- or -(CH2,o-S-(CH2)n-
M
2 is selected from: a) the group of C 1 lower alkyl, C,-C 6 lower alkoxy, C 3
-C
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Co alkyl, preferably alkyl, C,-Co alkoxy, preferably alkoxy, -NO 2
-NH
2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Co alkyl, preferably alkyl, C,-C 0 alkoxy, preferably C 1 alkoxy, -NO 2
-NH
2 -CN, or -CF; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 0 alkyl, preferably alkyl, C,-Co alkoxy, preferably C 1 alkoxy, -CHO, -NO 2
-NH
2 -CN,
CF
3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-CIo alkyl, preferably C 1 alkyl, C 1 -Clo alkoxy, preferably alkoxy, -CHO, -NO 2
-NH
2 -CN, -CF 3 or -OH; R, is selected from C,-C 6 lower alkyl, C 1
-C
6 lower alkoxy, 3 cycloalkyl, 3 cycloalkyl, -(CH 2 2 )n-C 3
-C
5 cycloalkyl, or the groups of: WO 99/43654 PCT/US99/03898 a) -(CH 2 ),-phenyl-O-phenyl, -(CH,)n-phenyl-CH 2 -phenyl, -(CH,),-O-phenyl-
CH
2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2
-CH
2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: O 0 Y O (CH2)rr,. A(CH 2
S
0 O (CH)n (CH2) 0 (CH2 S (CHY)n 1(CH2)r O
(CH
2 Y wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3
-C,
cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 -OH, 6 alkyl, C,-C, 6 alkoxy, -NO 2
-NH
2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or b) a moiety of the formulae -(CH 2
-(CH
2 or -(CH 2 wherein A is the moiety:
D
C
B
wherein D is H, C,-C 6 lower alkyl, C-C, 6 lower alkoxy, -(CH 2 )n-CF 3 or -CF; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, 6 alkyl, C,-C, 6 alkoxy, -NH, or -NO 2 or a pharmaceutically acceptable salt thereof.
A preferred group among the compounds above are those in which the R, substitution is at the indole or indoline ring's 5-position and the other substituents are as defined above.
Another preferred group of this invention are those of the formulae: 26 WO 99/43654 PCT/US99/03898 0 or O
R
1 R3 R4
N
R2
I
Rs R1 R3 R4 or
N
R2
I
R
wherein: R, is selected form H, halogen, -CF 3 -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH,, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
VO
R
6 7 N R7 R6 o O R7
R
6
O
R
6 R7 N
R
6
R
6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 alkyl, alkoxy, -CF3, or -OH;
R
7 is selected from C-C6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), 6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, alkoxy, -NH 2 -NO2 -CF3, or -OH; R, is selected from H, halogen, -CN, -CHO, -CF3, -OH, Ci-Clo alkyl, preferably C,-
C
6 alkyl, alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2
-N-SO,-C,-C
6 alkyl, or alkyl; 27 WO 99/43654 WO 9943654PCTIUS99/03898
R
3 is selected from -COOH, -C(0)-COOH, -(CH 2 -(CH,),-C00H, -CH=CH-COOH,
-(CH
2 ),,-tetrazole, 0 N "4 1C6 lower aikyl) lower alkyl), or
-P-OH
0 ,or 0 or a moiety selected from the formulae -L'-M 1 wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 0 -C(Z)-NH-S0 2 or -C(Z)-NH-SO,-(CH 2 M' is selected from the group of -COOH, -(CH 2 ),-C00H, -(CH 2 )n-C(O)-CO0H, tetrazole,
R/;
R
8 WO 99/43654 WO 9943654PCT/1JS99/03898 HN N 0 11
P-OH
O/0 S X 0 O or R8 i N-1 R9 Rio
R
8 in each appearance, is independently selected from
(CH
2 )n-C(O)-COOH, tetrazole, H, -COOH, -(CH 2 )n-COOH, 0 11
P-OH
0 ,or OH;
R
9 is selected from H, halogen, -CF, -OH, -COOH, -(CH 2
),-COOH,
R
10 is selected from the group of H, halogen, -CF3 -OH, -COOH, -(CH 2
),,-COOH,
-(CH
2
,C-
6 alkYl, -O-CI-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 N-
R
9 R 9 WO 99/43654 WO 9943654PCTIUS99/03898 0 'll,(Cl-C 6 lower alkyl) N (C1 C lower alkyl, or 0 s Z -C lower ha oalkyl' is selected from H, C 1
-C
6 lower alkyl, C 1
-C
6 cycloalkyl, -C3 -COOH, -(CH 2 COOH, -(CH 2
).-C(O)-COOH,
R
8
R
-(CH
2 with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 3 RV, Rq, RIO, and/or R 1 1 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 0H 0 OH or N n is an integer from 0 to 3; R. is selected from H, -C3 1
C
6 lower alkyl, C,-C 6 lower alkoxy, C 3
-C
10 cycloalkyl, -CI-C 6 alkyl-C 3
-C
10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2
-M
2
L
2 indicates a linking or bridging group of the formulae -(CH 2
-(CH
2
-(CH
2 2
-(CH
2 2 0 or -C2nS(H)-
M
2 is selected from: a) the group of C 1
-C
6 lower alkyl, C 1
-C
6 lower alkoxy, C 3
-CI
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from I to 3 substituents selected from halogen, C 1
-C
10 alkyl, preferably C 1
-C
6 alkyl, C,-C 10 alkoxy, preferably C 1
-C
6 alkoxy, -NO 2
-NH
2 -CN, or -CF 3 or WO 99/43654 PCT[US99/03898 b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C, 0 alkyl, S 10 preferably C,-C 6 alkyl, C,-Co alkoxy, preferably alkoxy, -NO 2 -NH2, -CN, or -CF,; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -Co, alkyl, preferably C,-C 6 alkyl, C,-Co alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -CN,
CF
3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Cio alkyl, preferably C,-C 6 alkyl, C 1 -Co, alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -NH2 -CN, -CF 3 or -OH;
R
5 is selected from C,-C 6 lower alkyl, C-C 6 lower alkoxy, -(CH 2 )n-C 3
-C
5 cycloalkyl or (CH 2
-(CH
2 or -(CH 2 )n-O-A wherein A is selected from WO 99/43654 WO 9943654PCT/US99/03898
D
N
0D Z- D 0 0
N
D
S
so Oc N1 D is H, C 1
-C
6 lower alkyl, C 1
-C
6 lower alkoxy,- or C3
R,
2 is H, CI -C 6 lower alkyl, C 1
-C
6 lower alkoxy, or -F WO 99/43654 PTU9/39 PCTIUS99/03898 or a pharmaceutically acceptable salt thereof.
Other compounds of this invention have the following formulae: I
R
4 R,
R
3
R
4 or R2 wherein: R, is selected form H, halogen, -C31 -OH, -C -C 6 alkyl, C,-C 6 alkoxy, -NO 2
-NH,,
phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: 0
R
6 NRN7 0 R7 0K 0 N6
S
or 0 0
R
6 is selected from H, 1,_6 alkyl, C 1
-C
6 alkoxy, phenyl, -0-phenyl, benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -N21 -C3 or -OH;
R
7 is selected from -CF, 1,_6 alkyl, C 1
-C
6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(CI-C 6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -0-phenyl, benzyl or O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1_6 alkyl, C 1
-C
6 alkoxy, -NH 2
-NO
2
-CE
3 or -OH;
R
2 is selected from H, halogen, -CN, -CHO, -CF -1OH, CICI alkyl, preferably Cr-
C
6 alkyl, C 1 -Cl 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -CN, -NO 2
-NH
2
-NH-C
1
-C
6 alkyl, -N(C 1
-C
6 alkyl)2, -N-S0 2
-C,-C
6 alkyl, or -SO -C 1
-C
6 alkyl; WO 99/43654 PCTIUS99/03898
R
3 is selected from -COOH, -C(O)-COOH, -(CH 2
-(CH
2
),,-COOH,
-CH=CH-COOH, -(CH 2 ),,-tetrazole, 0~ N (C 1
-C
6 lower alkyl) IN (Cl-C 6 lower alkyl), or
/-P-OH
0 0 11
-S-OH
11 or 0 or a moiety selected from the formulae or L22 L' is a bridging or linking moiety selected from a chemical bond, -(CH 2
-(CH
2
-(CH
2 1
-C(O)-(CH
2
-(CH
2 2 2 2 )n-I -C(Z)-NH-S0 2 or -C(Z)-NH-SO 2
-(CH
2 M' is selected from the group of -COOH, -(CH 2 ).-COOH, -(CH 2 tetrazole,I
R
9 0 HN N WO 99/43654 WO 9943654PCTIUS99/03898 0 Ri
R
11 1
R
8 0 0 L is a bridging or linking moiety selected from a chemical bond
-(CH
2
-(CH
2 )n-C(O)-(CH 2
-(CH
2 )n-O-(CH 2
-(CH
2 2 -C(Z)-NH-S0 2 or -C(Z)-NH-S0 2
-(CH
2
M
2 is the moiety
R
8 in each appearance, is independently selected from H, -COOH, -(CH 2
(CH
2 )n-C(O)-CO0H, tetrazole, 0
P-OH
11 0 ,or
OH
R
9 is selected from H, halogen, -CF 3 -OH, -COOH, -(CH 2
),,-COOH,
-(CH
2 -C 1
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 Rio is selected from the group of H, halogen, -CF, -OH, -COOH, -(CH 2 )n-COOH, -(CH29.-C(O)-COOH,
-C
1
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 WO 99/43654 WO 9943654PCT/US99/03898 o 0 0 R 8
R
8
FR,
00 0Q N N
""N
N
0 00
S.
N~ (1C-C 6 lower alkyl .rC6 lower alkyl) N (Cl-C6lower haloalkyl,
R
11 is selected from H, C 1
-C
6 lower alkyl, C 1
-C
6 cycloalkyl, -C,3 -COOH, -(CH 2 COOH, -(CH 2
R
8
R
-(CH
2 with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 3 L 2
M
2
R
8
R
9 R1 0 and/or RI, shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 0
P-OH
0 0 0 OHor n is an integer from 0 to 3;
R
4 is selected from H, -CF31 -C 6 lower alkyl, C, -C 6 lower alkoxy, C 3
-CI
0 cycloalkyl, -C 1
-C
6 alkyl-C 3
-C
10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 3
-M
3 L 3 indicates a linking or bridging group of the formulae -(CH 2 36 WO 99/43654 PCT/US99/03898
-(CH
2 )n-C(O)-(CH 2
-(CH
2 )n-O-(CH 2 or -(CH2)-S-(CH2 M' is selected from: a) the group of lower alkyl, C,-C 6 lower alkoxy, C 3
-C,
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 0 alkyl, preferably alkyl, C,-CI 0 alkoxy, preferably C,-C,6 alkoxy, -NH 2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents .selected from halogen, C,-C 0 alkyl, preferably alkyl, C,-Cjo alkoxy, preferably C1-C, alkoxy, -NO 2 -CN, or -CF,; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C 1 alkyl, C,-Clo alkoxy, preferably C 1 alkoxy, -CHO, -NO 2 -NH2 -CN, CF, or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, alkyl, preferably C,-C 6 alkyl, C 1 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NH2, -CN, -CF or -OH; R, is selected from C 1 lower alkyl, C 1 lower alkoxy, -(CH 2 )n-C 3
-C
5 cycloalkyl,
-(CH
2 )n-S-(CH 2 )n-C 3
-C
5 cycloalkyl, 3 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 ),-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-
CH
2 -phenyl, -(CH 2 ),-phenyl-(O-CH 2 -phenyl) 2
-CH
2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: 37 WO 99/43654 PCT/US99/03898 0 0 '(CH2)r y Y 2)r S 0 O (CH 2 )nl ACH2) O y (CH2)rN S (CH 2 )r, -(CH2 6
(CH
2 n O Y wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3
-C,
cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF, -OH, alkyl, C 1 alkoxy, -NH 2
NO
2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or b) is the moiety: a moiety of the formulae -(CH 2
-(CH
2 or -(CH 2 wherein A wherein D is H, C 1 lower alkyl, lower alkoxy, -CF or -(CH2),-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 -OH, -C 1 alkyl, C 1
-C
6 alkoxy, -NH 2 or -NO 2 or a pharmaceutically acceptable salt thereof.
Another preferred group of this invention are those of the formulae: 38 WO 99/43654 PTU9/39 PCT/US99/03898 Ri R3 R4
N
R2
I
R1 R 3 or R2I wherein: R, is selected form H, halogen, -CF, -OH, -C 6 alkyl, C 1
-C
6 alkoxy, -NO 2 phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
RR
0 0 0 07 R7
S
or 0 0
R
6 is selected from H, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, phenyl, -0-phenyl, benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from I to 3 substituents selected from halogen, C 1 alkyl, C 1
-C
6 alkoxy, -NH 2 -N2' -C3 or -OH;
R
7 is selected from -C3 1,_6 alkyl, C 1
-C
6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(C 1
-C
6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NO 2 -N21 or -OH;
R
2 is selected from H, halogen, -CN, -CHO, -F1OH, C I-C 1 0 alkyl, preferably Cr
C
6 alkyl, C 1
-C
1 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -CN, -NO 2 -N2 NH-C 1
-C
6 alkyl, -N(C 1
-C
6 alkyl) 2 -N-S0 2
C,-C
6 alkyl, or -S02-C,_C 6 alkyl;
R
3 is selected from -COOH, -C(O)-COOH, -(CH 2
-(CH
2
),,-COOH,
-CH=CH-COOH, -(CH 2 1
-C
6 lower alkyl), -(CH 2
-C
6 lower haloalkyl), 39 WO 99/43654 WO 9943654PCTIUS99/03898
N
0 Rio 0
N
0
N
0 'R9 N (CH2)
OH
0 0 Y
H
2 'rN.
H
0 0 0 0 S R 8
/'R
H ,or -n(H 2 Cr- N .N Rjj R, is selected from H, -COOH, -(CH 2
-(CH
2
R
9 is selected from H, halogen, -CF, -OH, -COGH, -(CH 2
),,-COOH,
-(CH
2 -C -C 6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 Rio is selected from the group of H, halogen, -CF3 -OH, -COOH, -(CH 2
),,-COOH,
-(CH
2 )n-C(O)-COOH,
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 WO 99/43654 PCT/US99/03898 o 0 0 R8 N- /Rg N
N
N (C 1
-C
6 lower alkyl)
S
N~ (>C-C 6 lower alkyl 0 0"0
NS'
N' ~(C-C6 lower haloalkyl:
R
1 is selected from H, C 1
-C
6 lower alkyl, -COOH,
-(CH
2 )n-C(0)-CooH, or n is an integer from 0 to 3;
R
4 is selected from H, -CF3, C 1
-C
6 lower alkyl, C 1
-C
6 lower alkoxy, CI-C 0 cycloalkyl, -C,-C 6 alkyl-C 3
-C
0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2
_M
2
L
2 indicates a linking or bridging group of the formulae -(CH 2
-(CH
2
-(CH
2 2
-(CH
2 )n-O-(CH 2 or
M
2 is selected from: a) the group of C 1
-C
6 lower alkyl, C-C 6 lower alkoxy, C 3 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
0 alkyl, preferably C 1
-C
6 alkyl, C 1 -Cl 0 alkoxy, preferably C 1
-C
6 alkoxy, -NO 2 -NH21 -CN, or -CF 3 or 41 WO 99/43654 PCTIUS99/03898 b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -Co alkyl, preferably C,-C6 alkyl, C,-Clo alkoxy, preferably C 1
-C
6 alkoxy, -NO 2 -CN, or -CF3; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Clo alkyl, preferably CI-C 6 alkyl, C,-Co alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -NH2 -CN,
CF
3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, preferably CI-C 6 alkyl, Ci-Co alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -NH2 -CN, -CF 3 or -OH;
R
5 is selected from Ci-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2
-C
3
-C
5 cycloalkyl or (CH 2
-(CH
2 or -(CH 2 wherein A is selected from: D D 42 WO 99/43654 WO 9943654PCTJUS99/03898
D
N,
S
AD
NJ/ R1
D
IN
0
KII
DzD C:0
NJ
A'D
D is H, C-C 6 lower alkyl, C 1
-C
6 lower alkoxy, or C3 R2is H, C -C6 lower alkyl, C 1
-C
6 lower alkoxy, or -CF3; or a pharmaceutically acceptable salt thereof.
The compounds of this invention have the following formulae: 43 WO 99/43654 PCT[US99/03898 N or r wherein: R, is selected form H, halogen, -CF, -OH, -C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NO 2 phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R6 R6 0 R6R6 R R7 or 0 or
R
6 is selected from H, C 1
-C
6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0beuzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NO 2
-NH
2
-CF
3 or -OH;
R
7 is selected from -CF 3
C
1
-C
6 alkyl, CI-C 6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(C 1
-C
6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, th-iazolyl, -0-phenyl, benzyl or O-benzyl, the rings of these groups being optionally substituted by from I to 3 substituents selected from halogen, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -NO 2 N21 -C3, or -OH; 44 WO 99/43654 PTU9/39 PCTIUS99/03898 R, is selected from H, halogen, -CN, -CHO, -CF 3 -OH, C 1 alkyl, preferably C,-
C
6 alkyl, C,-C, 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 -N -C16 alkyl, -N(C,-C 6 alkyl), -NS 2
_C-C
6 alkyl, or -S0 2
-C,-C
6 alkyl;
R
3 is selected from -COOH, -C(O)-COOH, -(CH 2
-(CH
2
),,-COOH,
-CH=CH-COOH, -(CH 2 1 -tetrazole, 0 N~ Cl-C 6 lower alkyl) lower alkyl) .or 0 11 7-P-OH- /1 '1 0 cli or a moiety selected from the formulae. wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2
-C(Z)-N(R
6
-C(Z)-N(R
6
)-(CH
2 6 6
)-(CH
2 -C(Z)-NH-S0 2 or C(Z)-NH-S0 2
-(CH
2 M' is selected from the group of -CCOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, WO 99/43654P TS9 0 89 PCTIUS99/03898
H
9 0 R8
IX/\
H N N-
R
8 R9, 9 0-P -OH 0~ O 0
S
OHor in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH,
(CH
2 tetrazole, 0 7P OH 0 O 0 ,o S H
R
9 is selected from H, halogen, -C 3 -COOH, -(CH 2
),,-COOH,
-(CH
2 )n-C(O)-COOH,
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 Rio is selected from the group of H, halogen, -CF, -OH, -COOH, -(CH 2 )n-COOH,
-(CH
2 -C 1
-C
6 alkyl, -O-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 46 WO 99/43654 PCT/US99/03898 R8
N-"
SR,
z
R
8
R,
z lower alkyl) o 00
S
N (C1-C6 lower alkyl -C lower haloalky (Cl-Crlower haloalkyl,'
R,
1 is selected from H, C,-C 6 lower alkyl, C 1
-C
6 cycloalkyl, -CF3, -COOH, -(CH 2 COOH, -(CH 2 )n-C(O)-COOH,
R
N- R9
R
8
(CH
2 )n with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R 8 Rg, RI 0 and/or shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 0 O 0 0 .O-P-OH" H or 5 OHo BN 8 n is an integer from 0 to 3; Ri~ii~;$lr3~rr*ri~ii~iir7~n~i~nii~~;jr~i WO 99/43654 PCT/US99/03898
R
4 is selected from H, -CF 3
C,-C
6 lower alkyl, lower alkoxy, C 3 cycloalkyl, -C,-C6 alkyl-C 3 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2
-M
2
L
2 indicates a linking or bridging group of the formulae
-(CH
2
-(CH
2 )n-C(O)-(CH 2
-(CH
2 )n-O-(CH 2 or -(CH 2 )n-S-(CH 2
C(O)C(O)X;
where X is O or N,
M
2 is selected from: a) the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3
-C,
0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Co alkyl, preferably C,-C 6 alkyl, alkoxy, preferably C,-C 6 alkoxy, -NO -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Co alkyl, preferably C,-C 6 alkyl, C,-Co alkoxy, preferably C,-C6 alkoxy, -NO 2
-NH
2 -CN, or -CF3; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-Co alkyl, preferably C,-C 6 alkyl, Ci-Clo alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 -NH2 -CN,
CF
3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C, 0 alkyl, preferably C,-C6 alkyl, C,-Clo alkoxy, preferably C-C 6 alkoxy, -CHO, -NO 2 -NH2, -CN, -CF 3 or -OH; 48 11 01-- _.1_11.11 I- ".-1-1.1,-111-1-11-1 -111-- 1-1 1- 11-111, 11 WO 99/43654 PCT/US99/03898 R, is selected from -(CH 2 )n-S-(CH 2 3
-C
5 cycloalkyl, -(CH2)n-O-(CH 2 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 -phenyl-CH,-phenyl, -(CH 2 ),-O-phenyl-
CH
2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2
-CH
2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: O 0 Y O 11-Y /m(CH2)nl,, S I_-Y 0 O1 I* (CH2)n,, 0 ,(CH2)r, S ,-(CH2)n, (CH2 O 0 (CH2) wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3
-C
cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF, -OH, 6 alkyl, C 1
-C,
6 alkoxy, -NO 2
NH
2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or b) a moiety of the formula (CH) Y wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C-C,6 alkyl, CI-C, 6 alkoxy,
-NH
2
-NO
2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or c) a moiety of the formulae -(CH 2
-(CH
2 or -(CH 2 wherein A is the moiety:
D
C
B
wherein 49 WO 99/43654 PCT/US99/03898 D is H, C,-C 6 lower alkyl, lower alkoxy, -(CH 2
),-CF
3 or -CF 3 B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 or a pharmaceutically acceptable salt thereof.
In a further preferred group within the subgenus above, R, is benzyloxy and R 5 are as defined above.
Yet another preferred group herein are the compounds of the formulae: and
R
4
R,
wherein: R, is selected form H, halogen, -CF3, -OH, -CI-C 6 alkyl, C 1
-C
6 alkoxy, -NO 2
-NH
2 phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: 0 0
R~
R7 R6
R
6
N.N
R7 i 6 or 0 0 R6 R N N R6 R7 O
N
0 or
R
6 is selected from H, alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -0benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, alkyl, C-C 6 alkoxy, -NH 2 -NO2, -CF3, or -OH; WO 99/43654 PCT/US99/03898
R
7 is selected from -CF, 1,-6 alkyl, C 1
-C
6 alkoxy, -NH-(C 1
-C
6 alkyl), -N-(C 1
-C
6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, C 1
-C
6 alkoxy, -N21 -C3 or -OH;
R
3 isselected from -COOH, -C(O)-COOH, -(CH 2 1 -C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH,
-(CH
2 )nC(O)NS(O)(O)(C 1
-C
6 lower alkyl), -(CH 2
)NC(O)NS(O)(O)(CI-C
6 lower haloalkyl), RR8 R8R9 R N N 7
N'
RioN~~
R
8
N
0 0
"'N
0 R9 0 N IJ/I 9 N (CH2) >OH Rio 0 0 0 N H )O H N H WO 99/43654 PTU9/39 PCTIUS99/03898 S R 8 N
R
0 H 0
R
0 Hi Rio or
R
8 and R 9 are independently selected from H, halogen, -CF3 -OH, -COOH, -(CH29.- COOH, -(CH 2
-C
1
-C
6 alkyl, -0-C -C 6 alkyl, -NH(C 1
-C
6 alkyl), or -N(C 1
-C
6 alkyl) 2 RW is selected from the group of H, halogen, -C 3 -COOH, -(CH 2
),,-COOH,
-(CH
2
-C
1
-C
6 alkyl, -0-C 1
-C
6 alkyl, -NH(C 1
-C
6 alkyl), -N(C 1
-C
6 alkyl) 2 0 0% /0 or N (Cl-C 6 lower alkyl) 0 00 0 0.
N SZ I-C6 lower alkyl N ((C 1
-C
6 lower haloalkyl:
R
11 is selected from H, C 1
-C
6 lower alkyl, -CF3 -COOH, -(CH 2
).-COOH,
-(CH
2 or 52 WO 99/43654 WO 9943654PCT/US99/03898 n is an integer from 0 to 3; R4 is selected from H, -CF 31C -c lower alkyl, C 1
-C
6 lower alkoxy, or halogen; R, i selected from C 1
-C
6 lower alkyl, C 1
-C
6 lower alkoxy, -(CH 2 )n-C 3
-C
5 cycloalkyl or the groups of: a) -C(O)-O-(CH 2 3
-C
5 cycloalkyl, -(CH 2 ),,-phenyl, -(CH 2 ),,-S-phenyl,
(CH
2 ),-phenyl-O-phenyl, -(CH 2 ),-phenyl-CH 2 -phenyl, -(CH 2 ).-O-phenyl-CH 2 -phenyl,
(CH
2 ),,-phenyl-(O-CH 2 -phenyl) 2 -C(O)-O-phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, C(O)-O-napthyl, -(CH 2 ),,-S-napthyl, -(CH 2 ),,-S-pyridinyl, -(CH 2 ),,-pyridinyl or napthyl, the phenyl, py'ridinyl and napthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3 -OH, 1C-6 alkyl, C 1
-C
6 alkoxy,
NH
2 or -NO 2 or b) a moiety of the formula -(CH 2 or -(CI- 2 wherein A is the moiety:
B
wherein D is H, CX- 6 lower alkyl, C 1
-C
6 lower alkoxy, or -CF 3 B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3 -OH, 1C-6 alkyl, C 1
-C
6 alkoxy, -NH 2 or -NO 2 or a pharmaceutically acceptable salt thereof.
Detailed Description of the Invention 53 WO 99/43654 PCT/US99/03898 As used herein, the terms "aryl" and "substituted aryl" are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms. Among these aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties. The aryl and heteroaryl groups of this invention also include the following: a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine; or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indolineisoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine.
The "substituted aryl" groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C,0 alkyl, preferably C,-C 6 alkyl, C,-C, 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, -NO 2
-NH
2 -CN, -CF, or -OH or combinations thereof, such as -CH 2
CF
3
-NH(CH
3 etc.
A preferred subset of these groups, optionally substituted as just described, include moieties formed from benzene, pyridine, napthylene or quinoline rings. A further preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings. A preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
The alkyl, alkenyl and alkinyl groups referred to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched. Halogens herein are understood to include F, Cl, Br and I.
54 WO 99/43654 PCT[US99/03898 As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 116 below).
A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA 2 in any available assay (preferably an assay described below in Example 116 or Example 117) for enzyme activity. In preferred embodiments, a compound has an IC 50 value of less than about 25 pM, preferably less than about 6 pM, in the LysoPC assay; an IC 5 0 value of less than about 50 pM in the vesicle assay; an IC 50 value of less than about 1 pM in the PMN assay; an IC 5 0 value of less than about 15 PM in the Coumarine assay; and/or measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat carrageenan-induced footpad edema test.
Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA 2 activity and, therefore, are useful in "treating" treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention.
Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically WO 99/43654 PCT/US99/03898 acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S.
Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S.
Patent No. 4,737,323, all of which are incorporated herein by reference.
As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
In practicing the method of treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection.
A4A-VXtWC*~. WO 99/43654 PCT/US99/03898 When a therapeutically effective amount of compounds of the present invention is administered orally, compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet formn, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention.
When admninistered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention.
When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
The amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0. 1 g'g to about 100 mng (preferably about .1I mg to about WO 99/43654 PCT/US99/03898 mg, more preferably about 1 mg to about 2 mg) of compound of the present invention per kg body weight.
The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
Compounds of the present invention invention can be made according to the methods and examples described below. Synthesis of preferred compounds of the present invention are described in the examples below.
Method A The indole may be alkylated at the c-3 position with the appropriate alkyl bromide and treatment with a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C 100 Alternatively it may be alkylated in a two step procedure by treatment of the indole with n-BuLi in a solvent such as THF or ether followed by ZnC12 and then concentrated and treated with the appropriate alkylating agent in a variety of solvents such as THF, ether, toluene or benzene. The indole nitrogen may then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide. The ester can be hydrolyzed under basic conditions with sodium hydroxide in water and methanol and THF. Alternatively it may be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperatures (50 "C 100 The product acid by be coupled to a sulfonamide by the agency of a variety of coupling reagents such as DCC, EDCI or carbonyl diimidazole in a solvent such as THF, methylene chloride, dichloroethane or DMF in the presence of a base such as triethyl amine and/or N, N-dimethyl pyridine. In the case of R1 nitro the nitro group can be reduced by exposure to Pt/C in the presence of hydrogen in a solvent such as methanol, ethyl acetate or THF. The resulting amine can be acylated or sulfonylated by exposure to the appropriate agent in the presence of a base such as triethyl amine, sodium bicarbonate or pyridine in a biphasic solvent system such as methylene chloride:water or THF:water or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine. The resulting 58 S V V -P-iThu Ir.i~bnl.XrVVjrrRh.ri.'. ii -r i WO 99/43654 PCTIUS99/03898 acid may then be hydrolyzed and modified as described above. Also in the case RlI Br, it may be replaced with the copper salt of the desired nucleophile such as thiomethoxide, methoxide or suiphinic acid.
Method A Ag(I)0 Dionane N 60 OC H RZ_ ,-0M NaH
DMF
R3-Br NaOH MeOH
THF
Pt/C
H
2
THF
CH
2
CI-
2
EDCI
DMAP
R
4 S0 2
NH
2 0 59 WO 99/43654 PCT/US99/03898 NaHC03 CH2C02 NaOH MeOH
THF
CH
2
CI
EDCI
SR DMAP R4 R 4
SO
2
NH
2
R'
NH
2 nitro, halogen alkyl 5,6-methylenedioxy methoxy R2
R
3 H, MeO alkyl, alkenyl, aryl
R
4 alkyl, aryl heterocyclic
R
5 aryl carbamate alkyl urea alkyl amide aryl amide sulfonamide
R
6 H, halogen, methoxy Method B The indoleglyoxalyl chloride may be reacted with the desired amino ester in a biphasic system with methylene chloride and saturated sodium bicarbonate or in a monophasic system with a solvent such as methylene chloride, ethyl acetate or THF and a base such as triethylamine, Hunigs base or pyridine. The indole nitrogen may then be alkylated with a variety of alkylating reagents in a solvent such as DMF, DMSO or THF and a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide. The ester may then be hydrolyzed with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
U1--ill-- IIII~I~II II* IU IYIY~~iljl b I i~:~irl) rmrl *x~n IU ar*irii~i~;inrr* -~-l(jTi ~hj-~lr~r~*IVZL*I" i iiill'.lllililU ;i II WO 99/43654 PCT/US99/03898 Method B CH2C12 Sat'd bicarb NaH
DMF
R'Br NaOH MeOH
THF
Method C The 3-carboxyindole is elaborated via reductive amination by allowing the aldehyde to condense with an amino ester in a solvent such as methylene chloride or dichloromethane with or without acetic acid. The resulting imine is reduced in-situ with a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The acid is then prepared by hydrolysis of the resulting ester with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
I II illS' ly illl 1~ 1( IIIII I_ UL( I)r .T*ll~lll jl*-~yl~ l~-~11 411~~~11111. Ill~i~llK l ~yhl~l 1 blL~ iil~-- WO 99/43654 PCT/US99/03898 Method C
H
HN- I)NaBH(OAc) 3 0 acetic acid
H
2)NaOH O R MeOH
THF
OOR'
RI alkyl
,I-
CN xI. or ROH OR I H N
J-
Method D may be treated with a base such at methyl or ethyl grignard and acylated at the 3-position with ethyloxychloride in a suitable solvent such at ether or THF. The indole nitrogen may then be alkylated with a benzylbromide by the action of a base such as sodium hydride or n-butyllithium in a solvent such a THF or DMF. The ester is then hydrolysed under basic conditions with sodium hydroxide or tetrabutylammonium hydroxide in a suitable solvent system such at water:MeOH:THF. Coupling of the appropriate aminoester may then be effected by the use of a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF. The target acid may the be revealed by hydrolysis of the ester under the same conditions discussed above.
WO 99/43654 WO 9943654PCTIU S99/03 898 Method D 0oJ I)EtMgBr 0 C Et2OI )NaH DMF 2)cthyloxychloride -2)R 1 Br NaOH THF. MeOH NaOH
THF
MeOH- EDCI, DMF aminoester R 1 aryl
R
2 ary], C02H Method E Indole-3-acetic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh3)4 as a catalyst in a mixed solvent (ethanolbenzene-water) at elevated temperature to give the 1-alkyl-5-substituted indole.
WO 99/43654 PCT/US99/03898 Method E RSBr 'Pr 2 NEt R'B(OH)2
(C
6
H
5 4 Pd Na 2
CO
3
SN
R
III
CF
3 Nz Method F Alkylation of the nitrogen atom of I with a suitable base such a sodium hydride or potassium carbonate and an alkyl halide gave the aldehyde 1I. The aldehyde could be transformed to the thiazolidinedione III using a base such as piperdine and isolated with an acid such as acetic acid. Deprotonation with a suitable base such as sodium hydride and alkylation on the nitrogen atom of the thiazolidinedione with selected electrophiles such as alkyl or benzyl halides provided compounds such as IV.
64 WO 99/43654 PCT/US99/03898 Method F NaH, DMF 0 0
H
piperidine i NaH R-Br DMF 7 7 R COH or C0 2
H
Method G The nitro-indole I was converted to the unsaturated ester via a Horer-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran. Reduction of the nitro group of II can be accomplished via hydrogenation with palladium on carbon in the presence of hydrogen and acylation of the resulting amine under Schotten-Bowmann conditions to give amides such as III. Saponification of the ester function gave the acid-indole
IV.
WO 99/43654 PCT/US99/03898 Method G
CO
2 Me HO trimethoxyphosphonoacetate 02N trimethoxyphosphonoacetate 0 2 Cg
CI
1) H2, Pd-C, THF 2) NaHCO 3 Aqueous
CH
2 Ci 2 CO H t H CO 2 Me N
H
NI N H NaOH 0N
THF
MeOH
III
Method H 5-Chloro-2-methylindole could be reductively alkylated at the 3-position with a suitable aldehyde in the presence of an acid such as trifluoroacetic acid and a reducing agent such as triethylsilane in a suitable solvent such as methylene chloride to give the ester II. The nitrogen atom could be alkylated by treatment with a suitable base such as sodium hydride and diphenyl bromo methane and the resulting compound III could be saponified to give IV.
WO 99/43654 PCT/US99/03898 Method H CMe OHC -CO 2 Me CO 2
M
H Me STFA, EtzSiH, CH 2 C1 2
O
O
C H 11 R-Br -2 e COMe )C N NaOH N MeOH IV
THF
Method I The starting indole is C3 functionalized by either reaction of DMF/POC13 or by reacting the magnesium salt of the indole with methyl oxalyl chloride. The resulting esters and aldehydes were then Nalkylated by treating the salt of the indole, generated by treating the indole with a strong base, with a variety of alkyl halides. In th case of the aldehydes, when r' is a nitro group, the nitro is reduced to the amine using Pt/C and H2 or copper acetate/sodium borohydride and then acylated usind various acid chlorides, isocyanates, chloroformates or reductively alkylated using aldehydes and sodium triacetoxyborohydride. These aldehydes could then be oxidised to the desired acid which could be coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product. The esters generated above could be treated in a similar fashion. The ester could hydrolyzed and then coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product.
67 WO 99/43654 WO 9943654PCTIUS99/03898 Method 1(a) I DMFIPOCI 3 R \NHIM zz: N RN"X H N R'=N0 2 1) H-,/Pt 2)R-"'COCI 3) NAHPO 4 /tBuOH NaO-,CI 1) CICOCOCI/NR C0 2
R'
or EDCIINR C0 2
R"
2) NaOHJITHFIMeOH Method 1(b) R 1) R"MgXICHOCCOCI
H
R'=N0 2 1) i)HIPt 3)NaOH-ITHF/MeOH NaHIDMF
R"X
1) CICOCOCIINR"C0 2
R"
or EDCIINR C0 2
R"
2) Na0HITHFMeOH Method J The starting amine was treated with various sulfonyl chlorides in the presence of pyridiine and then the excess sulfonyichioride was scavenged by adding a polymer bound amine. The WO 99/43654 PCT/US99/03898 desired products where then hydrolyzed using sodium hydroxide in THF/MeOH and the reaction was aidified using IR-120 resin to yield the desired products.
Method J 0- H2N, H 1) RSO 2 Cl/Pyridine 'N NH2 -N NH 2 0-
H
R
x N. -j 1) NaOH/THF/MeOH 2) Amberlite IR120
OH
R N
N'
Method K The starting indole was bis alkylated by the addition of a strong base such as sodium hydride and then an alkylating agent such as an alkyl or aryl halide followed by the hydrolysis of the resulting ester with sodium hydroxide in THF/MeOH. The acid was then coupled with an alkyl or aryl amino ester and then hydrolyzed to yield the desired acid.
Method K CO0 2
N
H
1) NaH/R"X 2) NaOH/THF/MeOH
CO
2
H
R"
1) CICOCOC1/NR"'C 2
R""
or
EDCI/NR"CO
2
R""
2) NaOHITHF/MeOH WO 99/43654 PCT/US99/03898 Example 1 [(cvclopentvloxv)carbonvllamino}-1-propvl-1H-indol-3-vl)methyll-3methoxvbenzoic acid Step 1 To a solution of 5-nitro indole (21.24 g, 131 mmol) in dioxane (128 mL) in a reaction vessel wrapped in aluminum foil is added silver(I)oxide (30.34 g, 131 mmoL, 1.5 eq) and methyl 4-(bromomethyl)-3-methoxy-benzoate (34 g, 131 mmol) and the mixture is brought to 60 °C and stirred 20 h. The reaction is cooled, filtered through celite, taken up in ethyl acetate (500 mL), washed with brine (2 X 50 mL), dried (MgSO 4 and filtered. The crude material was purified by silica chromatography (15% ethyl acetate hexanes) to afford the desired product (5.8 g, Step 2 The C3-alkylated indole (1.5 g, 4.4 mmol) was dissolved with 15 mL THF. In a separate flask, NaH (185 g, 4.61 mmol) was suspended with 25 mL THF at 0 oC. The solution of starting material was cannulated into the NaH suspension, giving a deep red solution. This was then allowed to stir at room temperature for 10 minutes. 1-iodopropane was added (0.47 mL, 1.1 mmol) and the reaction was allowed to proceed overnight at room temperature. As the reaction was not complete (TLC) and additional 0.5 mL of 1-iodopropane was added and the reaction continued for another 3 h. There was no change in the TLC and the reaction was poured into cold 1 N HCI and extracted with CH 2
CI
2 (3 X 75 mL). The combined organic layers were dried over MgSO 4 filtered and evaporated to yield the crude N-alkylated nitroindole. The crude material was absorbed onto silica and loaded onto a silica gel column.
The column was eluted with 100% CH 2 Cl 2 to give the pure yellow N-alkylated nitroindole (0.96 g, 57%).
Step 3 The N-alkylated nitroindole (0.95 g) was dissolved with 40 mL anhydrous THF. The system was purged with argon. To the clear, yellow solution, Pt/C (0.462 g) was added. The argon was then removed by evacuation and hydrogen was introduced to the system. The reaction was stirred 6.5 h. The hydrogen was evacuated and argon was then purged through the system. The reaction mixture was filtered through celite with THF. The solvent was removed by rotary evaporation to give the crude amine as a dark oil.
Chromatography ethyl acetate/CH 2 Cl 2 afforded the desired product (0.7 g, Step 4 The amine from above (0.7 g) was dissolved in 40 mL CH 2
CI
2 4methylmorpholine (0.3 mL, 3.0 mmol) and cyclopentyl chloroformate (383 mg, 2.57 mmol) were then added to give a yellow/orange solution. The reaction was allowed to proceed at room temperature for 3 h. The reaction mixture was acidified with 1 N HC1 and the mixture was extracted with 50 mL CH 2 C1 2 The combined organic phases were washed with brine, dried over MgSO 4 filtered and concentrated to give the crude carbamate. The crude product was absorbed onto silica gel and loaded onto a silica gel column. The column was eluted with 100% CH,C1 2 to afford the desired product (0.87 g, 39%) as a yellow foam.
r;r -r r-r r, u.UI^.I. .irr~mrllr ii r--L--LI I~ ri--l---ll l( lni~~l..l r.-~i~l*lli~l) lilll~l~l~L1;1~~71:; .I 1.1 .liTii--jl *llll:li~;iri~.~ ii.l~~jlli .)iitrT~ii~j lll *~~lllinj^ji-ji~W ~Vilillii~i~/ i-*jll4l~y tiil)*i WO 99/43654 PCT/US99/03898 Step 5 The carbamate (0.831 g) was dissolved with hydrolysis solution (2:1:1 THF:MeOH:2N NaOH) and the reaction was allowed to proceed for 5.25 h. The reaction was acidified to pH 2 with 2N HCI and extracted with CHCl,. The organic layer was washed with water and brine. The combined organic layers were then dried over MgSO 4 filtered and evaporated to yield the crude acid, which was recrystallized from CH 2
CI
2 to afford the title compound (0.575 g, 71%) as pink crystals.
MS: m/z 449 Example 2 Cvclopentvl N-1 3 2 -methoxv-4-(f[(2-methvlphenvl)sulfonvllamino}carbonvl) benzvll-1-propvl-1H-indol-5-yl}carbamate Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 3 4 -[(1-benzhvdrvl-5-f[(cvclopentvloxv)carbonvlamino-lH-indol-3vl)methvll-3-methoxvbenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 4 [(cvclopentvloxv)carbonvllamino}.1-(2-naphthvlmethvl)-1H-indol-3vllmethyl}-3-methoxvbenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
WO 99/43654 PCT/US99/03898 Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
MS: m/z 547 Example 4-f [(cvclopentvloxv)carbonvl amino 1-1-(cvclopropvlmethyl)-1H-indol-3vllmethyl}-3-methoxvbenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
MS: m/z 461 Example 6 4- [5-f [(cvclopentvloxy)carbonvllaminol-1-(4-pyridinvlmethyl)-1H-indol-3vllmethvll-3-methoxvbenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 7 4-[(5-f[(cvclopentvloxv)carbonvllamino}-1-isopropvl-1H-indol-3vl)methyll- 3-methoxvbenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
WO 99/43654 PCT/US99/03898 Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
MS: m/z 449 Example 8 4-[(1-cyclopentvl-5-{[(cyclopentvloxv)carbonvllamino}-1H-indol-3vl)methvil-3-methoxybenzoic acid Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
MS: m/z 475 Example 9 4-[(1-benzhydryl-5-{[(butylamino)carbonyllamino}-1H-indol-3-vl)methvll-3methoxvbenzoic acid The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the intermediate 5-amino indole is prepared as in Example 1, step 3, using the 5-nitro indole intermediate. The intermediate urea is prepared as in Example 1, step 4, using the appropriate acylating agent. The title compound is prepared as in Example 1, step 5, using the urea intermediate.
MS: m/z 560 Example 4-({1-benzhydryl-5-[(methylsulfonyl)aminol-lH-indol-3-yl}methyl)-3methoxvbenzoic acid-- The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent followed by preparation of the intermediate 5-amino indole as in Example 1, step 3, using the 5-nitro indole. The intermediate sulfonamide is next prepared as in Example 1, step 4, using the appropriate acylating agent. The title compound is then prepared as in Example 1, step 5, using the sulfonamide intermediate. MS: m/z 539 -7---rJ4S C .A v WO 99/43654 PCT/US99/03898 Example 11 4-({1-benzhvdrvl-5-[(cyclopentvicarbonyl)aminol-lH-indol-3-vl}methvl)-3methoxvbenzoic acid The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and intermediate 5-amino indole is prepared as in Example 1, step 3, using this 5-nitro indole intermediate. The corresponding intermediate amide is then prepared as in Example 1, step 4, using the appropriate acylating agent. The final title compound is prepared as in Example 1, step 5, using this amide intermediate. MS: m/z (M-l) 557 Example 12 4-[(1-benzhydrvl-5-nitro-1H-indol-3-vl)methyll-3-methoxvbenzoic acid The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the title compound is prepared as in Example 1, step 5, using this intermediate. MS: m/z 657 Exmaple 13 4-r(1-benzhvdryl-5-bromo-1H-indol-3-vl)methyll-3-methoxybenzoic acid The intermediate 5-bromo indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z 526 Example 14 4-[(1-benzhvdryl-5-fluoro-1H-indol-3-vl)methyll-3-methoxvbenzoic acid The intermediate 5-fluoro indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1)464 Example 4-[(1-benzhvdrvl-5-methvl-1H-indol-3-vl)methyll-3-methoxvbenzoic acid The intermediate 5-methyl indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using-the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1)460 4 W V WO 99/43654 PCT/US99/03898 Example 16 4-f(5-benzhvdrvl-5H-[l,31dioxolo[4.5-flindol-7-vl)methvll-3-methoxvbenzoic acid The intermediate 5,6-methylenedioxy indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z 490 Example 17 4-[(1-benzhvdrvl-5-cvano-1H-indol-3-vl)methyll-3-methoxvbenzoic acid Step 1 To the intermediate from Example 13, step 2 (0.25 g, 0.46 mmol), in DMF (1 mL) is added CuCN (0.05g, 1.2 eq) and the reaction mixture is stirred at 145 °C overnight and then cooled.
To the cooled reaction mixture is added FeCl 3 (0.09 g, 1.2 eq). The reaction mixture is stirred min, taken up in ethyl acetate (30 mL), washed with brine (3 X 10 mL), dried (MgSO 4 filtered and concentrated. The product was purified by silica chromatography (20% ethyl acetate/hexanes) to afford the intermediate ester (0.2 g, 89%) as a colorless oil.
Step 2 To the intermediate ester (0.2 0.41 mmol) in DMF (2 mL) is added sodium thiomethoxide (0.1 g, 3.4 eq)and the reaction mixture is stirred at 90 oC for 10 min. The reaction is cooled, poured into ethyl acetate (5 mL), washed with sodium biphosphate (1 X 2 mL), brine (2 X 2 mL), dried (MgSO4), filtered and concentrated. Purification by silica chromatography (1% acetic acid, 25% ethyl acetate/hexanes) afforded the title compound (0.114 g, 59%) as a colorless amorphous powder. MS: m/z 471 Example 18 [1-benzhvdrvl-5-(methylsulfonyl)-1H-indol-3-vllmethyl -3methoxybenzoic acid Step 1 To the intermediate from Example 13, step 3 (1 g, 1.9 mmol), in a solution of THF (2 mL) and methanol (2 mL) is added sodium hydroxide (0.41 mL, 4.63 M, 1 eq). The mixture is stirred for 20 min and then concentrated. The residual water is chased off by the addition of toluene and it's removal (3 X) a white powder (1 g, 100%).
Step 2 To the sodium salt prepared above (0.88 g, 1.6 mmol) in DMF (3 mL) is added methanesulfinic acid, sodium salt (0.72 g, 4.4 eq) and Cul (0.74 g, 2.4 eq). The reaction mixture is stirred at 130 °C overnight, cooled, taken up in ethyl acetate (50 mL) and acetic acid ~irJrVi WO 99/43654 PCT/US99/03898 (10 mL), filtered (celite), washed with brine (4 X 10 mL), dried (MgSO 4 filtered and concentrated. Silica chromatography acetic acid, 25% ethyl acetate/hexanes 1% acetic acid, 50% ethyl acetate/hexanes) afforded the title compound (0.2 g, 24%) as a colorless amorphous solid. MS: m/z 524 Example 19 Cvclopentvl N-{1-benzhdrl-3-r2-methox-4-([(2carbamate To the product of Example 3, step 4 (0.5 g, 0.87 mmol), in CH 2
C
2 (4 mL) is added EDCI (0.2 g, 1.0 mmol, 1.2 eq), DMAP (0.011 g, 0.087 mmol, 0.1 eq) and ortho-toluene sulfonamide. The reaction is stirred overnight at room temperature, taken up in ethyl acetate mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO,), filtered and concentrated. Silica chromatography acetic acid, 25% ethyl acetate/hexanes) afforded the title compound (0.4 g, 63%) as a colorless solid.
Example Cvclopentvl N-13-[2-methox-4-({I(2-methlphenvl)sulfonyllamino carbonvl)benzvll-1-propvl-1H-indol-5-yl carbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 1, step 5, and the appropriate sulfonamide.
Example 21 Cyclopentvl N-{1-(cvclopropvlmethyl)-3-[r2-methoxv-4-([(2carbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 5, step 4, and the appropriate sulfonamide. MS: m/z 614 Example 22 Cyclopentyvl N-r3-[2-methox-4-({[(2-methlphen)sulfonvllaminolcarbonvl) benzvll-1-(4-pyridinvlmethyl)-1H-indol-5-vllcarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 6, step 4, and the appropriate sulfonamide. MS: m/z 651 76 ~i-unYil-ni--iyl l*'i--~ir6ii~ili~R ;^i~r WO 99/43654 PCT/US99/03898 Examnle 23 Cyclopentyl N-43-[2-methoxv-4-(II(2methvlphenvI)sulfonvIamino carbonvI)benzvyI -1(2-naphthvlmethl) -I H- The title compound is prepared as illustrated in Example 19 starting with the product of Example 4, step 4, and the appropriate sulfonamide. MS: m/z 700 Example 24 Cvclopentl N-fl-isopropl-3-[2-methoxv-4-U r(2methvlphenvl )sulfonvllamino Icarbonvl)benzvll- 1H-indol-5-vl Icarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 7, step 4, and the appropriate sulfonamide. MS: mlz 602 Example Cvclopentvl N-f1-cclopdntl-3-[2-methox-4-(r(2-methylphenyl) The title compound is prepared as illustrated in Example 19 starting with the product of Example 8, step 4, and the appropriate sulfonamide. MS: m/z 628 Example 26 Cvclopentvl N-1l-benzhvdrl-3[2-methoxv-4- (I F trifluoromethyllsulfonvI aminoIcarbonyl)benz IH-indol -5 -yIcarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z 704 Example 27 cvclopentvl N-fl-benzhvdrl-3-(2-methox-4f The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: mlz 650 77 i i~ar~u~iin-- ii WO 99/43654 PCTIUS99/03898 Example 28 cyclopentyl N-fI-benzhvdrvl-3-[4-(fH(2chIorophenvl)sulfonlIamino) carbon)-2-methoxybenzyIl yi Icarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 29 cyclopentyl N-(3-14-[(f[5-(acetlimino)-4-methyl-4.5-dihydro-1.3.4thiadiazol-2-vllsulfonvl Iamino)carbonvlI -2-methoxvbenzvl I-1 -benzbvdrvl- The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example cvcloDentl N-(1-benzhvdryl-3-14-[U vlicarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 31 cvcloDentI N-[1-benzhvdrl-3-(4-H (benzvlsulfonvl)aminolcarbonvll-2- The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z 726 Example 32 cvclopentvl N-I 1-benzhvdryl-3-l4-U [(2,4-dimethl-13-thiazol-5vysulfonvll aminocarbon vl)-2-methoxvbenzyll 1H-indol-5-yI Icarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z 747 78 WO 99/43654 PCT/US99/03898 Example 33 cvcloPentl N-11-benzhvdrl-3-r4-UIf(3.5-dimethvl-4isoxazolvl)sulfonyllamino Icarbonvl)-2-methoxvbenzllI vyicarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z 731 Example 34 cyclopentl N-(3-14-Uf1rs-(acetlamino)-1.3.4-thiadiazol-2vilsulfonvi )amino)carbonvll-2-metboxbenzvl 1-l-benzhvdrvl-1H-indol-5yDcarbamate The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example cvclopentl N-(l-benzhvdrvl-3-2-methoxv-4-[(f[4-(3-methyl.5oxo-4.5 dihydro- 1H- vrazol- vI)phenvllsulfonyllaminocarbonyllbenzyl -11-indol- The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 36 1H-indol-3-vl)methvll -3-methoxvbenzovl 1-2methvlbenzenesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 12, step 2, and the appropriate sulfonamide. MS: m/z 644 Example 37 N-1 -benzhydrvl-5-nitro-H-indol-3-I~methyll -3.
methoxvbenzovl l(trifluoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 12, step 2, and the appropriate sulfonamide. MS: mlz 622 79 WO 99/43654 PCTIUS99/03898 Example 38 N- 4( benzhvdrvlmo rindo 3v)methvil-3-methoxb z -2m ethvlbenzen esul Con amid e The title compound is prepared as illustrated in Example 19 starting with the product of Example 13, step 2, and the appropriate sulfonamide. MS: m/z 679 Example 39 N-14-l(I-benzhdrvl-5-bromo.1H.indol-3-yI )ethvll-3methoxvbenzovl I(trifluoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 13, step 2, and the appropriate sulfonamide.
MS: m/z 657 Example N-fl-benzhydrvl3-[2-methoxv-4-(f r(trifuoromethv)sulfonvyl amino 1 carbonvl)benzvll-l H-indol-5-yI lcvclopentanecarboxamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 11, step 4, and the appropriate sulfonamide.
MS: m/z 688 Example 41 N-[4-UL l-benzhvdrvl-5-l(methylsulfonvI)aminoI I H-indol-3-llmethvl)l3.
methoxvbenzovll(trifjuoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 10, step 4, and the appropriate sulfonamide.
MS: m/z 670 Examrle 42 N-I4-11I-benzhvdrvl-5-f (butvlamino)carbonvllaminol..H.indoI 3 yl)methvll-3-methoxvbenzovIl(trifluoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 9, step 4, and the appropriate sulfonamide.
MS: m/z 691 ~awr-ii~r~C~rj~ill~"lY~-'"F-~ WO 99/43654 PCT/US99/03898 Example 43 N-{1-benzhydrvI-3-[2-methoxy-4-({[(2-methylphenvl)sulfonvllamino} carbonvl)benzvl- 1H-indol-5-vl }cclopentanecarboxamide The title compound is prepared as illustrated in Example 19 starting with the product of Example 11, step 4, and the appropriate sulfonamide.
MS: m/z 710 Example 44 4 -({5-[(cvclopentvlcarbonvl)aminol-1[phenvl(2-pyridinvl)methyll-1H-indol- 3-yl}methvl)-3-methoxvbenzoic acid Step 1 The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2 The intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z 738 Example -benzhvdryl-5-[(benzvlsulfonyl)amino 1H-indol-3-vl}methyl)-3methoxvbenzovll (trifluoro)methanesulfonamide Step 1 The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2 The intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4 The title compound is prepared as illustrated in Exariple 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z 746 WO 99/43654 PCT/US99/03898 Example 46 N- 1-benzhydryl-3-[2-methoxy-4-({ [(trifluoromethyl)sulfonvlamino} carbonyl)benzvl-l H-indol-5-yll-3-thiophenecarboxamide Step 1 The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2 The intermediate amide is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z 702 Example 49 benzvl N-{1-benzhvdrvl-3-r2-methoxy-4- Step 1 The intermediate 5-amino indole is prepared asin Example 1, step 3.
Step 2 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z 726 Example 4-[(1-benzhydryl-5-nitro-1H-indol-3-vl)methyllbenzoic acid Step 1 The intermediate 3-alkylated 5-nitroindole is prepared as illustrated in Example 1, step 1, using the appropriate alkylating agent.
82 WO 99/43654 PCT/US99/03898 Step 2 The intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 3, step 1.
Step 3 The title compound is prepared as illustrated in Example 1, step MS: m/z 461 Example 51 4-r(1-benzhydrvl-5-bromo-1H-indol-3-vl)methyllbenzoic acid Step 1 The intermediate 3-alkylated 5-bromoindole is prepared as illustrated in Example 13, step 1, using the appropriate alkylating agent.
Step 2 The intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 13, step 2.
Step 3 The title compound is prepared as illustrated in Example 13, step 3.
MS: m/z 494 Example 52 4-[(1-benzhydryl-5-{ (cyclopentyloxy)carbonyllamino}-lH-indol-3vl)methyllbenzoic acid Step 1 Starting with the material prepared in Example 50, step 2, the desired intermediate is prepared as illustrated in Example 3, step 2.
Step 2 The intermediate carbamate is prepared from the above intermediate as illustrated in Example 3, step 3.
Step 3 The title compound is prepared from the above intermediate as illustrated in Example 3, step 4.
MS: m/z 543 Example 53 cyclopentvl N-{1-benzhydrvl-3-[4-({(2-methylphenvl)sulfonyllamino} The title compound is prepared from the product of Example 52, step 3, as illustrated in Example 19. MS: m/z 697 83 P; l- r WO 99/43654 PCT[US99/03898 Example 54 cyclopentyl N-11 1-benzhydryl -34I4-U (f(trifluorometh yl)sul fonyl ]arnino carbon yl)benzy] 1- 1H-indol -5-vl Icarbamnate The title compound is prepared from the product of Example 52, step 3, as illustrated in Example 26. MS: m/z 674 Exam~le N-1 4- 1 -benz yd ryl-5 -nitro- IH- indoJ -3-vI~methyl I benzoyl I (trifi uo rOmethanesulfonamide The title compound is prepared from the product of Example 55, step 3, as illustrated in Example 26. MS: m/z 592 Example 56 N-14-r(l1-benzhydryl-5-nitro-lH-indoi-3-yl)methyllbenzoyl 1-2methylbenzenesulfonamide The title compound is prepared from the product of Example 55, step 3, as illustrated in Example 19. MS: m/z 614 Example 57 N 14- M (-benzby d ryl -5-b rom o-1I H-in dol -3-vI )m ethyl]I ben zoy 11-2methylbenzenesulfonamide The title compound is prepared from the product of Example 5 1, step 3, as illustrated in Example 38. MS: m/z 649 Example 58 N-f 4-[I-benzhydryl-5-bromo-lH-indol-3-yl)methyllbenzoylI (trif luo rO)me than esuIf onamide The title compound is prepared from the product of Example 51 step 3 as illustrated in Example 39. MS: ml/z 627 Example 59 3 -(1 2 4 -benzylbenzyl)-1H-indol-3-yll-2-oxoacetyllamino)benzoic acid Step 1 To a solution of methyl 3-am-inobenzoate (2.4 g, 16.0 mmol) in CH 2
CI
2 mL) and saturated sodium bicarbonate (50 mL) at 5 'C is added 3-indolyiglyoxalyl chloride g, 14.4 minol). The reaction is stirred to room temperature over 2 h, taken up in ethyl acetate (200 m1L), washed with brine (3 X 50 ml), dried (MgSO 4 filtered and concentrated.
84 WO 99/43654 PCT/US99/03898 Crystallization of the crude material afforded the desired intermediate (2.7 g, 58%) as a colorless solid.
Step 2 To a solution of the above intermediate (0.3 g, 0.93 mmol) in DMF (1.5 mL) at 0 oC is added potassium bis(trimethylsilyl)amide (0.41 g, 2.06 mmol). After the reaction is stirred at room temperature 30 min 4-benzylbenzyl bromide (0.27 g, 1.03 mmol) is added.
The reaction is stirred 3 h, taken up in ethyl acetate (10 mL), washed with brine (3 X 2 mL), dried (MgSO 4 filtered and concentrated. Radial silica chromatography (2 mm, 10% ethyl acetate/hexanes) afforded the desired intermediate (0.19 g, 41%) as a colorless oil.
Step 3 The ester obtained in step 2 was treated with sodium hydroxide (2 mL, 5 M) in THF (5 mL) and MeOH (2 mL). The reaction was stirred overnight, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO 4 filtered and concentrated. Trituration of the material in ethyl acetate with hexanes afforded the title compound (0.105 g, 60%) as a colorless solid. MS: m/z 487 Example 3-({2-fl-(4-{[3.5-bis(trifluoromethvl)phenoxylmethyl benzvl)-lH-indol-3vll-2-oxoacetvl}amino)benzoic acid The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2 The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z 639 Example 61 3-{[2-(1-benzhvdryl-1H-indol-3-vl)-2-oxoacetyllamino}benzoic acid The intermediate prepared in Example 59, step 1, was N-1 alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2 The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z 473 ;ir; ~r~illOh~~hi~W~~;I~i~2li~i~i--l ;li-~"-'i-~iJlii;r-i--ii-l*r WO 99/43654 PCT/US99/03898 Example 62 3-[(2-11-[3-(4-benzvlphenoxv)propvll-1H-indol-3-yl}-2oxoacetvl)aminolbenzoic acid Step 1 The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2 The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z 531 Example 63 3-[(2-{1-r3,4-bis(benzvloxy)benzyl]-lH-indol-3-vlH-2oxoacetyl)aminolbenzoic acid Step 1 The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2 The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z 609 Example 64 3-[(2-{1-[2-(benzylsulfonvl)benzyll-1H-indol-3-vl}-2oxoacetvl)aminolbenzoic acid Step 1 The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2 The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z 551 Example 3-r( 1-benzhydryl-5-[(cvclopentylcarbonyl)aminol-lH-indol-3vl}methvl)aminolbenzoic acid Step 1 To a solution of the aldehyde prepared in Example 114, step 3 (0.3 g, 0.7 mmol) in dichloroethane (2 mL) and DMF (1 mL) is added methyl 3-amino benzoate (0.113 g, 0.735 86 -~;l~liUii~iliiiZ1 i l~rairurXr*:~a~~hI~~r~W(i~'in-- WO 99/43654 PCT/US99/03898 mmol, 1.05 eq) and acetic acid (0.13 mL, 2.1 mmol, 3 eq). After stirring 30 min sodium triacetoxyborohydride (0.18 g, 0.84 mmol, 1.2 eq) is added and the reaction is allowed to stir an additional 4 h after which it is taken up in ethyl acetate (20 mL), washed with saturated sodium bicarbonate (1 X 10 mL), brine (2 X 5 mL), dried (MgSO 4 filtered and concentrated.
Silica chromatography (30% ethyl acetate/hexanes) afforded the desired intermediate (0.24 g, 60%) as a colorless oil.
Step 2 The product ester was hydrolyzed as described in Example 59 step 3 to give the title compound (0.11 g, MS: m/z 542 Example 66 -benzhydryl-5-[(cyclopentylcarbonyl)amino- 1H-indol-3yl}methyl)piperazinolacetic acid The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z 549 Example 67 -benzhvdryl-5-[(cyclopentylcarbonvl)aminol-1H-indol-3-vl}methyl)- 3-oxo-2-piperazinyllacetic acid The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z 563 Example 68 2-[({1-benzhydrvl-5-r(cyclopentylcarbonyl)aminol-lH-indol-3yl}methyl)aminol-3-hydroxypropanoic acid The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z 510 Example 69 2-l[-(4-benzvlbenzyl)-5-(benzyloxy)-lH-indol-3-yll-2-oxoacetic acid Step 1 Ethylmagnesium bromide (3M in ether, 57 mL) was diluted in ether (50 mL).
(12.7 g) dissolved in ether (150 mL) was added to the Grignard solution at 78 After 1.25 h, ethyloxalyl chloride (17.12 g) was added. The reaction was stirred min, quenched with saturated sodium bicarbonate, taken up in ethyl acetate and washed with water, dried (MgSO 4 filtered and concentrated. The resulting solid was triturated with ethanol 87 WO 99/43654 PCT/US99/03898 and stirred for 1 h. The desired product (5.75 g, 31%) was isolated as a yellow solid and used without further purification.
Step 2 To the above indole in DMF at 0 °C was added sodium hydride (0.4 g, dispersion in oil). After warming to room temperature, 4-benzylbenzylbromide (2.2 g) was added and the mixture was stirred overnight. As the reaction was not yet done (TLC) additional 4-benzylbenzylbromide (1.0 g) was added and the reaction stirred for 2.5 h. The reaction was taken up in ethyl acetate and washed with water, dried (MgSO 4 filtered and concentrated.
Chromatography (20% ethyl acetate/hexanes) afforded the desired compound (3.1 g Step 3 The above ester was placed in a solution of NaOH (2N):THF:MeOH (1:2:1) and stirred overnight at room temperature. The reaction was acidified with 6 N HCI and the product extracted with ethyl acetate. The organic layers were dried (MgS04), filtered and concentrated. The solid was triturated with ethanol and stirred for 1 h. The solid was filtered and dried affording the title compound (1.85 g) as a yellow solid. MS: m/z 474 Example 2-{5-(benzvloxy)-l -[2.4-bis(trifluoromethvl)benzyl]-lH-indol-3-vl}-2oxoacetic acid The indole prepared in Example 69, step 1, was alkylated with the appropriate alkyl bromide and hydrolyzed as described in Example 69, steps 2 and 3.
MS: m/z 520 Example 71 2- [1-(4-benzvlbenzvl)-5-(benzyloxv)-lH-indol-3-yl-2oxoacetvl}amino)benzoic acid Step 1 To a solution of the acid from Example 69, step 3, (0.810 g) in THF (28 mL) was added CDI. The reaction was stirred 30 min and then ethyl 3-aminobenzoate (0.330 g) was added and the reaction was stirred overnight. The reaction mixture was taken up in ethyl acetate and washed with water, dried (MgSO 4 filtered and concentrated. The crude material was triturated with ethanol and stirred for 1 h, filtered and dried. The desired product (0.76 g, was isolated as a yellow solid.
S 35 Step 2 The above ester was dissolved in NaOH (2N):THF:MeOH and stirred 4h. The mixture was acidified with 6 N HC1 and extracted with ethyl acetate. The combined organic layers were dried (MgSO 4 filtered and concentrated. The crude solid was triturated with ethanol/hexane to afford the title compound (0.48 g, 69%) as a yellow solid.
88 WO 99/43654 PCT/US99/03898 Example 72 5-[(2-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyvil-1H-indol-3-vl-2oxoacetvl)aminolisophthalic acid The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
MS: m/z 683 Example 73 3- (2-15-(benzvloxyv)-l- 24-bis(trifluoromethyl)benzvil-1H-indol-3-yl 1-2oxoacetvl)aminolbenzoic acid The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
MS: m/z 639 Example 74 5-(12-1-(4-benzvlbenzvl)-5-(benzvlox)-1H-indol-3-yll-2-oxoacetyllamino)- 2-[(5-chloro-3-pyridinvl)oxlbenzoic acid The alkylated indole from Example 69 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
Example 5-r(2-15-(benzvloxy)-l-[2,4-bis(trifluoromethyl)benzvil-1H-indol-3-vl -2oxoacetvl)aminol-2-I(5-chloro-3-pyDvridinl)oxylbenzoic acid The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
Example 76 2-fl-(4-benzvlbenzvl)-5-(benzvloxy)-lH-indol-3-yll-N-[3-({[(4methvlphenvl)sulfonvllaminolcarbonl)Dhenvll-2-oxoacetamide To the acid obtained in Example 71 (0.1 g) in CH 2
CI
2 (10 mL) is added THF 5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixture was stirred a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stirred overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO 4 filtered and concentrated. Chromatography MeOHICH 2 Cl 2 afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z 746 89 WO 99/43654 PCT/US99/03898 Example 77 2-[5-bromo-1-(cclopropvlmethl)-1H-indol-3-vllacetic acid To 5-bromoindole-3-acetic acid (890 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (12 mL) at 0 'C were added 'Pr,NEt (21 mmol) and bromomethylcyclopropane (10.5 mmol). The reaction mixture was heated at 50 'C for 19 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH 2
PO
4 dried over MgSO 4 and evaporated to dryness. Purification on silica gel column 30% EtOAc in hexane) yielded 927 mg (86 yield) of the product.
Example 78 2-f1-(cclopropvlmethl)-5-(2-thienvl)-1H-indol-3-vllacetic acid To a sealed tube containing 2-[5-bromo--(cyclopropylmethyl)-1H-indol-3-yl]acetic acid (100 mg, 0.32 mmol), 2-thiopheneboronic acid (124 mg, 0.97 mmol), (CH 4 Pd (37 mg, 0.032 mmol), Na 2
CO
3 (2.6 mmol) in a mixture of benzene/EtOH/H,O 4.5 mL) was heated at 85 'C for 19 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The mixture was washed with NaHPO 4 dried over MgSO 4 and evaporated to give the crude product which was purified on silica gel column 33% EtOAc in hexane with 1 HCOOH) to give 79 mg (78% yield) of the product.
Example 79 2-l1-(cclopropmtvlmethyl)-5-3-(trifluoromethyl)phenvll-1H-indol-3-vlacetic acid The title compound was prepared according to the procedure described in Example 78 except that 3-(trifluoromethyl)phenylboronic acid was used.
Example 2-[5-(1-benzofuran-2-yl)-1-benzvl-1H-indol-3-yllacetic acid The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo- 1 -benzyl- 1 H-indol-3-yl]acetic acid and benzo[b]furan-2-boronic acid were used.
Example 81 2-(1-benzvl-5-phenvl-1H-indol-3-vl)acetic acid The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo- 1 -benzyl- 1 H-indol-3-yl]acetic acid and phenylboronic acid were used.
WO 99/43654 PCT/US99/03898 Example 82A 5-((E)-{1-[3-(3-benzylphenoxy)propyl]-1H-indol-3-yl}methylidene)-1,3thiazolane-2,4-dione Step 1 The procedure in Example 22 was followed using 3-formyl indole (0.4g, 2.8mmol), sodium hydride (0.102g, 3.0mmol) and the iodide (0.97g, 2.8mmol) in DMF (10ml). Flash chromatography (Hex/EtOAc, 1/1) gave 0.86g of the desired intermediate.
Step 2 The intermediate from step 1 (0.8 g, 2.2 mmol) and 2.4-thiazolidinedione (0.25, g, 2.2 mmol) was dissolved in toluene (5 mL). Piperidine (0.064 mL, 0.6 mmol) and acetic acid (0.012 mL) were added and the mixture was heated to reflux for 2h. The reaction was allowed to cool to rt, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine dried (MgSO4), filtered and concentrated. Flash chromatography (hexane/ ethyl acetate 3/2) afforded the title compound (0.345 g as an orange solid.
Example 82 B 4-{[5-((E)-{1-[3-(3-benzylphenoxy)propyl]-1H-indol-3-yl}methylidene)-2,4dioxo-1,3-thiazolan-3-yl]methyl}benzoic acid The procedure in Example 22 steps 1 and 2 were followed to give 0.14g (47% for 2 steps) of the title compound as a yellow powder.
Example 82 C 2-[5-((E)-{1-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methylidene)-2,4dioxo-1,3-thiazolan-3-yl]acetic acid The procedure in Example 22 steps 1 and 2 were followed to give 0.107g (42% for 2 steps) of the title compound as a yellow powder.
Example 83 3-{1-[3-(3-benzylphenoxy)propyl]-1H-indol-3-yl}propanoic acid The procedure in Example 22 step 1 was followed except 2 eq. of sodium hydride was used and 0.142g of the title compound was isolated as a white oily solid.
91 WO 99/43654 PCT/US99/03898 Example 84 3-1 -benzhydrvl-5-[(cvclopentylcarbonl)aminol- 1 H-indol-3-yl}propanoic acid Step 1 To a solution of the aldehyde from Example 114, stepl (1.0g, 2.8mmol) in toluene (20ml) was added carbomethoxyethylidene triphenylphosphorane (0.98g, 2.9mmol). The mixture was heated overnight at reflux and then concentrated. The residue was dissolved in
CH
2 Cl 2 and silica gel was added. The mixture was concentrated and the resulting solid was purified by flash chromatography (Hex/EtOAc, Compound 30 1.01g was isolated as a yellow solid.
Step 2 To a solution of the above intermediate (0.lg, 0.24mmol) in THF (10ml), was added platinum on activated carbon Pt, 0.05g, 50 Hydrogen gas was bubbled into the suspension for 2min, the vessel was sealed tightly and the reaction was stirred overnight at rt.
Argon gas was then bubbled through the reaction for 15min before the mixture was filtered through a pad of Celite. The pad was washed with EtOAc and the filtrate was concentrated.
The residue was dissolved in CH 2 C1 2 (5ml). Aqueous saturated NaHCO 3 (3ml) was added, followed by cyclopentanecarbonyl chloride (0.036ml). The biphasic mixture was stirred for 2h at rt and diluted with CH 2 Cl 2 The organic layer was washed with water and brine, dried and concentrated to a white solid. Recrystallization from EtOAc/Hex gave 0.11g of the desired intermediate as a white solid.
Step 3 Hydrolysis of the above ester with NaOH (IN, 2 mL) in THF (2mL) and MeoOH (2 mL) followed by recrystallization from hot EtOAc afforded 0.054g of the title compound as a white solid.
Example N-(1-benzhydryl-3-{3-[(methylsulfonyl)amino]-3-oxopropyl}-lH-indol-5yl)cyclopentanecarboxamide To a solution of the acid from Example 84 step 3 (0.1g, 0.22mmol) in THF (5ml) was added methanesulfonamide (0.027g, 0.28mmol), EDCI (0.54g, 0.28mmol) and DMAP (0.012g, 0.lmmol). The mixture was heated at 50 0 C overnight then diluted with EtOAc, washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 1/1) gave 0.lg of the title compound as a white solid.
92 Snnir~-yrrT"a~ji i~ ;I;y~i~N ji~i- WO 99/43654 PCTIUS99/03898 Example 86 A (E)-3-{1-benzhydryl-5-[(cyclopentylcarbonyl)amino]-1H-indol-3-yl}-2propenoic acid Stepl The same procedure as Example 84 step 2 was used to prepare the desired intermediate from the nitroindole (Example 114 step 11.
Step 2 The procedures in Example 84, step 1 and 3 were used to prepare the title compound from the above intermediate.
Example 86 B N-(1-benzhydryl-3-{(E)-3-[(methylsulfonyl)amino]-3-oxo-1-propenyl}-1H- The acid from Example 86A was used to prepare the title compound according to the procedure in example Example 87A (E)-3-{1-benzhydryl-5-nitro-1H-indol-3-yl}-2-propenoic acid The ester from Example 84 step 1 was saponified according to the procedure in Example 84 step 3 and recrystallization from hot EtOAc afforded 0. 155g of the title compound as a white solid.
Example 87B N-((E)-3-{1-benzhydryl-5-nitro-1H-indol-3-yl}-2propenoyl)methanesulfonamide The procedure in Example 85 was used to prepare the title compound from the product of Example 87A.
Example 88 4-[(1-benzhvdrvl-5-chloro-2-methl-1H-indol-3-vl)methyllbenzoic acid Step 1 To an ice-cold (0 0 C) solution of trifluoroacetic acid (1.7ml, 15mmol) and triethylsilane (4.8ml, 30mmol) in CHC21, (20mL) was added a solution of 5-chloro-2-methylindole (1.66g, l0mmol) and methyl 4-formylbenzoate (1.8g, 1 Immol) in CHC1 2 (50mL) over a period of min. The resulting homogeneous solution was stirred at 0 0 C for lh and rt for 2h, at which time EtOAc (150mL) and aqueous sodium bicarbonate (to pH=8) was added. The organic layer was washed with water and brine, dried over MgSO 4 and concentrated. Flash chromatography (Hex/EtOAc, 4/1) gave 1.98g of desired intermediate as a light-tan solid.
93 ;lliY--iX~"~ i ~-liii~iiY -I-iY-iYX- II1Piiil ~LX~lhj~j~ WO 99/43654 PCT/US99/03898 Step 2 Sodium hydride (0.2g, 5mmol) was washed with dry hexanes (3xl0ml) and then suspended in DMF (6mL) and cooled to 0°C. A solution of the above intermediate (1.57g, in DMF (4mL) was dropwise at 0°C and the resulting mixture was stirred for 30min at which time the diphenylbromomethane (1.24g, 5mmol) was added. The mixture was allowed to reach rt and stirred for an additional 48h. EtOAc (30mL) was added followed by aqueous NaH 2
PO
4 solution (10ml). The organic layer was washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 7/1) provided 0.98g of the desired intermediate as a ivory foam.
Step 3 The above intermediate was saponified according to the procedure in Example 84 step 3. Flash chromatography (EtOAc) provided 0.3g of the title compound as a tan crystalline solid.
MS: m/z 464 Example 8 9 4-f [1-benzhydryl-5-( [4-(trifluoromethvyl)phenvllsulfonv )amino)- 1 H-indol-3vlmethyl}-3-methoxybenzoic acid Step The intermediate from Example 3 step 2 (leq) (see scheme was weighed in to a flask along with the 4-trilflouromethylbenzene sulfonyl chloride (1.2 eq) and then they were flushed with nitrogen, taken up in dichloroethane (0.15 M) and then pyridine was added (1.2 eq) at which time the reaction was left to stir overnight and then worked up by the addition of the polymer bound amine Parlow, J.J, Mischke, D. Woodard, S.S.J. Org. Chem.
1997, 62, 55908-5919) (1.6g/immol) and the resulting slurry was stirred a minimum of minutes and then it was filtered and washed with dichloroethane and the dichloroethane solution was dried and concentrated to yield 98% of the desired product with high purity.
Step 2 The crude material from step was dissolved THF/MeOH and then 4N NaOH was added 3 eq) and the reaction was stirred until complete hydrolysis was observed by TLC. At this point the reaction quenched with enough amberlite ir 120 to make the solution acidic and then the resin was filtered off and rinsed and the desired product was obtained in 94% yield by drying and concentrating the solution. MS: m/z 669 Example 90 (acetvlamino)-4-methyl-1.3-thiazol-5-vlsulfonv I}amino)-1benzhydrvl-1H-indol-3-vllmethyl -3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 76% of the title compound after chromatographic purification.
94 WO 99/43654 PCT/US99/03898 Step 2: An analogous proceedure to step 2 for Example 89 above yielded 83% of the desired product. MS: m/z 679 Example 91 4-r(1-benzhvdryl-5- [(4-chloro-3-nitrophenvl)sulfonvllaminol- H-indol-3vl)methvll-3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 54% of the desired product after chromatographic purification. MS: m/z 681 Example 92 4-r(1-benzhvdrvl-5- [(dimethylamino)sulfonvilamino}-1H-indol-3-yl)methyll- 3- Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 49% of the title compound after chromatographic purification.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product. MS: m/z 568 Example 93 [1-benzhydryl-5-({ [4-(trifluoromethoxv)phenyllsulfonvl }amino)-1H-indol- 3-vllmethvll-3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product. MS: m/z 685 Example 94 4-[(1-benzhydryl-5-{[(2-methylphenvl)sulfonvllamino-1H-indol-3yl)methvll-3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 56% of the title compound after chromatographic purification.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 82% of the desired product. MS: m/z 615 ~IXj;Pllj,~~, iti~-u-rcy,~unl~riruLll~hiiiiii WO 99/43654 PCT/US99/03898 Example 4-[(1-benzhvdryl-5-{ (5-chloro-1.3-dimethIvl-1H-pvrazol-4vl)sulfonvllamino}-lH-indol-3-vl)methyl-3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 96% of the desired product.
MS: m/z 655 Example 96 4-[(1-benzhvdryl-5-{ [(35-dimethyl-4-isoxazolvl)sulfonvllamino}-lH-indol-3vl)methvll-3-methoxvbenzoic acid Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 89% of the desired product.
MS: m/z 621 Example 97 Cvclopentvl-N-{3-[4-(aminocarbonvl)-2-methoxybenzyll--benzhydryl-lH- The compound of Example 3 (1.0 eq) was dissolved in THF (0.15M) and then carbonyl diimidizole (1.2 eq) was added and the-reaction was stirred under N 2 for three hours at which time ammonium hydroxide was added (3ml/g) and the reaction was stirred overnight when TIC analysis showed it was complete. To the reaction was added water and ethyl acetate, the layers were separated and the aqueous layer was extracted three times, the combined organic extracts were dried concentrated and chromatographed to yield 64% of the desired primary amide.
Example 98 cvclopentyl N-l -benzhvdrvl-3- 2-methoxy-4-(1H-1,2.3,4-tetraazol-5carbamate Step 1 To the compound of Example 97 (1.0 eq) under N 2 was added CH 2 C1, (0.06M) and then (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (5.0 eq) portion wise over 5 hours and then the slurry was stirred overnight at which time TLC analysis indicated the reaction was complete so it was concentrated and chromatographed to yield 78% of the desired product.
96 r~t~ E iu.~-I~il~~~ii~-;L~iiii~ iiY""~i :uii- WO 99/43654 PCT/US99/03898 Step 2 To the nitrile (1.0 eq) isolated in step 1 was add sodium azide (3 eq) and triethyl amine hydrochloride (1.5 eq) and n-methyl-2-pryrrolidinone (0.05m) and then the reaction was heated to reflux under an inert atmosphere for 2.5 hours when it was poured into ice and water that was then acidified to pH 2 and the product was filtered off and then further purified by preparative chromatography to yield the desired compound in 22% yield. MS: m/z 597 Example 99 I -benzh vdrvl-5-[(cyclopentylcarbonyl)amino- 1 H-indol-3vlcarbonvl)amino-3-thiophenecarboxvlic acid step 1 To the indole acid (1.0 eq) was added the amine (1.2 eq) the dimethylaminopyridine mol 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq) and then DMF(0.3M) and the reaction was stirred under nitrogen for 24 hours at 40°C for 24 hours at which time it was poured into 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water 2X, dried, concentrated and chromatographed to yield 38% of the amide.
Step 2 The ester from the previous step was dissolved in THF/MeOH and then IN NaOH was added and the reaction was stirred for until TLC analysis showed that the reaction was complete. The reaction was then concentrated, diluted with water, acidified to pH 2 with conc HCL, extracted with ethyl acetate 3X, the combined organics were dried over magnesium sulfate concentrated and purified via chromatography to yield the desired acid in 64% yield.
Example 100 1-benzhvdrvyl-5- [(cvclopentvylcarbon yv)aminol- 1 H-indol-3vy}carbonvl)aminolbenzoic acid Step 1: The acid (see scheme was coupled with the appropriate amino ester following the procedure in Example 99, step one, except the reaction was run at room temperature and that the procedure yielded 80% of the desired product isolated by recrystalization.
Step 2: The nitro ester from step one (1.0 eq) was weighed into a flask along with 5% Platinum on Carbon (40 wt%) and the vessel was sealed with a septum and evacuated and flushed with argon 3X, then freshly distilled THF is added and the reaction is evacuated 2X and after the second evacuation a balloon of hydrogen inserted into the septum. The reaction is left under atmospheric hydrogen for 16 hours at which time tic analysis indicates complete reduction and the reaction is flushed with argon and then filtered through a bed of celite and the catalyst is 97 WO 99/43654 PCT/US99/03898 washed exhaustively with ethyl acetate, the filtrate was dried and concentrated and purified via chromatography to deliver 71% of the desired amine.
step 3: The amine (1.0 eq) was dissolved in dichloromethane (0.3M) and then an equivalent amount of saturated sodium bicarbonate was added and finally the acid chloride introduced.
The biphasic reaction mixture was vigorously stirred until TLC analysis indicated that the reaction was complete (generally a few hours) and then the reaction was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed to yield the desired amide in 41% yield.
Step 4: According to step 2, Example 99, the ester was hydrolyzed to the acid and yielded 71% of the final product. MS: m/z 556 Example 101 1-benzhydrvl-5-[(cvclopentvlcarbonvI)aminol-1H-indol-3vl}carbonvl)aminolpropanoic acid step 1 To the final product in Example 114 (1.Oeq) in dichloromethane (0.1M) at 0°C was added oxallyl chloride (2.0 eq) and then a few drops of DMF. The reaction was stirred a few hours at room temperature and concentrated and azeotroped 2X with toluene and placed on the high vacuum for 2 hours before being used crude for the next step.
Step 2: To the acid chloride generated in step 1 was added dichloromethane (0.1M) and then a solution of alanine methyl ester (1.05eq, free base) in dichloromethane (1.OM) and then triethylamine (1.5eq)was added and the resulting mixture was stirred overnight and worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired amide.
Step 3: The ester from step 2 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
Example 102 N-[1-benzhydryl-3-({[(2-methvlphenvl)sulfonyllamino}carbonvl)-lH-indol-5vllcyclopentanecarboxamide Step 1: The acid chloride (1.0 eq) synthesized in step 1, Example 101, was weighed into a flask along with o-tolylsulfonamide (1.5eq), DMAP (0.1 eq) and taken up in dichloromethane (0.1M) under nitrogen and then triethylamine (1.5eq) was added and the resulting mixture was stirred for 12 hours and then worked up by the addition of 1/2 saturated ammonium chloride, 98 u'"uLs c iu WO 99/43654 PCT/US99/03898 the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired acylsulfonamide in 52% yield.
Example 103 1-benzhydryl-5-[(cvclopentylcarbonvl)aminol-lH-indol-3-vl}-2oxoacetvl)aminolpropanoic acid Step 1: According to the general procedure in step 1, Example 101, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid. MS: m/z 536 Example 104 3-[(2-{1-benzhydryl-5-[(cyclopentvlcarbonvl)aminol-lH-indol-3-vl}-2oxoacetyl)aminolbenzoic acid Step 1: According to the general procedure in step 1, Example 99, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid. MS: m/z 584 Example 105 3-({2-l1-(4-benzvlbenzyl)-5-(benzyloxy)-1H-indol-3-vllacetvl}amino)benzoic acid Step 1 An oven dried flask was charged with 5-benzyloxy indole-3-acetic acid (1 eq) (see scheme-1) and anhydrous DMF (0.18 M) under nitrogen. Reaction mixture was then cooled to 0°C and to this was added NaH (2.2eq, 60% dispersion in mineral oil), stirred at 25°C for lh followed by addition of a solution of the appropriate benzyl bromide (2.2eq, 40% purity) (see scheme-1, steps 5,6) in anhydrous DMF, stirred overnight. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 66% yield.
Step 2 Dissolved the indole derivative from step 1(1 eq) (see scheme-1) in THF/MeOH/HO 2 (3:1:1 0.094 M) and to this was added LiOHH 2 0 (1.2 eq), stirred at 25"C, overnight. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 74% yield.
99 WO 99/43654 PCT/US99/03898 Step 3 To the acid from step 2 (1 eq) (see scheme-1) was added methyl 3-aminobenzoate (1.05 eq), EDCI (1.37 eq) and DMAP (0.2 eq) followed by anhydrous DMF (0.086M), stirred at overnight. Workup with ethyl acetate/lN HCI followed by chromatographic purification afforded the desired product in 80% yield.
Step 4 Dissolved the ester (1 eq) from step 3 (see scheme-1) in THF/MeOH/H 2 O (3:1:1 0.04 M) and to this was added LiOHH 2 0 (1.2 eq), stirred at 25C, overnight. Workup with ethyl acetate/IN HCI followed by trituration with CH,Cl/hexane for 0.5h and then recrystallization from CH 2 2C1 afforded the titled product in 97% yield. MS: m/z 579 Example 106 3-r(2-{5-(benzvloxv)-1-[2.4-bis(trifluoromethvl)benzvl].1H-indol-3vl}acetvl)aminol benzoic acid Step 1 Following procedure in step 1 of example 105, scheme-1 and using the appropriate benzyl bromide afforded the desired product in 50% yield after chromatographic purification.
Step 2 Following procedure in step 2 example 105, scheme-1 and using the appropriate indole derivative afforded the desired product in 67% yield after chromatographic purification.
Step 3 Following procedure in step 3 example 105, scheme-1 and using the appropriate indole derivative afforded the desired product in 75% yield after chromatographic purification.
Step 4 Following procedure in step 4 example 105, scheme-1 and using the appropriate indole afforded the desired product in 63% yield after chromatographic purification.
MS: m/z 625 Example 107 5-(benzvloxv)-1-[2,4-bis(trifluoromethvl)benzvl]-2-methyl-lH-indole-3carboxvlic acid Step 1: The 5-Hydroxy-2-Methylindole-3-Carboxylate (1 eq) was combined with benzyl bromide (1.3 eq) and K 2 CO, (325 mesh, 1.3 eq) in CH 3 CN (0.1 The resulting mixture was heated to reflux for 2 h. An additional amount of benzyl bromide (0.2 eq) and the heating was continued for 2 h. The reaction was worked up by addition of water and extraction-with CH C1 2 The organic extracts were washed with water, dried and concentrated. Flash 100 WO 99/43654 PCTfUS99/03898 chromatography provided the desired benzyl ether (63 yield), as well as the corresponding N,O-bisbenzyl derivative (22 yield).
Step 2: An ice cooled solution of the benzyl ether from step 1 (1 eq) in dry DMF (0.25 M) was treated with NaH (60 in mineral oil, 1.1 eq). 2,4-Bis trifluoromethyl benzyl bromide (1.1 eq) was added after 1 h and the resulting mixture was stirred at 25°C for 2 h. Solvent was evaporated under vacuo, the residue was dissolved in EtOAc, washed with water, dried and concentrated. The desired product was obtained in 77 yield after recrystallization from hexane/CHCl 3 Step 3: The product from step 2 (1 eq) in THF/MeOH was heated to reflux with IN NaOH (12 eq). After 48 h the reaction was quenched with AcOH and solvent was evaporated.
The resulting product was recrystallized to afford crude material in 72 yield. Further purification by flash chromatography followed by recrystallization provided pure title compound. MS: m/z 506 Example 108 5-[({5-(benzvloxv)-l-r2.4-bis(trifluoromethvl)benzvl-2-methyl-1H-indol-3yl}carbonvl)aminolisophthalic acid Step 1: The acid prepared in step 3 (1 eq) of example 108 was reacted with EDCI (2 eq) and dimethyl 5-aminophthalate (5 eq) in THF (0.02 M) in the presence of DMAP (2 eq). The reaction was heated to reflux for 48 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 32 yield.
Step 2: The material from step 1 (1 eq) was hydrolyzed by the action of LiOHH 2 0 (2.2 eq) in THF/MeOH/water 0.07 After stirring at 25'C overnight, the reaction mixture was quenched with AcOH and solvent was evaporated. EtOAc/water work up and trituration in hexane/CHCl, afforded the title compound in 82 yield. MS: m/z 669 Example 109 5-(benzvloxv)-2-methvl-l-(2-naphthvlmethyl)-.H-indole-3-carboxvlic acid Step 1: An analogous procedure to step 2 example 108 using the main product of step 1 above and the appropriate bromide yielded the desired N-substituted indole in 71 yield after recrystallization.
Step 2: The ester from step 2 above (1 eq) in THF/MeOH was heated to reflux with 4N KOH (2 eq). After 5 days solvent was evaporated and the residue partitioned between IN HCI and CHC13. The organic extract was washed, dried and concentrated. The title compound was obtained in 92 yield after chromatographic purification and crystallization. MS: m/z (M -1 420 3AC,~~.VVWfl CCCC,~f WO 99/43654 PCT/US99/03898 Example 110 [5-(benzvioxv)-2-methvl-1-(2-naphthvlmethvl)- 1H-indol-3vllcarbonvl }amino)isophthalic acid Step 1: The acid in Example 109 was converted in the corresponding amide following an analogous procedure to step 1 of Example 108. The product was contaminated with the aniline starting material which could only be partially removed by chromatography.
Step 2: Hydrolysis of the crude material following step 2 Example 108 provided the title compound after chromatographic purification (4 yield in Example 109).
Example 111 1-benzvl-5-(benzyloxy)-2-methyl-1H-indole-3-carboxvlic acid Step 1: The minor product of step 1 (1 eq) Example 107 was dissolved in THF (0.1 M).
KOH (2 eq) and 18-crown-6 (2 eq) were added and the resulting mixture was heated to reflux for 1.5 days. Work up as on step 2 Example 108 above provided the title compound in 32 yield. MS: m/z 370 Example 112 3-[(2-{5-(benzyloxy)-l-(4-chlorobenzyl)-2-[(2-naphthylsulfanyl)methyl]-lHindol-3-yl}-2-oxoacetyl)amino]benzoic acid Step 1 The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 °C under nitrogen for 1 h. Workup with NaOH and water followed by concentration afforded crude product (100%).
Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 and treated with tbutyldimethylsilyl chloride (1.16 eq) and imidazole (1.26 eq) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product Step 3 The silyl ether from step 2 was dissolved in methylene chloride (0.26 and treated with BOC anhydride (1.24 eq), triethylamine (1.53 eq) and DMAP (0.21 eq) at 25 °C for 3 d.
Workup and chromatographic purification afforded the pure product Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid/ water/ THF (0.04 M) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (100%).
Steps 5 The alcohol from step 4 was dissolved in methylene chloride (0.2 and under nitrogen at -40°C treated with triethylamine (1.33 eq), and mesyl chloride (1.23 eq) for 1 h. In a separate dry flask was weighed naphthalene-2-thiol (1.31 eq), and THF (1 M) was added, followed by lithium hexamethyldisilazide (IN in THF, 1 eq) and this mixture was 102 WO 99/43654 PCT/US99/03898 stirred at 25°C for 30 min. The resulting solution was then added dropwise, over 30 minutes, to the above mesylate solution, at -40'C. The reaction mixture was allowed to warm to and stirred there for 4.5 h. Workup and chromatographic purification afforded the BOC thioether.
Step 6 The purified BOC thioether from step 5 was heated under nitrogen at 160- 170°C for 1.25 h, and recrystallized from ethyl acetate and hexanes to afford the free indole thioether in 64% yield.
Step 7 The indole thioether from step 6 was dissolved in DMF (0.2 and treated with sodium hydride (1.1 eq) at 25°C for 45 min. 4-Chlorobenzyl chloride (1.3 eq) and KI (cat.) were added, and the mixture was stirred at 25*C for 3 d. Workup (ethyl acetate/water) and trituration (ethyl acetate/hexanes) afforded the pure product Step 8: A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to 70 The product of step 7 in scheme 21 (1 eq) in ether (0.55 M) was added and the reaction mixture was stirred at °C for 2 h. After the addition of methyl oxalyl chloride (3 eq) in ether (1.5 M) the reaction was stirred at 40 °C for 2 h, allowed to warm to 25 Quenched with sodium bicarbonate EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone.
Step 9 The ester from step 8 was hydrolyzed using the general method in step 2 example 108 to yield the desired alpha keto acid.
Step 10 The indole thioether from step 9 was dissolved in dry methylene chloride (0.05 and treated with oxalyl chloride (2.05 eq) at 0°C for 1 h. In a separate dry flask were weighed 3-aminobenzoic acid (10 eq) and triethylamine (15 eq) in methylene chloride (0.5 The resulting solution was then added dropwise, at 0°C, and the mixture was allowed to warm to 25C overnight. Workup (methylene chloride/aqueous HCI) and repeated purification by chromatography afforded the pure title compound product.
Step 11 The product from step 9 was hydrolyzed using the procedure from step 2 Example 108 to yield the desired compound in 28%. MS: m/z 709 Example 113 3-[(2-{5-(benzvloxv)-l-methvl-2-[(2-naphthylsulfanvl)methyll-H-indol-3vl}-2-oxoacetvi)aminolbenzoic acid Step 1 Following step 4 of the above procedure using, methyl iodide followed by trituration (ethyl acetate/hexanes) afforded the pure product 103 V-X"~;-~~il~~lilll.F iii i WO 99/43654 PCT/US99/03898 Step 2 An analogous procedure to step 5 through step 11 above yielded 58% of the title compound. MS: m/z 599 Example 114 1-benzhvdrvl-5-[(cyclopentvicarbonyl)amino]-1H-indole-3-carboxvlic acid Step 1 5-nitroindole was alkylated as in Example 3 step with the appropriate bromide to yield the desired N-alkylated product.
Step 2 The indole from step 1 (l.Oeq) was dissolved in DMF (0.4M) and treated with phosporous oxychloride (6.9 eq) at room temperature and then the mixture was stirred for 1 day at 80 C at which time the reaction was poured onto ice and triturated with ethyl acetate/hexanes, followed by workup with sodium bicarbonate/chloroform yielded the C3 formylated product.
Step 3 The nitro indole from step 2 was reduced according to the procedure in Example 100, step 2 to yield the amino aldehyde.
Step 4 The indole from step 3 was acylated according to the procedure from Example 100, step 3.
Step 5 The indole from step 4 (1.0 eq), 2 methyl-2butene (45 eq), sodium dihydrogen phosphate (11.6 eq). were dissolved in t-BuOH water (0.2M) and then sodium chlorite (11.6q) was added and the reaction was heated to 65 C for 24 hours.The reaction was diluted with water, extracted 3 times with ethyl acetate, dried and concentrated and then purified by chromatography to yield the title compound.
Example 115 2- 1-benzhvdryl-5-[(cyclopentvlcarbonyl)amino 1H-indol-3-vl -2-oxoacetic acid Step 1 Following the procedure of Example 69, 5-niroindole was acylated in the 3-position with ethylmagnesiumbromide and ethyloxalylchloride.
Step 2 The above intermediate was elaborated to the final product following steps of Example 114 to afford the title compound.
104 WO 99/43654 PCT/US99/03898 Example 116 Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of Tables I and II, assay results are reported as a percent inhibition at the concentration specified.
S- Coumarin Assay 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Nalytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 pL assay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing pM 7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4 pg cPLA2 in pL assay buffer. Hydrolysis of the 7-hydroxycounarimyl 6-heptenoate ester was monitored in a fluorometer by exciting at 360 nm and monitoring emission at 460 nm. Enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.
Table I Example PERCENT CONCENTRATION INHIBITION (micromolar) 1 7 18 100 170 2 50 32 3 50 51 6.25 6.4 41 17.5 19 37 38 43 44 22 23 23.5 105 WO 99/43654 PCTIUS99/03898 124 39 100 6.25 4 50 _50 I11 _50 I11 I41 I100 120 6 I11 I100 200 7 I11 235 8 I50 44 100 9I50 I13 EE 19 50 33.5 11 42 __50 12 12.5 27.5 130 37 12 50 03 __50_0.355 __50_0.385 ___50__0.35 __50_0.385 ___50__0.39 __50 0.4 0.4 106 WO 99/43654 PCT/1JS99/03898 0.44 __50 0.45 64 0.51 1.25 13 50 __50 __50 0.55__ 500.
0.7 0.75 0.95 81 14 50 I0.7 10.95 10.951 50 0.65 0.65 0.72 0.76 0.85 6.25 16 50 0.125 61 0.125 71 0.125 0.14 0.14 __50 0.14 0.17 0.17 0.25 6.25 17 50 0.7 J50 0.8 J50 J0.85 I 50 J0.98 18 50 1.2 __50 J1.3 J1.9 12 2 1 07 WO 99/43654 WO 9943654PCTIUS99/03898 19 50 2.2 4.2 5.8 6.25 7.8 9 11 12 I50 32 21 I50 22 I50 I38 23 I50 58 24 I42 I100 100 I50 13 17 26 I50 I2.4 27 I50 I6 6.4 28 I50 I4.2 4.4 29 50 3.4 16 50 8 J21 I24 31 50 I11 18 108 WO 99/43654 WO 9943654PCTIUJS99/03898 32 I50 I4 4.4 33 I50 I4.4 4.9 34 I50 2 57 123 142 ]50 41 36 50 0.22 0.25 0.32 0.45 37 50 0.4 0.55 0.65 38 -50 0.3 0.45 0.57 0.59 0.6 __50 0.6 0.6 0.6 0.6 0.64 0.7 0.7 0.85 0.85 1 __50 1 39 50 0.39 0.7 0.73 0.75 0.75 0.8 0.9 0.9 __50 1 __50 1 109 WO 99/43654 PCTIUS99/03898 __50 11.2 __50 1.3 __50 11.6 50 55 2.5 3 13.6 41 50 __50 4.3 42 50 2.2 3 3.8 50 12 44 50 1.65 1.7 1.75 1.9 2.1 __71 6.25 50 1.75 __50 1.8 1.9 2 __50 2.1 46 50 2.2 2.7 49 I50 1.8 2.3 50 0.8 0.8 0.85 1.05 1 WO 99/43654 WO 9943654PCTIUS99/03898 81 51 50 10.6 __50 10.8 0.9 52 50 19 __50 19 53 I50 I1 50 15.5' I 54 I50 I2.8 3.9 I 55 I50 1.35 1.35 I 56 j50 I0.98 1.2 57 50 1.05 1.38 1.4 I 58 I50 1.65 1.65 I 59 I50 6 12.5 50 12.5 I 61 I50 I10 54 12.5 I 62 I50 I7 86 12.5 I 63 I70 7 64 I50 I32 37 47 I72 WO 99/43654 WO 9943654PCT/US99/03898 66 50 200 19 200 67 j8 I100 31 400 68 I9 I100 18 400 69 50 12.5 j39 71 69 6 3.8 72 50 12.5 76 50 4 77 I50 I160 180 78 I50 110 79 I50 50 48 81 I50 46 100 82A I50 I46 82B I61 6.25 82C I50 I8 83 I50 48 112 WO 99/43654 WO 9943654PCT[US99/03898 84 22 ]100 1265 350 8531 1100 200 8A50 ~0 18 86B 87A I33 87B 50 J38 J38 I42.5 88 50 1.25 I1.25 I1.32 89 I50 I4.4 4.8 I50 I10.2 10.5 91 I50 I3.8 4.25 92 50 I11 I 50 I12.5 14.2 93 I50 4.2 4.9 94 I50 I7 I50 I11.5 13 96 I50 8 10.5 113 WO 99/43654 WO 9943654PCTIUS99/03898 97 50 94 98 150 4.8 6.25 8.7 99 13 38 100 100 100 100 50 24 101 I6 I100 49 400 102 I31 48 103 I50 I100 104 104 50 22 24 F 105 50 112.4 __50 7 06 150 I7 1 50 J12 107 50 7 37 50 37 108 67 6.25 48 109 28 WO 99/436
II
E
K
K
K
K
K
K
K
K
K
K
K
K
K
K
E
112 114 115 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 53 50 50 50 50 20 64 50 50 50 50 50 50 50 47 46 8 100 152 170 100 250 1.6 0.6 1 1.6 1.25 1.2 1.3 0.8 1.1 0.9 1.1 2 PCTIUS99/03898 50 10.6 115 WO 99/43654 PCT/US99/03898 1 132 50 1 0.4 133 50 1 0.3 134 50 1 0.8 135 50 0.7 136 50 0.4 137 50 0.8 138 50 0.4 Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure described below. The results are reported in Table II.
Rat Carrageenan-Induced Footpad Edema Test Each compound was suspended in 0.3ml absolute ethanol, 0.1 ml Tween-80 and ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0.1ml 1N NaOH was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All compounds remained in solution. Compounds were administered i.v. in a volume of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1% Type TV carrageenan into the hind footpad.
Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan.
116 WO 99/43654 WO 9943654PCTIUS99/03898 Table 11 Example ROUTE DOSE IPERCENT of (mg/Kg) INHIBITION
ADMIN.
1 I IV I 5 I 2.51 IV 5 16.61 2 IV 5 15.87 3 Iv 5 10.38 Po 5 21.5 I V 5 22.84 IV 5 14.86 P0- 20 19.56 IV 5 10.38 4 W 5 24.13 IV I 5 8.88 IV 5 24.28 7 IV 5 -0.65 8 IV -5 -5.7 9 IV 5 4.46 IV 5 25.32 1I ILV 5 13.98 12 IP0O 2 I 0.19 Po 10 -0.38 13 IP0O 2 I 25.99 P0 10 23.63 14 P0 2 I 11.53 PO 10 8.14 IPO 2 I 7.05 P0 10 6.88 16 IP0O 2 3 3.8 Po 10 14.6 117 WO 99/43654 WO 9943654PCTIUS99/03898 17 PO 2 19.29 PO 10 34.52, 19 IV 5 21.17 WI 5 13.321 21 W I 5 J 16.18 I V 5 19.01 IV 5 8.66 22 TV I 9.I22 23 IV 5 15.71 1V 514.45 5 2.12.
24 5 8.33 24 IV 5 16.28 5 11.3 IV 5 2.73 IV 5 8.66 I 5 16.02 26 IV 5 1 25.31 27 WV 5 1 6.48 28 1V 5 0.29 IV 5138 PO 10 13.25 37 I PO 7.94 PO 10 3.36 38 I PO 2 I 15.44 PO 10 26.32 39 I PO 2 I 1.98 PO 10 -7.16 IV 5 8.21 41 IV 5 10.1 42 IV 5 7.72 118 WO 99/43654 WO 9943654PCT/US99/03898 44 IV 5 11.9 I 45 46 49 59 61 63 54 56 7
IV-
IV
IVZ
POl
POZ
POl
POT
POl POl POl POul
PO
PO
5ZL 5I 10.19 4.58 18.02 5.44 12.34 3.23 15-37 2 10 2 10 2 10 2 2 10 2 5 5 -6.75) 3.33 -1.81 11.35 2.47 14.29 7.02 21.51 4.22 9.34 10.44 20.68 13.85 9.96 2.9 18.33 19.59 2.84 25.34 10.78
-J
z z
ZI
z z z 71 rV 15 1 68 IV 5 -4.3 119 WO 99/43654 WO 9943654PCT/US99/03898 76 IV 5 14.84 IV 5 10.18 82B IV 5 4.94 84 IV 5 6.15 IV 5 7.13 86A IV 5 7.4 I87A IPO 2 I 12.89 PO 10 25.44 I87B IPO 3 f 17.92 PO 10 31.4 I 89 I PO 2 I 14.34 I PO 10 16.38 IPO 2 I -0.18 PO 10 2.7 I 91 I PO 2 I 13.5 PO 10 14.67 I92 IPO 2 I 27.36 PO 10 21.34 I93 IPO 2 -3.02 PO 10 9.91 P4GPO 3 3.13 PO 10 4.46~j77 PO 2 19.04 PO 10274 96 PO 2 I 29.42 PO 10 21.99 97 IV 5 21.31 98 T7V 5 18.39 I99 IPO 10 I 22.77 PO 2 24.51 1 120 WO 99/43654 PCT/US99/03898 100 PO 2 6.14 PO 10 20.7 101 PO 10 12.45 PO 2 11.17 102 PO 2 2.56 PO 10 8.48 103 PO 10 17.31 PO 2 16.5 104 PO 2 14.49 PO 10 6.01 105 IV 5 1.51 114 PO 2 12.15 PO 10 22.19 115 PO 2 1.24 PO 10 18.46 Example 117 2-{4-[(1-benzhvdrvl-6-chloro-1H-indol-3-vl)methvl1-2.6dimethylphenoxy acetic acid Step 1: To 1-benzhydryl-6-chloro-1H-indole (1.0 eq) and methyl 2-(4-formyl-2,6dimethylphenoxy)acetate (0.6 eq) in CH2CI2 (0.1M) at 0°C was added neat triethysilane (3eq) followed by triflouroacetic acid (3eq). After 10 minutes at 0°C the reaction was warmed to room temperature and stirred until the initially formed spot by TLC yields a new spot. The reaction was then quenched by the addition of saturated sodium bicarbonate, diluted with
CH
2 CI, and washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and purified by column chromatography to yield 89% of the desired product.
Step 2 The resulting ester was hydrolyzed as in example 1 step 5 to yield the title compound after trituration and/or column chromatography. m/z 1)508.3 121 WO 99/43654 PCT/US99/03898 Example 118 2-{4-r(1-benzhvdrvl-6-chloro-H-indol-3-vj)methyll-3methoxvphenoxy acetic acid Step 1:This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and methyl 2- (4-formyl-3-methoxyphenoxy)acetate according to the procedure in Example 117 Step 1.
Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid.
Example 119 2-14-r(1-benzhvdryl-6-chloro-1H-indol-3-vl)methyllphenoxy acetic acid Step 1:This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and methyl 2- (4-formylphenoxy)acetate according to the procedure in Example 117 Step 1.
Step The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid.
Example 120 2-f4-i(1-benzhydryl-6-chloro-1H-indol-3-vl)methyll-3-chlorophenoxylacetic acid Step 1:This compound was prepared from the 1 -benzhydryl-6-chloro- 1H-indole and methyl 2- (3-chloro-4-formylphenoxy)acetate according to the procedure in Example 117 Step 1 in yield.
Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid.
Example 121 2-{4-r(l1-benzhvdryl-6-chloro- 1H-indol-3-vl)methyll-2methoxvphenoxvlacetic acid Step 1:This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and methyl 2- (4-formyl-2-methoxyphenoxy)acetate according to the procedure in Example 117 Step 1 in 71% yield.
Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 yield the title acid. m/z (M-1)510.2 122 WO 99/43654 PCT/US99/03898 Example 122 (E)-4-{4-f(1-benzhydryl-6-chloro-1H-indol-3-vl)methyllphenoxy}-2-butenoic acid Step 1: This compound was prepared from the 1-benzhydryl-6-chloro-lH-indole and formylphenoxy)-2-butenoate according to the procedure in Example 117 Step 1 in 91% yield.
Step 2:The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid. m/z (M-1)506.3 Example 123 4-{4-r(1-benzhydryl-6-chloro-1H-indol-3-yl)methyllanilino}-4-oxobutanooic acid Step 1 This intermediate compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and 4-nitrobenzaldehyde according to the procedure in Example 117 Step 1 in 42% yield.
Step 2 -benzhydryl-6-chloro-3-(4-nitrobenzyl)-1H-indole was reduced by dissolving in THF (0.1 subjecting it to 1 atmosphere of hydrogen gas in the presence of 10%platinum on carbon catalyst When the starting material had all been converted to a new spot by TLC analysis the reaction was filtered and concentrated to yield the desired intermediate in nearly quantitative yield.
Step 3:To the intermediate above (1.0 eq) in CH 2 Cl 2 (0.1M) at o0C was added triethylamine eq) followed by 3-carbomethoxyproprionyl chloride(1.5 eq). The reaction was warmed to room temperature, stirred until complete disappearance of starting material as monitored by TLC, and then worked by the addition of saturated sodium bicarbonate, dilution with CH 2
CI
2 and washing the organic layer with water, saturated sodium bicarbonate and brine, dried, concentration and purified by column chromatography to yield the desired compound in 81% yield.
Step4: The ester from step 3 was then hydrolyzed according to step 2 Example 117 to yield the title acid. m/z (M-1)521.3 Example 124 sodium 3-{4-[(1-benzhydrvl-6-chloro-1H-indol-3-yl)methyllanilino}-3oxopropanoic acid Step 1 The intermediate from example 117, step 1 was acylated with methyl malonyl chloride according to the procedure for step 1 of Example 117-in 82 yield.
Step 2 The ester was hydrolyzed according to step 2 for Example 123 to yield the title compound, m/z (M-1)507.2 123 WO 99/43654 PCT/US99/03898 Example 125 2-{4-r(1-benzhydrvl-6-chloro-1H-indol-3-vl)methyllanilino}-2-oxoacetic acid Step 1 The intermediate from example 117, step 1 was acylated with methyl oxalyl chloride according to the procedure for step 1 of Example 117 in 67 yield.
Step 2 The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound. m/z (M-1)493.2 Example 126 2-[(1-benzhydryl-6-chloro-1H-indol-3-yl)methvl]cyclopropanecarboxvlic acid Step 1: This intermediate compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and ethyl 2-formyl- 1-cyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 53% yield.
Step 2: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 93 yield. m/z (M-1)1414.2 Example 127 2-[(1-benzhvdrvl-6-chloro-5-fluoro-1H-indol-3vl)methyllcyclopropanecarboxvlic acid Step 1: 6-chloro-5-flouroindole was N-alkylated with benzhydryl bromide according to the procedure in Example 69 step 2 to yield the targetintermediate.
Step 2: The product from step 1 was C3 acylated with ethyl 2-formyl-1cyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 53% yield.
Step 3: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 73 yield. m/z (M-1)432.2 Examplel28 2-[(1-benzhydryl-5,6-dichloro- H-indol-3-yl)methyllcyclopropanecarboxvlic acid Step 1: 5,6-dichloroindole was n alkylated with benzhydryl bromide according to the procedure in Example 69 step 2 to yield the target intermediate in 70% yield.
Step 2: The intermediate from step 1 was C3 acylated with ethyl 2-formyl-lcyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 62% yield.
Step 3: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 73 yield. m/z (M-1)448.2 124 WO 99/43654 PCT/US99/03898 Example 129 1-bis(4-hvdroxyphenyl)methvll-6-chloro-1H-indol-3yllmethyl)cyclopropanecarboxvlic acid Step 1: 6-chloroindole was C3 alkylated with ethyl 2-formyl- 1-cyclopropanecarboxylate according to the procedure in Example 117 Step 1.
Step 2: The intermediate ffrom step 1 (2.0 eq.) was dissolved in THF (0.5 M) and cooled to and then triethylamine (2.0 eq) was added followed by methanesulfonyl chloride eq). The reaction was stirred at this temperature until TLC analysis indicated no more starting alcohol, and then it was cannulated directly into a mixture of the c3 alkylated indole from step 1 (1.0 eq) in DMF (1.0 M) at -20 0 C that had been stirred for 30 minutes at room temperature with sodium hydride (4.0 eq of a 60% dispersion). The resulting mixture was warmed to room temperature overnight and quenched when the reaction was deemed complete by the addition of saturated ammonium chloride, diluted with ethyl acetate and washed with saturated ammonium chloride, saturated sodium bicarbonate and water dried, concentrated and purified by column chromatography.
Step 3: The intermediate from step 2 was dissolved in THF (1.OM) and treated with a solution of tetrabutylammonium flouride (2.5 eq) and stirred at room temperature until TLC analysis indicates that both silyl ethers had been cleaved. The reaction was then poured into saturated ammonium chloride and extracted with ethyl acetate the combined organic washed were washed with water, brine, dried and concentrated and purified by column chromatography to yield the intermediate in 73 yield.
Step 4: The ester from step 3 was hydrolyzed according to step 2 for Example 123 to yield the title compound in 92% yield, m/z (M-1)447.12 Example 130 '4-[(1-benzhvdryl-6-chloro-1H-indol-3-vl)methvll-3-hydroxvbenzoic acid Step 1:This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and 4hydroxy-2-methoxybenzaldehyde according to the procedure in Example 117 Step 1.
Step 2: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound Example 131 '4-[(1-benzhvdrvl-6-chloro-1H-indol-3.vl)methvll-3-(3hvdroxypropoxy)benzoic acid Step 1: The intermediate from Example 130, step 1, was dissolved in DMF solid potassium carbonate (3 eq) followed by 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.5 eq) was added and the reaction was left to stir for 24 hours at room temperature. The workup consisted 125 WO 99/43654 PCT/1US99/03898 of diluting with half saturated ammonium chloride and ethyl acetate, extracting aqueous layer with ethyl acetate washing the organic layer with water drying, concentration followed by purification via column chromatography.
Step 2: The intermediate from step 1 was dissolved in THF treated with glacial acetic acid (2.0 eq) and heated at 45°C for 24 hours, at which time the reaction was partitioned between saturated sodium bicarbonate and ethyl acetate, the combined organic layers where washed with water dried, concentrated and purified by column chromatography to yield 88% of the desired compound.
Step 3: The ester was hydrolyzed according to step 2 for Example 123 to yield the title compound. m/z (M-1)524.3 Example 132 '4-({1-[(4-aminophenyl)(phenyl)methyll-6-chloro-1H-indol-3-vl}methyl)-3methoxvbenzoic acid Step 1 :This compound was prepared from 6 chloroindole and methyl 2-(4-formyl-2methoxyphenoxy)acetate according to the procedure in Example 117 Step 1 in 61% yield.
Step 2: The intermediate from step 1 was N-alkylated according to the procedure for Example 129, step 2, with tert-butyl N- {4-[hydroxy(phenyl)methyl]phenyl }carbamate.
Step 3: The nitrogen protection was removed by heating the compound to 180°C to yield of the desired amino ester.
Step 4: The intermediate from step 3 was hydrolyzed following step 2 for Example 117 to yield the title compound in 78% yield. m/z (M-1)495.2 Example 133 '4-({6-chloro-1-[(4-methoxvphenvl)(phenvl)methvl- 1H-indol-3-vl }methyl)-3methoxybenzoic acid Step 1: The intermediate from Example 132, step 1, (1.0 eq) was dissolved in DMF (1.OM), cooled to 0°C, and treated with sodium hydride (1.5 eq) and stirred for 30 minutes to affect deprotonation. The l-[bromo(phenyl)methyl]-4-methoxybenzene (1.5 eq), as a solution in DMF was added to the anion and the reaction was warmed to room temperature, when the reaction was deemed complete by TLC analysis it was partitioned between ethyl acetate and half saturated ammonium chloride, extracting the aqueous layer with ethyl acetate (2X), washing the organic layer with water drying, concentration followed by purification via column chromatography yielded the desired intermediate.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound. m/z 1)510.2 126 WO 99/43654 PCTIUS99/03898 Example 134 '4-(1l-ibis(4-methoxyphenl)methvyll-6-chloro-1H-indol-3-vlmethvl)-3methoxvbenzoic acid Step 1: The intermediate from Example 132 was N-alkylated with l-[bromo(4methoxyphenyl)methyl]-4-methoxybenzene according to the procedure described in Example 133, step 1, to yield the desired intermediate.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound. m/z (M-1)540.3 Example 135 '4-(6-chloro-1-r(2-morpholinophenvl)(phenyl)methyl-1IH-indol-3vllmethl)-3-methoxvbenzoic acid Step 1: The intermediate from Example 132 was N-alkylated according to the procedure for Example 129, step 2, with the appropriate electrophile.
Step 2: The intermediate form step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound.
Example 136 4-({6-chloro-1-[(2,4-dimethoxy-5-primidinvl)(phenvi)methyll-1H-indol-3vlmethvl)-3-methoxvbenzoic acid Step 1: The intermediate from Example 132 was N-alkylated according to the procedure for Example 129, step 2, with the appropriate electrophile to yield the desired intermediate in 16% yield.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound. m/z (M-1)542.3 Example 137 '4-[(1-benzhdrl-6-chloro-1H-indol-3-vl)methyll-3-methoxvbenzoic acid Step 1:This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and the appropriate aldehyde according to the procedure in Example 117 Step 1.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound. m/z (M-1)481.14 127 Example 138 2 4 -[(1-benzhvdrvl-6-chloro.- 1H-indol.3-vI)methvil-3methoxvbenzoyl}amino)acetic acid Step 1: The intermediate from Example 137, step 2, treated with glycine ethyl ester according to the procedure in Example 76 to yield the desired ester.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound, nm/z (M-1)537.2 All patents and literature references cited herein are incorporated as if fully set forth herein.
Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to *69 exclude other additives, integers or process steps.
128 00 @0*
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055 0.* 00 0 *S 0 0 @0* S S 128 L
Claims (15)
1. A compound of the formula: R R 3 R4 R wherein: 4,* o o o R 1 is selected from H, halogen, -CF 3 -OH, -C1-Cio alkyl, -S-C-Clo alkyl, Ci-Cio alkoxy, -CN, -NO 2 -NH 2 phenyl, -O-phenyl, -S-phenyl, benzyl, -0- 10 benzyl, -S-benzyl or a moiety of the formulae: 0 O0 N6 R7 N 6 R7 O 0 0 R7 O 1 t° o oooo R7 R7/NR Rj R6 R7 or o R 6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C-C6 alkoxy, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 7 is selected from -OH, -CF 3 C1-C6 alkyl, C1-C6 alkoxy, -NH-(CI-C 6 alkyl), -N-(C1-C 6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being w:\jactyn\no delete\spec\623133 claims.doc i ~i i rtr;~.liiai,-; i-iiii .e 130 optionally substituted by from 1 to 3 substituents selected from halogen, -ON, 01-06 alkyl, 01-06 alkoxy, -NO 2 -NH 2 -OF 3 or -OH; R 2 is selected from H, halogen, -OF 3 -OH, -01-i00 alkyl, 01-Clo alkoxy, CHO, -ON, -NO 2 -NH 2 -NH-0 1 -0 6 alkyl, -N(C 1 -0 6 alkyl) 2 -N-S0 2 -C 1 -C 6 alkyl, or -S0 2 -C 1 -C 6 alkyl; R 3 is selected from -COOH, -O(O)-COOH, -(OH 2 )n-C(O)-COOH, -(CH 2 )n- OOOH, -CH=CH-OOOH, -(CH 2 )n-tetrazole, lowr o 00 N NN N (C 1 -C 6 lower alkyl) r 'Il -S -OH or a moiety selected from the formulae -L 1 -Ml; wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH2)n-C(o)(CH2n-, -(CH2)n-O'(CH2)n-,(CH2)n-S- (CH 2 -O(Z)-N(R 6 -0(Z)-N(R 6 )-(OH 2 6 N(R 6 )-(OH 2 -0(Z)-NH-SO 2 or -0(Z)-NH-SO 2 -(CH 2 Z is Oor S; w.acyn'no delete'specIRG23133 daims.doc 131 M 1 is selected from the group of -COOH, -(CH 2 ),-COOH, -(CH 2 COOHK tetrazole, HN\N S N 8 R9 Rio a. a. a. 0-P-OH Rul 0~ R 9 S R 8 in each appearance, is independently selected from H, -COOH, (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, R 9 is selected from H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(C 1 -C 6 alkyl), -N(0 1 -C 6 alkyl) 2 Rio is selected from the group of H, halogen, -CF 3 -OH, -(CH 2 )n-COOH, w: jac[Ynvlo deletexspedIN623133 claims.doc 132 -(CH 2 )n-C(O)-COOH, -Cl-C 6 alkyl, -O-Cl-C 6 alkyl, -NH(Ci-C 6 alkyl), -N(Ci-C 6 alkyl) 2 ~LN R/ 8 1 R S. S 50 C S R 8 -(CH 2 -(CH~n Z' lower alkyl) N R8 O ,R 8 -(CH 2 AR 9 ,or w:Vad~yn\no delete\speal623133 claims.doc 133 R 1 1 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, -CF 3 -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, R 8 R 8 -I R9 C 2nI- R (CH~ K with a proviso that the complete moiety at the indole 3-position created by any combination of R 3 L 1 R 8 R 9 R 10 io, and/or R 1 1 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S oo 10 0 S OH or n is an integer from 0 to 3; R 4 is selected from H, -CF 3 01-6 lower alkyl, C1-C6 lower alkoxy, C3- 15 Clo cycloalkyl, -C1-C6 alkyl-C 3 -C0 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 _M 2 IL 2 indicates a linking or bridging group of the formulae -(CH 2 -(CH 2 -(CH 2 )n-C(O)-(CH 2 -(CH 2 )n-O-(CH 2 or -(CH 2 )n-S- (CH 2 M 2 is selected from the group of C 1 -C 6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Clo alkyl, C1-Clo alkoxy, -NO 2 -NH 2 -CN, or -CF 3 or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered w:\jaclynno deletespeci623133 daims.doc ;rr~i~in~u~jrlr~rP~lirii~i i~r liil-; If-~lii ~j .jr; \~iii+ 134 heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Cio alkyl, C1-Cio alkoxy, -NO 2 -NH 2 -ON, or -CF 3 or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Cio alkyl, Ci-Cio alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, Cl-Cio alkoxy, -CHO, -NO 2 15 NH 2 -CN, -CF 3 or -OH; R 5 is a moiety of the formulae -(CH 2 -(CH 2 or -(CH 2 wherein A is 20 the moiety: D* C wherein D is H and B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 -OH, -Cl-C6 alkyl, C1-C6 alkoxy, -NH 2 -N(C 1 -C 6 2 -NH(C 1 -C 6 -NO 2 or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S; w:jaclyn\no delete\spec\623133 caims.doc 135 or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein R 1 R 4 and R 2 are hydrogen, or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 2 further wherein R, is in the indole 5-position, or a pharmaceutically acceptable salt thereof.
4. A compound of Claim 3 further wherein R, is a benzyloxy group, or a pharmaceutically acceptable salt thereof.
5. A compound of Claim 1 wherein R 3 is -L'-M 1 M 1 is the moiety: and L 1 and R 9 are as defined in Claim 1.
6. A compound of Claim 1 having the formulae: R, R 3 R2 RS wherein: R, is selected from H, halogen, -CF3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NO 2 -NH 2 CN, phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: w:\jaclyn no delete\specl623133 claims.doc 136 R7 S R 6 R7~ ~16 N~ 0i R 7N R 6 N N R N or R 6 is selected from H, 01-06 alkyl, 01-06 alkoxy, phenyl, -0-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -CF 3 or -OH; R 7 is selected from -OF 3 01-06 alkyl, 01-06 alkoxy, -NH-(Oi-C 6 alkyl), -N- (01-06 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -0- benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -CF 3 or -OH; R 2 is selected from H, halogen, -ON, -CHO, -CF 3 -OH, 01-Clo alkyl, Cj- 010 alkoxy, -CHO, -ON, -NO 2 -NH 2 -NH-0 1 -0 6 alkyl, -N(C 1 -C 6 alkyl) 2 -N-SO 2 01-06 alkyl, or -S02-01-C6 alkyl; R 3 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-OOOH, -(0H 2 )n- COOH, -OH=CH-COOH, -(0H 2 )n-tetrazole, N (C1-C6 lower alkyl) o N N NI lower alkyl) w: jadyn\wo deletespecM%23133 caims.doc 137 /O O S-OH i or a moiety selected from the formulae -L 1 -Ml; wherein Ll is a bridging or linking moiety selected from a chemical bond, ,-(CH 2 )n-S-(CH 2 -C(Z)-N(R 6 (R 6 )-(CH 2 (R 6 (R 6 )-(CH 2 H-SO 2 or H-SO 2 -(CH 2 M 1 is selected from the group of -COOH, -(CH 2 )n-COOH, -(CH 2 COOHK tetrazole, 0S ~R9 R Rio Rio HN\ N N\ 0i H1 o0 SOH or R 8 in each appearance, is independently selected from H, -000H, (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, w:N~adyn\nO delete~.pedi\623133 claims doc 138 9 ,or R 9 is selected from H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n-COOH, alkyl) 2 R 10 is selected from the group of H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n- COOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(C 1 -C 6 alkyl), -N(Cl-0 6 10 alkyl) 2 V S. 55*5 S N' R8 R9 M Z-- R8 R9 z N (Cl-C6lower alkyl) (Cl-C 6 lower alkyl IN' 1' N (CI-C 6 lower haloalkyl. R 1 1 is selected from H, 01-06 lower alkyl,01-06 cycloalkyl, -OF 3 -COOH, -(CH 2 )n-COOH, -(CH 2 )n-0(O)-COOH, w: Jacyn\no delete~speci\623133 ciaims.doc 139 R 8 R 8 1-h\R9 R 9 (CH2) with a proviso that the complete moiety at the indole 3-position created by any combination of R 3 L 1 M 1 R 8 R 9 R 10 io, and/or R 11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: OH S OH H or H N i n is an integer from 0 to 3; R 4 is selected from H, -CF 3 C 1 -0 6 lower alkyl, C1-C6 lower alkoxy, C3- Clo cycloalkyl, -C1-C6 alkyl-C3-C 1 0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 _M 2 15 L 2 indicates a linking or bridging group of the formulae -(CH 2 -(CH 2 -(CH 2 )n-C(O)-(CH 2 -(CH 2 )n-O-(CH 2 or -(CH 2 )n-S- (CH2)n-; M 2 is selected from: a) the group of C1-C6 lower alkyl, C1-C lower alkoxy, C3-010 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, C1-Clo alkoxy, -NO 2 -NH 2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five- membered heterocyclic ring being optionally substituted by from 1 to 3 w: aclynno deletespecA623133 claims.doc WA? 'P p- S ThWACAZY-AM-.,'. .SC~..Y,'Th.AAAV. C; flVM'V CSC~ ;.AC.V.AAAA 4C ~SVW' 'XVW. WAA'A.', CCC' 'ZAC.~CCC'CCCCflVC. C Ski. .'NA.CC .AC"C~C'CCCC. 140 substituents selected from halogen, Ci-Cio alkyl, Cl-Cio alkoxy, -NO 2 -NH 2 CN, or -CF 3 or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Cio alkyl, C-Cio alkoxy, -CHO, -NO 2 NH 2 -CN, -CF 3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O 5 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring 15 moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C-Clo alkyl, C1-Cio alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 5 is a moiety of the formulae -(CH 2 -(CH 2 or -(CH 2 )n-O-A, wherein A is the moiety: 20 B wherein D is H and B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF 3 -OH, -C1-C6 alkyl, C1-C6 alkoxy, NH 2 or-NO 2 or a pharmaceutically acceptable salt thereof.
7. A compound of Claim 5 wherein the R 1 substitution is at the indole ring's or a pharmaceutically acceptable salt thereof. w:\jadyn\no delete\speci623133 claims.doc 141
8. A compound of Claim 1 having the formula: wherein: R 1 is selected from H, halogen, -CF 3 -OH, -C 1 -C 6 alkyl, C1-C6 alkoxy, NO 2 -NH 2 phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
9. S. S 099 S 0O S SO 0O *9 9O 0* S. S 0 0e R7 RN N o 0 R7K R7N R 7 O N 0 R6 0 R 6 R7N 0 0@ 00 S S S S O**O SO S 9 R 6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO 2 -CF 3 or -OH; R 7 is selected from -CF 3 C1-C6 alkyl, C1-C6 alkoxy, -NH-(C 1 -C 6 alkyl), -N- (C1-C6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -0- benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, Ci-C6 alkoxy, -NH 2 -NO 2 -CF 3 or -OH; w:\jadyn\no delete\spec\623133 caims.doc 142 R 2 is selected from H, halogen, -ON, -CHO, -OF 3 -OH, 01-010 alkyl, Ci- 010 alkoxy, -CHO, -ON, -NO 2 -NH 2 -NH-Cl-C 6 alkyl, -N(Cl-C 6 alkyl) 2 -N-SO 2 01-06 alkyl, or -502-01-06 alkyl; R 3 is selected from -OOOH, -C(O)-COOH, -(0H 2 )n-C(O)-COOH, -(0H 2 )n- OOOH, -OH=OH-COOH, -(CH 2 )n-tetrazole,
11. S_ (ClC6lower alkyl) or lower alkyl) o C. 0- 0- /0-O _S-OH ti or a moiety selected from the formulae -L 1 -Ml; wherein Ll is a bridging or linking moiety selected from a chemical bond, 1 5 (0H 2 -(OH 2 -(0H 2 )n-C(O)-(OH 2 -(CH 2 )n-O-(OH 2 )n- ,-(OH 2 )n-S-(0H 2 -O(Z)-N(R 6 -C(Z)-N(R 6 )-(OH 2 6 0(O)-O(Z)-N(R 6 )-(OH 2 H-SO 2 or H-SO 2 -(CH 2 M' is selected from the group of -COOH, -(CH 2 )n-0OOH, -(CH 2 COOKH tetrazole, w:Ijaciyn\no delete\sPecA623133 ciaimsdoc 7I;R9 I-I 143 8 0 R 8 N R8 Rio Rio Rio SR N 0-F-OH Sf 0 0 R 8 in each appearance, is independently selected from H, -COOH,- (0H 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 9 \00 /0-P-OH S I NI-* :U or UI-; R 9 is selected from H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n-COOH, 10 -(CH 2 )n-C(O)-COOH, -Cl-C 6 alkyl, -0-01-06 alkyl, -NH(C 1 -C 6 alkyl), -N(Cl-0 6 alkyl) 2 Rio is selected from the group of H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n- COOH, 15 -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(C 1 -C 6 alkyl), -N(0 1 -0 6 alkyl) 2 V~R 9 R 8 N or RqR w ay~i eee~pc~633 Q am~o 144 S N (C-C 6 lower aikyl) A O N S (C-C 6 lower alkyl or N (C-C6 lower haloalkyl R 11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, -CF 3 -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, R 8 R 8 R9 R9 (CH) with a proviso that the complete moiety at the indole 3-position created by any combination of R 3 L 1 M 1 R 8 R 9 Rio, and/or R 11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: -OHR OH \Se 1 or 15 n is an integer from 0 to 3; R 4 is selected from H, -CF 3 01-06 lower alkyl, C1-C6 lower alkoxy, C3- Clo cycloalkyl, -C1-C6 alkyl-C3-Clo cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 L 2 indicates a linking or bridging group of the formulae -(CH 2 -(CH 2 -(CH 2 )n-C(O)-(CH 2 -(CH 2 )n-O-(CH 2 or -(CH2)n-S- (CH2)n- w:jacyn\no deletspecl623133 laims.doc 145 M 2 is selected from: a) the group of C 1 -C 6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, Ci-Clo alkoxy, -NO 2 -NH 2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five- membered heterocyclic ring being optionally substituted, by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, Ci-Clo alkoxy, -NO 2 -NH 2 CN, or -CF 3 or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C-Clo alkyl, Ci-Clo alkoxy, -CHO, -NO 2 NH 2 -CN, -CF 3 or -OH; or 9 9 25 e d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, Cl-Clo alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 5 is selected from (CH 2 -(CH 2 or -(CH 2 )n-O-A wherein A is selected from w:jacdyn\no delete\speci\623133 laims.doc 146 D N D D a. a. 0D 1 DO w:\jaclyn~no delete'specA623133 cjaims.doc 147 S or r r r r D is H and R 12 is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF 3 or a pharmaceutically acceptable salt thereof. 10 9. A compound of Claim 1 having the formula: R1 R3 R2 wherein: R 1 is selected form H, halogen, -CF 3 -OH, -C1-C6 alkyl, C1-Cs alkoxy, 15 NO 2 -NH 2 phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R.6 N6 R7 N 0 RR R7 O w:acdyn\no delete\spec\623133 daims.doc 148 R 6 RN 16 R7I- R7 R or R 6 is selected from H, 01-06 alkyl, 01-06 alkoxy, phenyl, -0-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -N H 2 -NO 2 -OF 3 or -OH; R 7 is selected from -CE 3 01-06 alkyl, 01-06 alkoxy, -NH-(0 1 -0 6 alkyl), -N- (01-06 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -0- phenyl, benzyl, or -O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -OF 3 or -OH; R 2 is selected from H, halogen, -ON, -OHO, -OF 3 -OH, 01-010 alkyl, 01- 010 alkoxy, -CHO, -ON, -NO 2 -NH 2 -NH-0 1 -0 6 alkyl, -N(0 1 -0 6 alkyl) 2 -N-SO 2 01-06 alkyl, or -S02-01-6 alkyl; R 3 is selected from -OOOH, -0(O)-COOH, -(OH 2 )n-C(O)-0OOH, -(0H 2 )n- OOOH, 20 -OH=OH-OOOH, -(0H 2 )n-tetrazole, N (C1-C6 lower alkyl)ky) or-No w:adynVno delete\ped\623133 daims.doc i~ r li;F *y 149 9 I-OH 0 0 -S -OH i or a moiety selected from the formulae -L 1 -M 1 or L 22; L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 H2)n-C(O)-(C H2)n-, -(CH2)n--(CH2)n-,-(CH2)n-S (CH2)n-, N(R 6 )-(CH 2 -0(Z)-NH-SO 2 or -0(Z)-NH-SO 2 -(CH 2 M 1 is selected from the group of -COOH, -(CH 2 )n-COOH, -(CH 2 COOH, tetrazole, r r r Dc r r r r R9 N R8 R9 Rio 11 'NH or N O-F-OHR R11 HN N L2 is a bridging or linking moiety selected from a chemical bond w.:jacyn~no deleteXspecaA23l33 daims.doc il~;i~-iaii i i;r~iri~ ^-ii -r ~-~ii 150 N(R 6 )-(CH 2 H-SO 2 or H-SO 2 -(CH 2 M 2 is the moiety R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 )n- COOH, -(CH 2 )n-C(O)-0OOH, tetrazole, 0-FO S ,or R 9 is selected from H, halogen, -CF 3 -OH, -COOH, -(CH 2 )n-COOH, :-(0H 2 )n-0(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(0 1 -0 6 alkyl), -N(0,-C 6 alkyl) 2 Rio is selected from the group of H, halogen, -OF 3 -OH, -000H, -(CH 2 )n- COOH, -(0H 2 )n-0(O)-0OOH, -01-06 alkyl, -0-01-06 alkyl, -NH(Ci-C 6 alkyl), -N(Cl-C 6 alkyl) 2 R R. RR 8 o r w:~adyn~io delete~spevi623l33 claims.doc 151 N (Cl-C6 lower alkyl) N (C-C6 lower alkyl N(Cl-C6 lower haloalkyl R11 is selected from H, Cl-C6 lower alkyl, Cl-C6 cycloalkyl, -CF3, -COOH, -(CH2)-COOH, -(CH2)-C(O)-COOH, yo, (C H 2) n with a proviso that the complete moiety at the indole 3-position created by any combination of R3, L, M1, L 2, M2, R8, R, Rjo, and/or R11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: n is an integer from 0 to 3; R4 is selected from H, -CF3, Cl-C6 lower alkyl, Cl-C6 lower alkoxy, C3- *fee.: C10 cycloalkyl, -Cl-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula 3_M3: L 3 indicates a linking or bridging group of the formulae -(CH2)n-O-(CH2)n, or -(CH2)n-S- (CH2)-; M3 is selected from: w: adyn\no delete\speci\23133 daims.doc 152 a) the group of C1-C6 lower alkyl, C1-C lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Clo alkyl, C1-Clo alkoxy, -NO 2 -NH 2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Clo alkyl, Ci-Clo alkoxy, -NO 2 -NH 2 CN, or -CF 3 or c) a six-membered heterocyclic ring containing one, two or three ring 15 heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C-Clo alkyl, Ci-Clo alkoxy, -CHO, -NO 2 NH 2 -CN, -CF 3 or -OH; or 25 *o.o o*o d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Co alkyl, Ci-Clo alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 5 is a moiety of the formulae -(CH 2 -(CH 2 or -(CH 2 )n-O-A, wherein A is the moiety: w:acyn\no deletespeci\623133 laims.doc i u -i i- i- i -iiin~~i 153 wherein D is H and B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF 3 -OH, -C1-C6 alkyl, C1-C6 alkoxy, NH 2 or-NO 2 or a pharmaceutically acceptable salt thereof. A compound of Claim 1 having the formula: wherein: R 1 is selected form H, halogen, -CF 3 -OH, -C1-C6 alkyl, C-C6 alkoxy, NO 2 phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: CCC CC.. C CCC.. R N O0 R6 O R6 R7/ON N 0 RR**0 R 6 R N or o\' w:\'acyn\no deletespeci\623133 daims.doc 154 R 6 is selected from H, C 1 -C 6 alkyl, 01-06 alkoxy, phenyl, -0-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -OF 3 or -OH; R 7 is selected from -OF 3 01-06 alkyl, 01-6 alkoxy, -NH-(0 1 -C 6 alkyl), -N- (01-06 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -0- benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NO 2 -NH 2 -OF 3 or -OH; R 2 is selected from H, halogen, -ON, -CHO, -OF 3 -OH, 01-010 alkyl, Cj- C1o alkoxy, -CHO, -ON, -NO 2 -NH 2 -NH-0 1 -C 6 alkyl, -N(0 1 -0 6 alkyl) 2 -N-SO 2 01-06 alkyl, or -S0 2 -C 1 -C 6 alkyl; R 3 is selected from -COOH, -0(O)-OOOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n- COOH, -CH=CH-COOH, -(CH 2 )nC(O)NS(O)(O)(C 1 -C 6 lower alkyl), -(CH- 2)NC(O)NS(O)(O)(1-C 6 lower haloalkyl), R9 89 R8 1\R8 19kN R9, 0 S RR8 R9 1 1 R 9 N N RY 0 w: jadyn~w deletespecA623133 daims.doc x~hrTT r vc 155 NH8 o V V V. Ia N R R 8 is selected from H, -000H, -(0H 2 )n-COOH, -(CH 2 )n-C(O)-0OOH; R 9 is selected from H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(C1-0 6 alkyl), -N(0 1 -0 6 al kyl )2; Rio is selected from the group of H, halogen, -OF 3 -OH, -COOH, -(CH 2 )n- 15 OOOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(0 1 -C 6 alkyl), N(Cli-C 6 alkyl) 2 V. *V V V C V V R8 or w:'4adyn~no delete\specM123133 ciaimdoc 156 NN S__ N (C-C 6 lower alkyl) 0 0 N (C1-C 6 lower alkyl N (C 1 -C 6 lower haloalkyl R 11 is selected from H, C1-C6 lower alkyl, -CF 3 -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, or R 8 R9 n is an integer from 0 to 3; S 10 R 4 is selected from H, -CF 3 01-06 lower alkyl, C1-C6 lower alkoxy, C3- Clo cycloalkyl, -C1-C6 alkyl-C 3 -0 1 o cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 1, )L2 indicates a linking or bridging group of the formulae -(CH 2 -(CH 2 -(CH 2 )n-C(O)-(CH 2 -(CH 2 )n-O-(CH 2 or -(CH 2 )n-S- (CH2)n-; M 2 is selected from: a) the group of C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Clo alkyl, C1-Co alkoxy, -NO 2 -NH 2 -ON, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, w:jadcyn\no delete\speci\623133 claims doc 157 thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -Clo alkyl, C1-Clo alkoxy, -NO 2 -NH 2 CN, or -CF 3 or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C1-Clo alkyl, C1-Clo alkoxy, -CHO, -NO 2 NH 2 -CN, -CF 3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Cl-Cio alkyl, C1-Clo alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 5 is (CH 2 -(CH 2 or -(CH 2 )n-O-A wherein A is selected from: SI..N S w:\jaclyn\no deletespeci623133 claims.doc ~ius~~r- i 158 D D D 0 0 R /2 so or C. C CC .C C. C. C C. CC C. D is H and w:~acyn'no delete~speciA623133 ciaims.doc 1. 11 Z. 159 R 12 is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, or -CF 3 or a pharmaceutically acceptable salt thereof. 11. A compound of Claim 1 having the formula: wherein: R 1 is selected form H, halogen, NO 2 -NH 2 phenyl, -O-phenyl, benzyl, formulae: -CF 3 -OH, -C 1 -C 6 alkyl, Cl-C6 alkoxy, -O-benzyl, -S-benzyl or a moiety of the R6 0 R7 ?6 R 7 N 0 R7 O f 6 R7 O N 0 RK R7 R N I- R 6 oR N or A R 6 is selected from H, C1-C6 alkyl, Cl-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO 2 -NH 2 -CF 3 or -OH; w:\jadyn\no deletespecd623133 daims doc 160 R 7 is selected from -OF 3 01-06 alkyl, 01-06 alkoxy, -NH-(Cl-06 alkyl), -N- (01-06 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -0- phenyl, benzyl or -O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NO 2 -N H 2 -OF 3 or -OH; R 2 is selected from H, halogen, -CN, -CHO, -OF 3 -OH, 01-010 alkyl, Cj- 010 alkoxy, -CHO, -ON, -NO 2 -NH 2 -NH-C 1 -0 6 alkyl, -N(Oi-0 6 alkyl) 2 -N-SO 2 01-06 alkyl, or -S02-CI-06 alkyl; R 3 is selected from -OOOH, -O(O)-OOOH, -(OH 2 )n-(O)-0OOH, -(OH 2 )n- OOOH, -OH=OH-OOOH, -(OH 2 )n-tetrazole, 4 *N (Cl-C 6 lower alkyl) or NN S j N N(C 1-C 6 lower alkyl) o 0 LK 0 H 91I or a moiety selected from the formulae -L 1 -Ml; wherein L' is. a bridging or linking moiety selected from a chemical bond, 6 )-(OH 2 H-SO 2 or H-SO 2 -(CH 2 w: adyn\no deltee~pecA623133 ciaims.doc 161 M 1 is selected from the group of -COOH, -(CH 2 -(CH 2 COOHK tetrazole, 8 R9 R9 Rio Rio R9 P-v 2 HN\ N /O9 1 S' O H o r e* R 8 in each appearance, is independently selected from H, -COOH, (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, Z -OH S OH R 9 is selected from H, halogen, -CE 3 -COOH, -(CH 2 )n-COOH1 -(CH 2 )n-C(O)-COOH, -Cl-C 6 alkyl, -0-01-06 alkyl, -NH(C1-0 6 alkyl), -N(Cl-C 6 alkyl) 2 RIO is selected from the group of H, halogen, -CF 3 -COOH, -(CH 2 )n- COOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(Ci-0 6 alkyl),- N(Cj-C 6 alkyl) 2 wAaclynvo delete\speviA623133 ciaimsdoc 162 R8 R8 N <R \R9 R 8 Z or N"S S N (Ci-C6 lower alkyl) O O S 5 N (C1-C 6 lower alkyl N (C 1 -C 6 lower haloalkyl R 11 is selected from H, C1-C6 lower alkyl, C1-C6 cycloalkyl, -CF 3 -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, R?8 R<8 (CH 2 with a proviso that the complete moiety at the indole 3-position created by any combination of R 3 L 1 M 1 R 8 R 9 R 10 and/or R 11 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: /O--OH s Oor N n is an integer from 0 to 3; w:\adyn\no delete\spei623133 daims.doc )m I I-ir ^rl, r ;r:lu :rlrm rr* ,r lr*l Irlxvnrhru urr~u.r*I -~cnl~ I~r*rl 7lrn~i*~: .~:iLlu~ Wlr*~Y~Y~jiiiSu Ill.liili~lli 163 R 4 is selected from H, -CF 3 01-06 lower alkyl, C 1 -C 6 lower alkoxy, C3- Clo cycloalkyl, -C1-C6 alkyl-C3-C 1 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 L 2 indicates a linking or bridging group of the formulae -(CH 2 -(CH 2 -(CH 2 )n-C(O)-(CH 2 -(CH 2 )n-O-(CH 2 or -(CH 2 )n-S- (CH2)n-, -C(O)C(O)X; where X is O or N, M 2 is selected from: a) the group of CI-C6 lower alkyl, Ci-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Clo alkyl, Ci-Cio alkoxy, -NO 2 -NH 2 -CN, or -CF 3 or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C-Cio alkyl, C1-Cio alkoxy, -NO 2 -NH 2 CN, or -CF 3 or c) a six-membered heterocyclic ring containing one, two or three ring 25 heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six- membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, C-Cio alkoxy, -CHO, -NO 2 NH 2 -CN, -CF 3 or -OH; or d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring w:acldynno deletespec\623133 claims.doc 164 moiety being optionally substituted by from 1 to 3 substituents selected from halogen, Cl-Clo alkyl, Cl-Clo alkoxy, -CHO, -NO 2 -NH 2 -CN, -CF 3 or -OH; R 5 is a moiety of the formulae -(CH 2 -(CH 2 or -(CH 2 )n-O-A, wherein A is the moiety: wherein D is H and B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF 3 -OH, -C1-C6 alkyl, C1-C6 alkoxy, NH 2 or-NO 2 or a pharmaceutically acceptable salt thereof. 9* 9* 9 9
12. A compound of Claim 1 having the formula: wherein: R 1 is selected form H, halogen, -CF 3 -OH, -C1-C6 alkyl, C-C6 alkoxy, NO 2 -NH 2 phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: w:\adcyn\o delete\spec\623133 dalms.doc 165 F16 N6 N R7 R~ R7 or R, R6 R6 0 or 0 R 6 is selected from H, 01-06 alkyl, 01-06 alkoxy, phenyl, -0-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -OF 3 or -OH; R 7 is selected from -OF 3 01-06 alkyl, 01-06 alkoxy, -NH-(Ci-C 6 alkyl), -N- (C 1 -C 6 alkyl) 2 pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -0- benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, 01-06 alkyl, 01-06 alkoxy, -NH 2 -NO 2 -OF 3 or -OH; R 3 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-0OOH, -(0H 2 )n- OOOH, -CH=CH-OOOH, -(0H 2 )n0(O)NS(O)(O)(C-C 6 lower alkyl), -(OH- 2)N(O)NS(O)(O)(l-C 6 lower haloalkyl), I9R RloR9 8 R. N R9N R S R 00 C Ri 0 Rio w:ajadyn\no deletepedi623l33 daims.doc ~uiYUjl*ilb~~Vn~r r~*l V~inri~.lr*~i~ir*~ n~i~~l 166 0 R 8 zxN~ N(C H2)n~o N _RANH 0 Ro 0 0 R 8 0 >0 o 0 S R80 R 0 HN R 8 an R Rindpnetyslce fRo HhaoerE,-H and 15 are isepnenl selected from tegopo H, halogen, -F 3 -OH, OH (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -01-06 alkyl, -0-01-06 alkyl, -NH(C1-C 6 alkyl), -N(Cl-C 6 alkyl) 2 w: actyn~no detete\speCi\623133 dalmsdoc 167 R8 QsO N 1 (Cl-C 6 lower alkyl R 1 1 is selected from H, CI-C 6 -(CH 2 )n-C(O)-COOH, or (C 1 -C 6 lower alkyl) N (C 1 -C 6 lower haloalkyl lower alkyl, -OF 3 -COOH, -(CH 2 )n-COOH, r c~ r r r r n is an integer from Oto 3; *r a R 4 is selected from H, -CE 3 01-C6 lower alkyl, 01-C6 lower alkoxy, or halogen; R 5 is a moiety of the formula -(CH 2 -(CH 2 or -(CH 2 )n-O-A, wherein A is the moiety: wherein D is H and w :jadynl delete\speB623133 daims.doc i, 168 B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -OF 3 -OH, -Cl-06 alkyl, Cl-C 6 alkoxy, -NH 2 or -NO 2 or a pharmaceutically acceptable salt thereof.
13. A compound selected from: a) -benzhydryl-5-{[(cyclopentyloxy)carbonyl]amino-1 H-indol-3- yl)methyl]-3-methoxybenzoic acid; b) 4-[(1I -benzhydryl-5-{[( butylamino)carbonyl]amino}-1 H-indol-3- yl)methyl]-3-methoxybenzoic acid; c) -benzhyd ryl-5-[(methylsulfonyl )amino]-1 H-indol-3-yl~methyl)- 3-methoxybenzoic acid; d) -benzhydryl-5-[(cyclopentylcarbonyl)amino]-lIH-indol-3-yI~methyl 3-methoxybenzoic acid; e) 4-[(lI -benzhydryl-5-nitro-1 H-indol-3-yl)methyl]-3-methoxybenzoicb U U acid; f) -benzhydryl-5-fluoro- 1 H-indol-3-yl)methyl]-3-methoxybenzoic acid; g) 4+11 -benzhydryl-5-methyl- 1 H-indol-3-yl)methyl]-3-methoxybenzoic acid; h) 4-[(5-benzhydry-5H-[1 ,3]d ioxolo[4 ,57flindol-7-yl)methyl]-3- methoxybenzoic acid; i) 1-benzhydryl-5-cyano- I H-indol-3-yl)methyl]-3-methoxybenzoic acid; w: jadyn*1o delete~speci\623133 daims.doc 169 j) -benzhyd ryl-5-(methylsulfonyl)-1 H-indol-3-yI]methyl}-3- methoxybenzoic acid; k) cyclopentyl-N-{1 -benzhydryl-3-[2-methoxy-4-({[(2- methylphenyl)sulfonyl] amino~carbonyl)benzyl]-1 H-indol-5-yI~carba mate; 1) cyclopentyl N-{1 -benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl) sulfonyl]amino~carbonyl)benzyl]-1 m) cyclopentyl N-[1 -benzhydryl-3-(2-methoxy-4- {[(methylsulfonyl)aminoj carbonyl~benzyl n) N-{1 -benzhyd ryl-3-[4-({[(2-chlorophenyl)sulfonyl]amino~carbonyl 15 2-methoxybenzyl]-1 o) cyclopentyl N-(3-{4-[({[5-(acetylimino)-4-methyl-4,5-d ihyd ro- 1,3,4- thiad iazol-2-yI]sulfonyl~amino)carbonyl]-2-methoxybenzyl}-1 -benzhydryl- I H- .ind ol-5-yI )ca rba mate; p) cyclopentyl N-[1 -benzhydryl-3-(4- {[(benzylsulfonyl)amino]carbonyl}-2-methoxybenzyl)-1 q) cyclopentyl N-{1 -benzhyd ryl-3-[4-({I(2,4-dimethyl-1 yI)sulfonyl]amino~carbonyl)-2-methoxybenzyl]- I H-i ndol-5-yIlca rba mate; r) cyclopentyl N-{1 -benzhydryl-3-[4-({[(3,5-dimethyl-4- isoxazolyl)sulfonyl]amino~carbonyl)-2-methoxybenzyl]-1 S) cyclopentyl N-(3-{4-[({[5-(acetylamino)-1 ,3,4-thiadiazol-2- yljsulfonyllamino)carbonyl]-2-methoxybenzyl}-1 -benzhyd ryl-1 yI)carbamate; actyn\rko delete\specA623133 claims.doc 170 t) cyclopentyl N-(lI-benzhyd ryl-3-{2-methoxy-4-[({[4-(3-methyl-5-oxo- ro-1 H-pyrazol-1 -yI)phenyl]sulfonyllamino)carbonyl] benzyl}-1 yI)carbamate; u) -benzhydryl-5-nitro-1 H-indol-3-yI)methyl]-3- methoxybenzoyl}-2-methylbenzenesulfonamide; v) -benzhyd ryl-5-nitro-1 H-indol-3-yI)methyl]-3- methoxybenzoyl} (trifluoro)methanesulfonamide; w) -benzhyd ryl-5-bromo-1 H-indol-3-yI)methyl]-3- methoxybenzoyl}-2-methylbenzenesulfonamide; x) I -benzhyd ryl-5-bromo-1 H-indol-3-yI )methyl]-3- 15 methoxybenzoyl} (trifluoro)methanesulfonamide; y) N-{1 -benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl )sulfonyl]amino} carbonyl)benzyl]-1 z) -benzhydry-5-[(methylsulfonyI)amino]-1 H-indol-3- yIlmethyl)-3-methoxybenzoyl](trifluoro)methanesulfonamide; aa) I -benzhydryl-5-{[(butylamino)carbonyl]amino-1 H-indol-3- a.....yI)methylj-3-methoxybenzoyl}(trifluoro) methane sulfonamide; ab) N-{1 -benzhydryl-3-[2-methoxy-4-({[(2- methylphenyl)sulfonyl]amino} carbonyl)benzyl]-1 yI~cyclopentanecarboxamide; ac) 4-({5-[(cyclopentylcarbonyl)amino]l- -[phenyl(2-pyrid inyl)methyl]- 1 H-indol-3-yl}methyl)-3-methoxybenzoic acid; ad) -benzhydryl-5-[(benzylsulfonyl)amino]-1 H-indol-3- yI}methyl )-3-methoxybenzoyl](trifluoro)methanesulfonamide; w: acyn\no delete\speciAG23133 clims doc 11-1 I I 171 ae) N-{1 -benzhydryl-3-112-methoxy-4-({[(trifluoromethyl)sulfonyl]amino} carbonyl)benzyl]-1 H-i nd ol-5-yI-3-th iop hen eca rboxa mid e; af) Benzyl N-{1-benzhydryl-3-[2-methoxy-4- ({[(trifluoromethyl)sulfonyl]amino) carbonyl )benzyll H H-i nd ol-5-yI~ca rba mate; ag) -benzhydryl-5-nitro-1 H-indol-3-yI )methyl] benzoic acid; ah) 4+[1 -benzhydryl-5-bromo-1 H-indol-3-yI )methyl]benzoic acid; ai) -benzhyd ryl-5-{[(cyclopentyloxy)carbonyl]amino}-1 H-indol-3- yI)methyl]benzoic acid; aj) cyclopentyl N-{1 -benzhyd methyiphenyl )sulfonyl]amino} carbonyl)benzyl]-1 H-i ndol-5-yI~carba mate ak) cyclopentyl N-{1 -benzhyd ryl-3-[4-({[(trifluoromethyl)sulfonyl]amino} carbonyl)benzyl]-1 H-indol-5-yI~carba mate; al) -benzhydryl-5-n itro-1 H-indol-3-yI)methylllbenzoyl} (trifl uoro)methanesulIfona mid e; am) -benzhydryl-5-n itro- I H-indol-3-yl)mnethyl]benzoyl}-2- methylbenzenesulfonamide; an) I -benzhyd ryl-5-bromo-1 H-indol-3-yI)methyllbenzoyl}-2- methylbenzenesulfonamide; ao) -benzhyd ryl-5-bromo-1 H-indol-3-yI)methyl]benzoyl} (trifluoro)methanesulfonamide; ap) -benzhydryl-1 H-indol-3-yI)-2-oxoacetyl]aminolbenzoic acid; w: aclyn~no delete~specf\623133 claimns doc 172 aq) -benzhydryl-5-[(cyclopentylcarbonyl)amino]- 1 H-indol-3- yIlmethyl)amino]benzoic acid; ar) -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yI}methyl) p ipe razi no] acetic acid; as) 2-[l -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yI~methyl)-3-oxo-2-pi perazi nyl] acetic acid; at) -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yI~methyl)amino]-3-hydroxypropanoic acid; au) 3-{l -benzhydryl-5-[(cyclopentylcarbonyl )amino]-1 H-indol-3- 15 yI~propanoic acid; av) N-(1 -benzhyd ryl-3-{3-[(methylsulfonyl)amino]-3-oxopropyl-1 H- aw) -benzhydryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yI-2-propenoic acid; ax) 1 -benzhydryl-3-{(E)-3-[(methylsu Ifonyl )amino]-3-oxo-1 propenyl}-1 ay) -benzhyd ryl-5-n itro-1 H-indol-3-yI}-2-propenoic acid ester; az) -benzhydryl-5-nitro-1 H-indol-3-yI}-2- propenoyl)methanesulfonamide; ba) -benzhydryl-5-({[4-(trifluoromethyl)phenyl]sulfonyllamino)-1 H- indol-3-yI]methyl}-3-methoxybenzoic acid; w~acfyn~so delete'speciAS23133 claims.doc 173 bb) 4-f{[5-({[2-(acetylamino)-4-methyl-1 ,3-thiazol-5-yI]su Ifonyl~amino)- 1 -benzhyd ryl-1 H-indol-3-y]methyl-3-methoxybenzoic acid; or bc) 4+[1 -benzhydryl-5-{[(4-chloro-3-nitrophenyl)sulfonyl]amino}- 1 H- indol-3-yI)methyl]-3-methoxybenzoic acid; bd) -benzhyd ryl-5-{[(d imethylamino)sulfonyl]amino-1 H-indol-3- yI)methyl]-3-methoxybenzoic acid; be) -benzhydryl-5-({[4-(trifluoromethoxy)phenyljsulfonyl~amino)- 1 H-indol-3-yI]methyl-3-methoxybenzoic acid; bf) 4+1( -benzhydryl-5-{[(2-methylphenyl)su Ifonyl]amino}-1 H-indol-3- yI)methyl]-3-methoxybenzoic acid; bg) 4+[1 -benzhydryl-5-{[(5-chloro-1 ,3-dimethyl-1 H-pyrazol-4- yI)sulfonyl]amino}-1 H-indol-3-yI)methyl]-3-methoxybenzoic acid; bh) -benzhydryl-5-{[(3 ,5-dimethyl-4-isoxazolyl)sulfonyl]amino}-1 H- indol-3-yl)methyl]-3-methoxybenzoic acid; bi) cyclopentyl N-{3-[4-(aminocarbonyl)-2-methoxybenzyl-1 benzhydryl-1 H-indol-5-yI~ca rba mate; bj) cyclopentyl N-{1 -benzhydryl-3-[2-methoxy-4-(1 H-i ,2,3,4- tetraazol-5-y)benzyl]-1 H -ind ol-5-yIlca rba mate; bk) -benzhydryl-5-[(cyclopentylcarbonyl)amino-1 H-indol-3- yI~carbonyl)amino]-3-thiophenecarboxylic acid; bi) -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yIlcarbonyl)amino]benzoic acid; w:4aclynVno delete'specA\623133 claims doc 174 bin) -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3- yI~carbonyl)amino]propanoic acid; bn) N-[1 -benzhydryl-3-({[(2-methylphenyl)sulfonyl]amino}carbonyl)- 1 bo) -benzhyd ryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3-yi}- 2-oxoacetyl)amino]propanoic acid; bp) -benzhydryl-5-[(cyclopentylcarbonyl)amino]-1 H-indol-3-y}- 2-oxoacetyl)amino]benzoic acid; bq) -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]-2,6- dimethylphenoxy} acetic acid; -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]-3- methoxyphenoxy} acetic acid; bs) -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]phenoxy~acetic acid; bt) -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]-3- chlorophenoxy~acetic acid; bu) -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]-2- methoxyphenoxy~acetic acid; by) I -benzhyd ryl-6-chloro-1 H-indol-3-yl)methyllphenoxy}-2- butenoic acid; bw) -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]anilino}-4- oxobutanooic acid; or w~adyr1'no delete~speciR623133 cialms.doc 4. 175 bx) Sodium -benzhydryl-6-chloro-1 H-indol-3-yI)methyl]an ilino}- 3-oxopropanoic acid; by) -benzhydryl-6-chloro- I H-indol-3-yI)methyl]anilino}-2- oxoacetic acid; bz) -benzhydryl-6-chloro-1 H-indol-3- yI)methyl]cyclopropanecarboxylic acid; ca) 2-[(l1 -benzhydryl-6-chloro-5-fluoro-1 H-indol-3- yI)methyljcyclopropane carboxylic acid; cb) 2+[1 -benzhyd ryl-5,6-d ichioro- I H-indol-3- yI)methyl]cyclopropanecarboxylic acid; 0* 0 0 009 0 00 0 @0 S. 9* 0 I. 0* 0 9* 0@ cc) -[bis(4-hyd roxyphenyl)methyl]-6-chloro-1 H-indol-3-yI~methyl) cyclopropanecarboxylic acid; cd) -benzhydryl-6-chloro-1 H-indol-3-yI )methyl]-3-hyd roxybenzoic acid; 00 @0 00 0 0 0 S. S 0 55 0 0 0 000000 0 ce) -benzhydryl-6-chloro-1 H-indol-3-yI )methyl]-3-(3- hydroxypropoxy) benzoic acid; cf) -[(4-aminophenyl)(phenyl)methyl]-6-chloro-1 H-indol-3- yI~methyl)-3-methoxybenzoic acid; cg) '4-({6-chloro-1 -[(4-methoxyphenyl)(phenyl)methyl]-I H-indol-3- yI}methyl)-3-methoxybenzoic acid; ch) -[bis(4-methoxyphenyl)methyl]-6-chloro-I H-indol-3- yI}methyl)-3-methoxybenzoic acid; w: acdyn~n delete'spedil623133 claimsdoc j z. 176 ci) '4-({6-chloro-1 -[(2-morpholinophenyl)(phenyl)methyl]-1 H-indol-3- yl}methyl)-3-methoxybenzoic acid; cj) 4-({6-chloro-1 -[(2,4-dimethoxy-5-pyrimidinyl)(phenyl)methyl]-1 H- indol-3-yl}methyl)-3-methoxybenzoic acid; ck) -benzhydryl-6-chloro-1 H-indol-3-yl)methyl]-3-methoxybenzoic acid; cl) -benzhydryl-6-chloro-1 H-indol-3-yl)methyl]-3- methoxybenzoyl} amino)acetic acid; and their pharmaceutically acceptable salts.
14. A pharmaceutical composition comprising a compound of any one of 15 Claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
15. A method for treating inflammation in a mammal, the method comprising 0 administering to a mammal in need thereof a pharmaceutically effective amount of a compound as claimed in Claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14.
16. A compound of claim 1, substantially as herein before described with reference to anyone of the examples. SDATED: 16 July, 2003 PHILLIPS ORMONDE FITZPATRICK Attorneys for: GENETICS INSTITUTE LLC. w:\adyn\no delete\speci\623133 daims.doc
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| PCT/US1999/003898 WO1999043654A2 (en) | 1998-02-25 | 1999-02-24 | Inhibitors of phospholipase enzymes |
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Families Citing this family (83)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19917504A1 (en) * | 1999-04-17 | 2000-10-19 | Dresden Arzneimittel | New hydroxy-indole derivatives, useful in treatment of degenerative joint disease, viral and parasitic infections, bronchial, dermatological, neurodegenerative and prostate disorders, etc. |
| JP2002513783A (en) * | 1998-05-01 | 2002-05-14 | イーライ・リリー・アンド・カンパニー | SPLA2 inhibitory compounds for treating diseases |
| TWI269654B (en) * | 1999-09-28 | 2007-01-01 | Baxter Healthcare Sa | N-substituted indole-3-glyoxylamide compounds having anti-tumor action |
| DE19951360A1 (en) | 1999-10-26 | 2001-05-03 | Aventis Pharma Gmbh | Substituted indoles |
| DE19962300A1 (en) * | 1999-12-23 | 2001-06-28 | Asta Medica Ag | New N-benzylindolyl glyoxylic acid derivatives are useful as antitumor agents |
| DE19963178A1 (en) * | 1999-12-27 | 2001-07-05 | Gruenenthal Gmbh | Substituted indole Mannich bases |
| DE10006139A1 (en) * | 2000-02-11 | 2001-08-16 | Merck Patent Gmbh | Indol-3-yl derivatives |
| AUPQ876400A0 (en) * | 2000-07-14 | 2000-08-03 | University Of Queensland, The | Compositions and method of using them |
| AU7705601A (en) | 2000-07-25 | 2002-02-05 | Merck & Co Inc | N-substituted indoles useful in the treatment of diabetes |
| DE10037310A1 (en) * | 2000-07-28 | 2002-02-07 | Asta Medica Ag | New indole derivatives and their use as medicines |
| DE60126997T2 (en) | 2000-10-20 | 2007-10-25 | Eisai R&D Management Co., Ltd. | NITROGEN-CONTAINING AROMATIC RING COMPOUNDS FOR THE TREATMENT OF TUMORARY DISEASES |
| CA2465534C (en) | 2000-11-02 | 2009-10-27 | Nigel H. Greig | Agents useful for reducing amyloid precursor protein and treating dementia and methods of use thereof |
| DK1397130T3 (en) | 2001-06-20 | 2007-11-12 | Wyeth Corp | Substituted Indole Acid Derivatives as Inhibitors of Plasminogen Activator Inhibitor-1 (PAI-1) |
| TWI224101B (en) | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
| EP1844771A3 (en) * | 2001-06-20 | 2007-11-07 | Wyeth | Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| JP2005500345A (en) | 2001-08-03 | 2005-01-06 | ファルマシア・アンド・アップジョン・カンパニー | 5-Arylsulfonylindole with 5-HT6 receptor affinity |
| JP2005504790A (en) | 2001-09-13 | 2005-02-17 | シンタ ファーマスーティカルズ コーポレイション | 3-glyoxylylamidoindole for treating cancer |
| US7605156B2 (en) | 2001-12-03 | 2009-10-20 | Wyeth | Methods for the use of inhibitors of cytosolic phospholipase A2 |
| US6984735B2 (en) | 2001-12-03 | 2006-01-10 | Wyeth | Process for making an aldehyde |
| US6635771B2 (en) | 2001-12-03 | 2003-10-21 | Wyeth | N-benzhydryl indole compounds |
| US7713964B2 (en) | 2001-12-03 | 2010-05-11 | Wyeth Llc | Methods for treating asthmatic conditions |
| US7101875B2 (en) | 2001-12-03 | 2006-09-05 | Wyeth | Methods for treating arthritic disorders |
| PL370445A1 (en) * | 2001-12-03 | 2005-05-30 | Wyeth | Inhibitors of cytosolic phospholipase a2 |
| US6797708B2 (en) | 2001-12-03 | 2004-09-28 | Wyeth | Inhibitors of cytosolic phospholipase A2 |
| AU2003224257A1 (en) * | 2002-04-09 | 2003-10-27 | Astex Technology Limited | Heterocyclic compounds and their use as modulators of p38 map kinase |
| AUPS282602A0 (en) | 2002-06-07 | 2002-06-27 | Garvan Institute Of Medical Research | Method of inhibiting cell proliferation |
| BR0313825A (en) | 2002-08-29 | 2005-07-12 | Merck & Co Inc | Compound, pharmaceutical composition, method for treating type 2 diabetes mellitus in a mammal, and, compound use |
| AU2003260085B2 (en) | 2002-08-29 | 2008-09-11 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
| UA80453C2 (en) | 2002-12-10 | 2007-09-25 | Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1) | |
| DK1569900T3 (en) | 2002-12-10 | 2006-10-23 | Wyeth Corp | Substituted 3-carbonyl-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| CA2509170A1 (en) | 2002-12-10 | 2004-06-24 | Wyeth | Substituted 3-alkyl and 3-arylalkyl 1h-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| WO2004052854A2 (en) * | 2002-12-10 | 2004-06-24 | Wyeth | Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| AU2003296323A1 (en) | 2002-12-10 | 2004-06-30 | Wyeth | Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1) |
| US7129264B2 (en) * | 2003-04-16 | 2006-10-31 | Bristol-Myers Squibb Company | Biarylmethyl indolines and indoles as antithromboembolic agents |
| US7141592B2 (en) | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
| US7163954B2 (en) | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
| US7265148B2 (en) | 2003-09-25 | 2007-09-04 | Wyeth | Substituted pyrrole-indoles |
| US7332521B2 (en) | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
| US7582773B2 (en) | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
| US7268159B2 (en) | 2003-09-25 | 2007-09-11 | Wyeth | Substituted indoles |
| US7342039B2 (en) | 2003-09-25 | 2008-03-11 | Wyeth | Substituted indole oximes |
| US7420083B2 (en) | 2003-09-25 | 2008-09-02 | Wyeth | Substituted aryloximes |
| US7351726B2 (en) | 2003-09-25 | 2008-04-01 | Wyeth | Substituted oxadiazolidinediones |
| US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
| US7411083B2 (en) | 2003-09-25 | 2008-08-12 | Wyeth | Substituted acetic acid derivatives |
| US7442805B2 (en) | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
| US7417063B2 (en) | 2004-04-13 | 2008-08-26 | Bristol-Myers Squibb Company | Bicyclic heterocycles useful as serine protease inhibitors |
| GB0412769D0 (en) | 2004-06-08 | 2004-07-07 | Novartis Ag | Organic compounds |
| US7705023B2 (en) | 2004-06-18 | 2010-04-27 | Biolipox Ab | Indoles useful in the treatment of inflammation |
| AU2005277138A1 (en) | 2004-08-23 | 2006-03-02 | Wyeth Holdings Corporation | Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (PAI-1) modulators useful in the treatment of thrombosis and cardiovascular diseases |
| KR20070053205A (en) | 2004-09-17 | 2007-05-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Medicinal composition |
| MX2007008759A (en) | 2005-01-19 | 2007-09-11 | Biolipox Ab | Indoles useful in the treatment of inflammation. |
| WO2007024294A2 (en) | 2005-05-03 | 2007-03-01 | Cgi Pharmaceuticals, Inc. | Certain substituted ureas, as modulators of kinase activity |
| GT200600228A (en) | 2005-05-27 | 2006-12-26 | INHIBITORS OF PHOSPHOLIPASE A2 CITOSOLICA | |
| WO2007015578A1 (en) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | Method for assay on the effect of vascularization inhibitor |
| BRPI0614340A2 (en) | 2005-08-17 | 2011-04-12 | Wyeth Corp | replaced indoles and methods of use |
| GB0525141D0 (en) | 2005-12-09 | 2006-01-18 | Novartis Ag | Organic compounds |
| US7645752B2 (en) | 2006-01-13 | 2010-01-12 | Wyeth Llc | Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors |
| MY146494A (en) | 2006-01-24 | 2012-08-15 | Lilly Co Eli | Indole sulfonamide modulators of progesterone receptors |
| WO2007092207A1 (en) * | 2006-02-03 | 2007-08-16 | Wyeth | Compositions for the delivery of substituted naphthyl indole derivatives and methods of their use |
| RU2448708C3 (en) | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | ANTI-TUMOR MEANS AGAINST THYROID CANCER CANCER |
| EA018724B1 (en) | 2006-08-07 | 2013-10-30 | Айронвуд Фармасьютикалз, Инк. | Indole compounds |
| WO2008026748A1 (en) | 2006-08-28 | 2008-03-06 | Eisai R & D Management Co., Ltd. | Antitumor agent for undifferentiated gastric cancer |
| MEP11809A (en) * | 2006-10-19 | 2011-12-20 | Indole compound | |
| CN101600694A (en) | 2007-01-29 | 2009-12-09 | 卫材R&D管理有限公司 | Composition for treatment of undifferentiated-type of gastric cancer |
| JP5638244B2 (en) | 2007-11-09 | 2014-12-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Combination of angiogenesis inhibitors and antitumor platinum complexes |
| BRPI0906433A2 (en) | 2008-01-31 | 2019-09-24 | Sanofi Aventis | cyclic indole-3-carboxamides, their preparation and their use as a pharmaceutical |
| KR101269393B1 (en) | 2008-04-28 | 2013-05-29 | 아사히 가세이 파마 가부시키가이샤 | Phenylpropionic acid derivative and use thereof |
| CA2802644C (en) | 2010-06-25 | 2017-02-21 | Eisai R & D Management Co., Ltd. | Antitumor agent using compounds having kinase inhibitory effect in combination |
| AR084433A1 (en) | 2010-12-22 | 2013-05-15 | Ironwood Pharmaceuticals Inc | FAAH INHIBITORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| CA2828946C (en) | 2011-04-18 | 2016-06-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
| WO2012166899A2 (en) | 2011-06-03 | 2012-12-06 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
| US8889730B2 (en) * | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| BR112015009004A8 (en) | 2012-12-21 | 2021-07-20 | Eisai R&D Man Co Ltd | amorphous form of quinoline derivative and method of production thereof |
| CA2912219C (en) | 2013-05-14 | 2021-11-16 | Eisai R&D Management Co., Ltd. | Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds |
| KR20230043234A (en) | 2014-08-28 | 2023-03-30 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | High-purity quinoline derivative and method for manufacturing same |
| AU2016224583B2 (en) | 2015-02-25 | 2021-06-03 | Eisai R&D Management Co., Ltd. | Method for suppressing bitterness of quinoline derivative |
| KR20170122809A (en) | 2015-03-04 | 2017-11-06 | 머크 샤프 앤드 돔 코포레이션 | A combination of a PD-1 antagonist and a VEGFR / FGFR / RET tyrosine kinase inhibitor to treat cancer |
| CA2988707C (en) | 2015-06-16 | 2023-10-10 | Eisai R&D Management Co., Ltd. | Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer |
| WO2017073060A1 (en) * | 2015-10-29 | 2017-05-04 | 国立大学法人東北大学 | Collagen production inhibitor |
| CN106810488B (en) * | 2015-11-27 | 2021-02-19 | 中国科学院上海药物研究所 | One class is used as GPR17 and CysLT1Compound of dual antagonist, preparation method and application thereof |
| CN108530354B (en) * | 2018-05-07 | 2019-12-10 | 青岛农业大学 | Synthesis method of benzenesulfonyl quinoline compound |
| MX2021003904A (en) | 2018-10-05 | 2021-10-26 | Annapurna Bio Inc | Compounds and compositions for treating conditions associated with apj receptor activity. |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3271416A (en) * | 1961-10-24 | 1966-09-06 | Merck & Co Inc | Indolyl aliphatic acids |
| GB1148909A (en) * | 1965-04-19 | 1969-04-16 | Sumitomo Chemical Co | Process for production of novel phenylhydrazone and phenylhydrazine derivatives |
| SE314373B (en) * | 1966-04-12 | 1969-09-08 | Sumitomo Chemical Co | |
| FR1583552A (en) * | 1967-04-11 | 1969-11-14 | ||
| FR2152377A1 (en) * | 1971-09-09 | 1973-04-27 | Sumitomo Chemical Co | 1-phenyl-2-methyl-5-alkyl or alkoxy-3-indolylacetic acid - derivs - antiinflammatory, analgesic, antipyretic |
| BE790679A (en) * | 1971-11-03 | 1973-04-27 | Ici Ltd | INDOLE DERIVATIVES |
| US4894386A (en) * | 1987-04-15 | 1990-01-16 | Ici Americas Inc. | Aliphatic carboxamides |
| CA1337202C (en) * | 1988-04-13 | 1995-10-03 | Victor Giulio Matassa | Cyclic amides which are leukotriene antagonists |
| GB8906032D0 (en) * | 1988-04-14 | 1989-04-26 | Ici America Inc | Hetera-aliphatic carboxamides |
| US5420289A (en) * | 1989-10-27 | 1995-05-30 | American Home Products Corporation | Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase |
| US5095031A (en) * | 1990-08-20 | 1992-03-10 | Abbott Laboratories | Indole derivatives which inhibit leukotriene biosynthesis |
| IL109311A0 (en) * | 1993-04-16 | 1994-07-31 | Lilly Co Eli | 1H-indole-3-acetamide sPla2 inhibitors |
| IL109309A (en) * | 1993-04-16 | 2000-06-29 | Lilly Co Eli | 1-H-indole-3-acetic acid hydrazide SPLA2 inhibitors and pharmaceutical compositions containing them |
| DE4338770A1 (en) * | 1993-11-12 | 1995-05-18 | Matthias Dr Lehr | Indole-2-alkanoic acids and their derivatives as inhibitors of phospholipase A¶2¶ |
| ES2377223T3 (en) * | 1994-04-01 | 2012-03-23 | Eli Lilly And Company | [[3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -11H-indole-4-IL] oxy] acetic acid methyl ester as an inhibitor of sPLA2 |
| US5604253A (en) * | 1995-05-22 | 1997-02-18 | Merck Frosst Canada, Inc. | N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors |
| US5639780A (en) * | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
| EP0863873B1 (en) * | 1995-10-10 | 1999-11-10 | Pfizer Inc. | Indole carbamates as leukotriene antagonists |
| KR100482268B1 (en) * | 1996-08-01 | 2005-04-14 | 메르클레 게엠베하 | Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a2 |
| WO1998008818A1 (en) * | 1996-08-26 | 1998-03-05 | Genetics Institute, Inc. | Inhibitors of phospholipase enzymes |
-
1999
- 1999-02-24 CN CN99805157A patent/CN1310706A/en active Pending
- 1999-02-24 EE EEP200000488A patent/EE200000488A/en unknown
- 1999-02-24 EP EP99908378A patent/EP1062205A2/en not_active Withdrawn
- 1999-02-24 HU HU0101146A patent/HUP0101146A3/en unknown
- 1999-02-24 AU AU27825/99A patent/AU765427B2/en not_active Ceased
- 1999-02-24 GE GEAP19995560A patent/GEP20032920B/en unknown
- 1999-02-24 KR KR1020007009457A patent/KR20010041344A/en not_active Application Discontinuation
- 1999-02-24 EA EA200000871A patent/EA003876B1/en not_active IP Right Cessation
- 1999-02-24 IL IL13771999A patent/IL137719A0/en unknown
- 1999-02-24 SK SK1275-2000A patent/SK12752000A3/en unknown
- 1999-02-24 TR TR2000/02447T patent/TR200002447T2/en unknown
- 1999-02-24 WO PCT/US1999/003898 patent/WO1999043654A2/en not_active Application Discontinuation
- 1999-02-24 CA CA002322162A patent/CA2322162A1/en not_active Abandoned
- 1999-02-24 PL PL99343007A patent/PL343007A1/en unknown
- 1999-02-24 JP JP2000533412A patent/JP2002504541A/en not_active Withdrawn
- 1999-02-24 BR BR9908275-6A patent/BR9908275A/en not_active IP Right Cessation
- 1999-02-24 ID IDW20001595A patent/ID26250A/en unknown
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2000
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- 2000-08-24 HR HR20000551A patent/HRP20000551A2/en not_active Application Discontinuation
- 2000-09-19 BG BG104779A patent/BG104779A/en unknown
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| EE200000488A (en) | 2002-02-15 |
| TR200002447T2 (en) | 2000-11-21 |
| IL137719A0 (en) | 2001-10-31 |
| EA003876B1 (en) | 2003-10-30 |
| EA200000871A1 (en) | 2001-04-23 |
| HUP0101146A3 (en) | 2001-11-28 |
| AU2782599A (en) | 1999-09-15 |
| SK12752000A3 (en) | 2001-03-12 |
| HRP20000551A2 (en) | 2001-04-30 |
| WO1999043654A3 (en) | 1999-10-28 |
| WO1999043654A2 (en) | 1999-09-02 |
| ID26250A (en) | 2000-12-07 |
| CA2322162A1 (en) | 1999-09-02 |
| KR20010041344A (en) | 2001-05-15 |
| NO20004219L (en) | 2000-10-23 |
| BR9908275A (en) | 2000-10-24 |
| PL343007A1 (en) | 2001-07-30 |
| NZ506329A (en) | 2004-01-30 |
| HUP0101146A2 (en) | 2001-08-28 |
| JP2002504541A (en) | 2002-02-12 |
| NO20004219D0 (en) | 2000-08-23 |
| BG104779A (en) | 2001-10-31 |
| EP1062205A2 (en) | 2000-12-27 |
| GEP20032920B (en) | 2003-03-25 |
| CN1310706A (en) | 2001-08-29 |
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